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GENETICS IN PSYCHIATRYGENETICS IN PSYCHIATRY
PRESENTER – DR. SRIRAM.R, FINAL YEAR MDPRESENTER – DR. SRIRAM.R, FINAL YEAR MD
PG PSYCHIATRYPG PSYCHIATRY
CHAIRPERSON – DR. R.RAJKUMAR,CHAIRPERSON – DR. R.RAJKUMAR,
ASSOCIATE PROF OF PSYCHIATRYASSOCIATE PROF OF PSYCHIATRY
Genetics in Psychiatry
Genetics in Psychiatry
Genetics in Psychiatry
GENETIC TERMS USED IN PSYCHIATRY
 Concordance: the probability that a pair of individuals will both have a certain
characteristic, given that one of the pair has the characteristic. For example, twins are
concordant when both have or both lack a given trait. (Lewontin,1982)
 Heritability: proportion of the variance of a phenotype (disease,trait) that is due to
genes, estimated from risks to twins and other relatives
 Mendelian disease: caused by a (usually rare) change(mutation) in DNA sequence on
one(dominant) or both(recessive) of an individual’s pair of chromosomes
 Complex disease: caused by an interaction of multiple genetic and/or environmental
factors
 Allele: A variant of the similar DNA sequence located at a given locus is called an allele.
 Haplotype: collection of specific alleles in a cluster of tightly-linked genes on
a chromosome that are likely to be inherited together
 Locus: a locus (plural loci) is the specific location of a gene, DNA sequence, or
position on a chromosome. Each chromosome carries many genes; humans' estimated
'haploid' protein coding genes are 20,000-25,000, on the 23 different chromosomes.
 Eg. The chromosomal locus of a gene might be written "6p21.3". Because "21"
refers to "region 2, band 1" this is read as "two one", not as "twenty-one". So the
entire locus is "six P two one point three"
 Genetic map: The ordered list of loci known for a particular genome is called a genetic
map. 
 Gene mapping: Gene mapping is the process of determining the locus for a
particular biological trait.
 Genetic linkage is the tendency of alleles that are located close together on
a chromosome to be inherited together during meiosis. Genes whose loci are nearer to
each other are less likely to be separated onto different chromatids during chromosomal
crossover, and are therefore said to be genetically linked. In other words, the nearer two
genes are on a chromosome, the lower is the chance of a swap occurring between them,
and the more likely they are to be inherited together.
 Linkage disequilibrium(LD): non-random association of alleles at two or more loci that
descend from single, ancestral chromosomes (Reich, 2001)
 A variant that is highly correlated with a truly causal variant will show a similar
statistical association to phenotype.
 If the LD is widespread, many fewer markers will need to be assayed (Psychiatric GWAS
consortium coordinating committee 2009)
 Mutation is a permanent change of the nucleotide sequence of the genome of
an organism, virus, or extrachromosomal DNA or other genetic elements
 SNP pronounced “snip”( Single nucleotide polymorphism)
 DNA sequence variation occurring commonly within a population (e.g. 1%) in which a
single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs
between members of a biological species or paired chromosomes
 Common SNPs: ≥5% frequency ~10million in the genome- targets of the GWAS
 Rare SNPs: <1% frequency
 Copy-number variations (CNVs)—a form of structural variation—are alterations of the DNA
of a genome that results in the cell having an abnormal or, for certain genes, a normal
variation in the number of copies of one or more sections of the DNA.
 CNVs correspond to relatively large regions of the genome that have been deleted
(fewer than the normal number) or duplicated (more than the normal number) on
certain chromosomes.
 For example, the chromosome that normally has sections in order as A-B-C-D might
instead have sections A-B-C-C-D (a duplication of "C") or A-B-D (a deletion of "C").
 This variation accounts for roughly 13% of human genomic DNA and each variation may range
from about one kilobase (1,000 nucleotide bases) to several megabases in size (Pawel et al,
2010)
 Genome-wide association study (GWA study, or GWAS), also known as whole genome
association study (WGA study, or WGAS) or common-variant association study (CVAS),
is an examination of many common genetic variants in different individuals to see if any
variant is associated with a trait.
 GWAS typically focus on associations between single-nucleotide
polymorphisms (SNPs) and traits like major diseases.
 compare the DNA of two groups of participants: people with the disease (cases) and
similar people without (controls). Each person gives a sample of DNA, from which
millions of genetic variants are read using SNP arrays.
 If one type of the variant (one allele) is more frequent in people with the disease,
the SNP is said to be "associated" with the disease.
 A polygene, multiple factor, multiple gene inheritance, or quantitative gene is a
group of non-allelic genes that together influence a phenotypic trait. The precise loci or
identities of the non-allelic genes are often unknown to biologists.
 The common disease-common variant (often abbreviated CD-CV) hypothesis predicts
that common disease-causing alleles, or variants, will be found in all human
populations which manifest a given disease.
 Common variants (not necessarily disease-causing) are known to exist in coding and
regulatory sequences of genes.
 According to the CD-CV hypothesis, some of those variants lead to susceptibility to
complex polygenic diseases.
 Each variant at each gene influencing a complex disease will have a small additive
or multiplicative effect on the disease phenotype
 Pleiotropy occurs when one gene influences multiple, seemingly unrelated phenotypic
traits, an example being phenylketonuria, which is a human disease that affects
multiple systems but is caused by one gene defect.
INTRODUCTIONINTRODUCTION
TOPICS IN PSYCHIATRIC GENETICSTOPICS IN PSYCHIATRIC GENETICS
• UNDERLYING CONCEPTSUNDERLYING CONCEPTS
• TECHNICAL ASPECTSTECHNICAL ASPECTS
• STUDY PRINCIPLES AND METHODSSTUDY PRINCIPLES AND METHODS
• FINDINGS IN INDIVIDUAL DISORDERSFINDINGS IN INDIVIDUAL DISORDERS
• LIMITATIONS AND CONTROVERSIESLIMITATIONS AND CONTROVERSIES
• ENDOPHENOTYPESENDOPHENOTYPES
• PREDICTING RESPONSE: PHARMACOGENOMICSPREDICTING RESPONSE: PHARMACOGENOMICS
• WHAT WE KNOW: GENETIC COUNSELLINGWHAT WE KNOW: GENETIC COUNSELLING
UNDERLYING CONCEPTSUNDERLYING CONCEPTS
• THE BIOPSYCHOSOCIAL HYPOTHESISTHE BIOPSYCHOSOCIAL HYPOTHESIS
• GENE – ENVIRONMENT INTERACTIONGENE – ENVIRONMENT INTERACTION
• MENDELIAN GENETICS AND BEYONDMENDELIAN GENETICS AND BEYOND
• GENETIC MODELSGENETIC MODELS
THE BIOPSYCHOSOCIAL HYPOTHESISTHE BIOPSYCHOSOCIAL HYPOTHESIS
BIOLOGICAL
CONTRIBUTION
Often genetically
related
PSYCHOLOGICAL
FACTORS
Traits, coping,
defenses
ENVIRONMENTAL
FACTORS
Family, social,
cultural, substances,
adverse life events
MENTAL
ILLNESS
GENE-ENVIRONMENT INTERACTIONGENE-ENVIRONMENT INTERACTION
• THE RELATIONSHIP BETWEEN GENES AND ENVIRONMENT IS NON-THE RELATIONSHIP BETWEEN GENES AND ENVIRONMENT IS NON-
LINEAR.LINEAR.
• OFTEN, IT IS THE INTERACTION OF ONE OR MORE GENETICOFTEN, IT IS THE INTERACTION OF ONE OR MORE GENETIC
VULNERABILITIES WITH ENVIRONMENTAL FACTORS THAT DETERMINESVULNERABILITIES WITH ENVIRONMENTAL FACTORS THAT DETERMINES
ILLNESS.ILLNESS.
• IN OTHER WORDS, BOTH ARE NECESSARY, BUT MAY NOT BEIN OTHER WORDS, BOTH ARE NECESSARY, BUT MAY NOT BE
SUFFICIENT TO PRODUCE THE ILLNESS.SUFFICIENT TO PRODUCE THE ILLNESS.
GENE-ENVIRONMENT INTERACTION:GENE-ENVIRONMENT INTERACTION:
AN EXAMPLEAN EXAMPLE (CASPI ET AL., 2003)(CASPI ET AL., 2003)
GENETIC CODE
Polymorphism of
the serotonin
transporter
(5-HTT)
LIFE STRESSORS
Adverse life events
in early life
DEPRESSION
in adult life
GENE-ENVIRONMENT INTERACTION:GENE-ENVIRONMENT INTERACTION:
A MORE COMPLEX EXAMPLEA MORE COMPLEX EXAMPLE
GENETIC CODE
Family history of
schizophrenia
(Gene – COMT? NR1?
CHRNA7? CNR1?)
PERSONALITY
schizotypal,
“schizotaxia”
CANNABIS USE
“SELF-
MEDICATION?” FIRST-
EPISODE
PSYCHOSIS
OTHER EXAMPLESOTHER EXAMPLES
• HPA AXIS GENES AND STRESS IN ALCOHOLISM – ACTS AS AHPA AXIS GENES AND STRESS IN ALCOHOLISM – ACTS AS A
MAINTAINING FACTOR AND CAUSE FOR RELAPSEMAINTAINING FACTOR AND CAUSE FOR RELAPSE
• THE DOPAMINE D2 RECEPTOR AND SEROTONIN TRANSPORTER GENES INTHE DOPAMINE D2 RECEPTOR AND SEROTONIN TRANSPORTER GENES IN
PTSD – ASSOCIATED WITH VULNERABILITYPTSD – ASSOCIATED WITH VULNERABILITY
• MONOAMINE OXIDASE A (MAOMONOAMINE OXIDASE A (MAOAA) GENES AND EARLY LIFE ADVERSITY –) GENES AND EARLY LIFE ADVERSITY –
ASSOCIATED WITH ADULT ANTISOCIAL BEHAVIOURASSOCIATED WITH ADULT ANTISOCIAL BEHAVIOUR
MENDELIAN GENETICSMENDELIAN GENETICS
• MORE APPLICABLE TOMORE APPLICABLE TO SINGLE-GENESINGLE-GENE DISORDERSDISORDERS
• PRINCIPLES OFPRINCIPLES OF DOMINANTDOMINANT ANDAND RECESSIVERECESSIVE GENESGENES
• ALLELESALLELES OF A GENEOF A GENE
• GENOTYPEGENOTYPE ANDAND PHENOTYPEPHENOTYPE
• PRINCIPLE OFPRINCIPLE OF SEGREGATIONSEGREGATION
• PRINCIPLE OFPRINCIPLE OF INDEPENDENT ASSORTMENTINDEPENDENT ASSORTMENT
• COMMONLY APPLIED IN NEUROPSYCHIATRIC DISORDERSCOMMONLY APPLIED IN NEUROPSYCHIATRIC DISORDERS
MENDELIAN DISORDERS IN PSYCHIATRYMENDELIAN DISORDERS IN PSYCHIATRY
• AUTOSOMAL DOMINANTAUTOSOMAL DOMINANT
HUNTINGTON'S DISEASEHUNTINGTON'S DISEASE
FAMILIAL ALZHEIMER'SFAMILIAL ALZHEIMER'S
• AUTOSOMAL RECESSIVEAUTOSOMAL RECESSIVE
WILSON'S DISEASEWILSON'S DISEASE
LYSOSOMAL DISORDERSLYSOSOMAL DISORDERS
PHENYLKETONURIAPHENYLKETONURIA
LATER MODIFICATIONS OF MENDEL'SLATER MODIFICATIONS OF MENDEL'S
CONCEPTSCONCEPTS
• LINKAGELINKAGE
• CO-DOMINANCECO-DOMINANCE
• PENETRANCEPENETRANCE
• EPISTASISEPISTASIS
• HARDY-WEINBERG EQUILIBRIUMHARDY-WEINBERG EQUILIBRIUM
• TRINUCLEOTIDE REPEATSTRINUCLEOTIDE REPEATS ANDAND ANTICIPATIONANTICIPATION
• EPIGENETICSEPIGENETICS ANDAND IMPRINTINGIMPRINTING
LINKAGELINKAGE
• AS PER MENDEL'S PRINCIPLES, GENES ARE INHERITED INDEPENDENTLYAS PER MENDEL'S PRINCIPLES, GENES ARE INHERITED INDEPENDENTLY
(ONE BY ONE) AND NOT IN BLOCKS.(ONE BY ONE) AND NOT IN BLOCKS.
• HOWEVER, IT HAS BEEN FOUND THAT CERTAIN TRAITS MAY BE INHERITEDHOWEVER, IT HAS BEEN FOUND THAT CERTAIN TRAITS MAY BE INHERITED
TOGETHER AND NOT SHOW INDEPENDENT ASSORTMENT.TOGETHER AND NOT SHOW INDEPENDENT ASSORTMENT.
• THIS IS DUE TO THEIR PROXIMITY ON THE RELEVANT SEGMENT OF THETHIS IS DUE TO THEIR PROXIMITY ON THE RELEVANT SEGMENT OF THE
CHROMOSOME.CHROMOSOME.
• THIS PHENOMENON IS CALLED LINKAGE.THIS PHENOMENON IS CALLED LINKAGE.
LINKAGE DISEQUILBRIUMLINKAGE DISEQUILBRIUM
• WE DO NOT KNOW WHICH GENES CAUSE PSYCHIATRIC DISORDERS.WE DO NOT KNOW WHICH GENES CAUSE PSYCHIATRIC DISORDERS.
• INSTEAD, WE USE MARKERS SPACED EVENLY ALONG THE GENOTYPEINSTEAD, WE USE MARKERS SPACED EVENLY ALONG THE GENOTYPE
TO LOCALIZE THEM.TO LOCALIZE THEM.
• THESE MARKERS MAY BE:THESE MARKERS MAY BE: RESTRICTION FRAGMENT LENGTHRESTRICTION FRAGMENT LENGTH
POLYMORPHISMS ANDPOLYMORPHISMS AND
SINGLE NUCLEOTIDE POLYMORPHISMSSINGLE NUCLEOTIDE POLYMORPHISMS
• MARKERS THAT ARE CLOSE TO A POSSIBLE DISEASE GENE WILL BEMARKERS THAT ARE CLOSE TO A POSSIBLE DISEASE GENE WILL BE
INHERITED ALONG WITH IT – THEY SHOW LINKAGEINHERITED ALONG WITH IT – THEY SHOW LINKAGE
• THIS IMPLIES THAT IF THE FREQUENCY OF A PARTICULAR MARKER ISTHIS IMPLIES THAT IF THE FREQUENCY OF A PARTICULAR MARKER IS
HIGHER IN AFFECTED SUBJECTS THAN CONTROLS, A DISEASE GENEHIGHER IN AFFECTED SUBJECTS THAN CONTROLS, A DISEASE GENE
MAY BE CLOSE TO IT.MAY BE CLOSE TO IT.
• THIS PHENOMENON IS CALLED LINKAGE DISEQUILBRIUM, BECAUSE INTHIS PHENOMENON IS CALLED LINKAGE DISEQUILBRIUM, BECAUSE IN
A NORMAL POPULATION, WE WOULD EXPECT EQUAL FREQUENCIES.A NORMAL POPULATION, WE WOULD EXPECT EQUAL FREQUENCIES.
CO-DOMINANCECO-DOMINANCE
• IN MENDEL'S MODEL, GENES EXIST AS DOMINANT AND RECESSIVE FORMSIN MENDEL'S MODEL, GENES EXIST AS DOMINANT AND RECESSIVE FORMS
OR ALLELESOR ALLELES
• HOWEVER, OTHER MODELS EXIST WHEREIN BOTH GENES MAY BOTH BEHOWEVER, OTHER MODELS EXIST WHEREIN BOTH GENES MAY BOTH BE
EXPRESSED EQUALLY, OR AT LEAST CONCURRENTLY.EXPRESSED EQUALLY, OR AT LEAST CONCURRENTLY.
• THIS PHENOMENON IS KNOWN AS CO-DOMINANCE: A COMMONTHIS PHENOMENON IS KNOWN AS CO-DOMINANCE: A COMMON
EXAMPLE WOULD BE THE ABO BLOOD GROUP GENES.EXAMPLE WOULD BE THE ABO BLOOD GROUP GENES.
PENETRANCEPENETRANCE
• IN MENDEL'S MODEL, A GENE EITHER MANIFESTS AS A GIVEN PHENOTYPEIN MENDEL'S MODEL, A GENE EITHER MANIFESTS AS A GIVEN PHENOTYPE
(1) OR NOT (0).(1) OR NOT (0).
• HOWEVER, SOME AUTOSOMAL DOMINANT HUMAN DISORDERS SHOWHOWEVER, SOME AUTOSOMAL DOMINANT HUMAN DISORDERS SHOW
MARKED VARIANCE IN PHENOTYPE, EVEN WHEN THE SAME GENE ISMARKED VARIANCE IN PHENOTYPE, EVEN WHEN THE SAME GENE IS
PRESENT.PRESENT.
• THIS IS KNOWN ASTHIS IS KNOWN AS PENETRANCEPENETRANCE, AND CAN CONFOUND GENETIC, AND CAN CONFOUND GENETIC
STUDIES BY OBSCURING THE PATTERN OF INHERITANCE.STUDIES BY OBSCURING THE PATTERN OF INHERITANCE.
EPISTASISEPISTASIS
• SOMETIMES, MORE THAN ONE GENE MAY BE REQUIRED FOR A GIVENSOMETIMES, MORE THAN ONE GENE MAY BE REQUIRED FOR A GIVEN
PHENOTYPE.PHENOTYPE.
• THESE TWO GENES ARE AT DIFFERENT LOCI.THESE TWO GENES ARE AT DIFFERENT LOCI.
• THEIR EFFECTS ARE INTERACTIVE, BUT NOT ADDITIVE.THEIR EFFECTS ARE INTERACTIVE, BUT NOT ADDITIVE.
• IN OTHER WORDS, GENES A AND B AT DIFFERENT LOCI LEAD TOIN OTHER WORDS, GENES A AND B AT DIFFERENT LOCI LEAD TO
PHENOTYPE C; NEITHER A NOR B ALONE LEAD TO C.PHENOTYPE C; NEITHER A NOR B ALONE LEAD TO C.
• THIS IS KNOWN AS GENE-GENE INTERACTION, OR EPISTASIS.THIS IS KNOWN AS GENE-GENE INTERACTION, OR EPISTASIS.
HARDY-WEINBERG EQUILIBRIUMHARDY-WEINBERG EQUILIBRIUM
• SUPPOSE THAT TWO ALLELES P AND Q OF A GENE EXIST, AND THEIRSUPPOSE THAT TWO ALLELES P AND Q OF A GENE EXIST, AND THEIR
RELATIVE FREQUENCIES IN A POPULATION ARERELATIVE FREQUENCIES IN A POPULATION ARE PP ANDAND Q.Q.
• THE SUM OFTHE SUM OF PP ANDAND QQ IS 1.IS 1.
• IT CAN BE SHOWN THAT THE FREQUENCY OF GENOTYPES IN THEIT CAN BE SHOWN THAT THE FREQUENCY OF GENOTYPES IN THE
POPULATION WOULD BEPOPULATION WOULD BE
PP22
+ 2PQ + Q+ 2PQ + Q22
• THIS IS KNOWN ASTHIS IS KNOWN AS HARDY-WEINBERGHARDY-WEINBERG EQUILIBRIUM.EQUILIBRIUM.
AN EXAMPLEAN EXAMPLE
• CONSIDER A GENE M FOR MUSICAL TALENT.CONSIDER A GENE M FOR MUSICAL TALENT.
• FORMFORM PP (MORE TALENT) IS PRESENT IN 60%(MORE TALENT) IS PRESENT IN 60% (0.6)(0.6) OF A GIVEN POPULATION.OF A GIVEN POPULATION. PP ANDAND QQ
ARE CO-DOMINANT.ARE CO-DOMINANT.
• Q = 1 – P = 0.4Q = 1 – P = 0.4
• IF HARDY-WEINBERG EQUILIBRIUM HOLDS, THE FREQUENCIES WOULD BE:IF HARDY-WEINBERG EQUILIBRIUM HOLDS, THE FREQUENCIES WOULD BE:
PP22
: 0.36 (0.6 X 0.6) – VERY TALENTED: 0.36 (0.6 X 0.6) – VERY TALENTED
2PQ : 0.48 (2 X 0.6 X 0.4) – FAIR TALENT2PQ : 0.48 (2 X 0.6 X 0.4) – FAIR TALENT
QQ22
: 0.16 (0.4 X 0.4) – LEAST TALENT: 0.16 (0.4 X 0.4) – LEAST TALENT
ASSUMPTIONS IN THE HARDY-WEINBERGASSUMPTIONS IN THE HARDY-WEINBERG
EQUILIBRIUMEQUILIBRIUM
• MATING IS RANDOM – IF GOOD MUSICIANSMATING IS RANDOM – IF GOOD MUSICIANS (PP)(PP) SELECTIVELYSELECTIVELY
MARRY GOOD MUSICIANSMARRY GOOD MUSICIANS (PP)(PP), THIS ASSUMPTION DOES NOT, THIS ASSUMPTION DOES NOT
HOLD.HOLD.
• THERE IS NO SELECTION – IF GOOD MUSICIANS HAVE ATHERE IS NO SELECTION – IF GOOD MUSICIANS HAVE A
SHORTER LIFE SPAN OR REDUCED REPRODUCTIVE CAPACITY,SHORTER LIFE SPAN OR REDUCED REPRODUCTIVE CAPACITY,
PPPP WOULD BE SELECTED OUT.WOULD BE SELECTED OUT.
• THERE IS NO EMIGRATION – IF POOR MUSICIANS MIGRATE TOTHERE IS NO EMIGRATION – IF POOR MUSICIANS MIGRATE TO
THE U.S., THE FREQUENCY OFTHE U.S., THE FREQUENCY OF QQQQ IN INDIA WOULD FALLIN INDIA WOULD FALL
• THERE ARE NO MUTATIONS (FOR EXAMPLE, CREATING A NEWTHERE ARE NO MUTATIONS (FOR EXAMPLE, CREATING A NEW
ALLELEALLELE RR THAT CONFERS MORE TALENT)THAT CONFERS MORE TALENT)
TRINUCLEOTIDETRINUCLEOTIDE REPEATSREPEATS
• CERTAIN GENES ARE NOTICED TO CONTAIN REPEATING SEQUENCES OFCERTAIN GENES ARE NOTICED TO CONTAIN REPEATING SEQUENCES OF
TRINUCLEOTIDE BASES, SUCH AS CAG OR CGG.TRINUCLEOTIDE BASES, SUCH AS CAG OR CGG.
• THE NUMBER OF THESE REPEATS AFFECTS THE FUNCTIONING OF THE GENETHE NUMBER OF THESE REPEATS AFFECTS THE FUNCTIONING OF THE GENE
AND MAY LEAD TO DISEASE.AND MAY LEAD TO DISEASE.
• THESE DISORDERS ARE KNOWN ASTHESE DISORDERS ARE KNOWN AS TRINUCLEOTIDE REPEAT DISORDERSTRINUCLEOTIDE REPEAT DISORDERS..
EXAMPLES OF TRINUCLEOTIDE REPEATEXAMPLES OF TRINUCLEOTIDE REPEAT
DISORDERSDISORDERS
• HUNTINGTON'S DISEASE –HUNTINGTON'S DISEASE – CAG REPEATS IN THE HUNTINGTIN GENE ONCAG REPEATS IN THE HUNTINGTIN GENE ON
CHROMOSOME 4.CHROMOSOME 4.
• SPINOCEREBELLAR ATAXIA –SPINOCEREBELLAR ATAXIA – CAG REPEATS ON VARIOUS CHROMOSOMES (6, 12, 16)CAG REPEATS ON VARIOUS CHROMOSOMES (6, 12, 16)
• FRAGILE X SYNDROME –FRAGILE X SYNDROME – CGG REPEATS ON THE LONG ARM OF CHROMOSOME X.CGG REPEATS ON THE LONG ARM OF CHROMOSOME X.
• ? SCHIZOPHRENIA –? SCHIZOPHRENIA – ONE GENETIC MODEL OF SCHIZOPHRENIA INVOLVES CAGONE GENETIC MODEL OF SCHIZOPHRENIA INVOLVES CAG
REPEATS AT 6P, 8P AND 22Q, AND PERHAPS OTHER AREASREPEATS AT 6P, 8P AND 22Q, AND PERHAPS OTHER AREAS
NUMBERS AND SEVERITYNUMBERS AND SEVERITY
• THE NUMBER OF REPEATS OFTEN CORRELATES WITH THE PHENOTYPE.THE NUMBER OF REPEATS OFTEN CORRELATES WITH THE PHENOTYPE.
• FOR EXAMPLE, IN HUNTINGTON'S DISEASE, CLINICAL SYMPTOMSFOR EXAMPLE, IN HUNTINGTON'S DISEASE, CLINICAL SYMPTOMS
USUALLY APPEAR WHEN THEREUSUALLY APPEAR WHEN THERE ARE >38 CAGARE >38 CAG REPEATS.REPEATS.
• IN FRAGILE X SYNDROME,IN FRAGILE X SYNDROME, <43 CGG REPEATS ARE NORMAL, 43-200 ARE<43 CGG REPEATS ARE NORMAL, 43-200 ARE
CARRIERS, AND >200 HAVE THE CLINICAL SYNDROMECARRIERS, AND >200 HAVE THE CLINICAL SYNDROME..
ANTICIPATIONANTICIPATION
• WHEN A TRINUCLEOTIDE REPEAT DISEASE GENE IS TRANSMITTED TOWHEN A TRINUCLEOTIDE REPEAT DISEASE GENE IS TRANSMITTED TO
OFFSPRING, THE NUMBER OF REPEATS MAY UNDERGO EXPANSION.OFFSPRING, THE NUMBER OF REPEATS MAY UNDERGO EXPANSION.
• THIS MAY BE RELATED TO THE ORIGIN OF THE GENE – IN HUNTINGTON'S,THIS MAY BE RELATED TO THE ORIGIN OF THE GENE – IN HUNTINGTON'S,
PATERNAL GENES ARE MORE LIKELY TO EXPAND.PATERNAL GENES ARE MORE LIKELY TO EXPAND.
• THIS LEADS TO OFFSPRING DEVELOPING THE ILLNESS AT AN EARLIER AGETHIS LEADS TO OFFSPRING DEVELOPING THE ILLNESS AT AN EARLIER AGE
AND WITH GREATER SEVERITY; THIS PROCESS IS KNOWN ASAND WITH GREATER SEVERITY; THIS PROCESS IS KNOWN AS ANTICIPATIONANTICIPATION..
EPIGENETICSEPIGENETICS
• THUS FAR, WE HAVE CONSIDERED THE DNA SEQUENCE OF GENES AS BEING OFTHUS FAR, WE HAVE CONSIDERED THE DNA SEQUENCE OF GENES AS BEING OF
PRIME IMPORTANCE.PRIME IMPORTANCE.
• HOWEVER, GENES IN DNA EXIST IN CHROMOSOMES, ASSOCIATED WITHHOWEVER, GENES IN DNA EXIST IN CHROMOSOMES, ASSOCIATED WITH
PROTEINSPROTEINS (HISTONES)(HISTONES)..
• THE CHEMICAL STRUCTURE OF DNA CAN UNDERGO MODIFICATIONS, SUCH ASTHE CHEMICAL STRUCTURE OF DNA CAN UNDERGO MODIFICATIONS, SUCH AS
METHYLATION, PHOSPHORYLATION, ACETYLATION, ETCMETHYLATION, PHOSPHORYLATION, ACETYLATION, ETC
• THE AMINO ACIDS OF HISTONES CAN ALSO UNDERGO SUCH MODIFICATIONS.THE AMINO ACIDS OF HISTONES CAN ALSO UNDERGO SUCH MODIFICATIONS.
• THESE CHANGES DOTHESE CHANGES DO NOTNOT ALTER THE SEQUENCE OF NUCLEOTIDES IN GENES.ALTER THE SEQUENCE OF NUCLEOTIDES IN GENES.
• HOWEVER, THEY MAY AFFECT THE ACTIVATION AND LEVEL OF EXPRESSION OFHOWEVER, THEY MAY AFFECT THE ACTIVATION AND LEVEL OF EXPRESSION OF
THE RESPECTIVE GENES.THE RESPECTIVE GENES.
• THESE PROCESSES ARE COLLECTIVELY CALLEDTHESE PROCESSES ARE COLLECTIVELY CALLED EPIGENETIC MODIFICATIONSEPIGENETIC MODIFICATIONS,,
AND SHARE CERTAIN INTERESTING PROPERTIESAND SHARE CERTAIN INTERESTING PROPERTIES
EPIGENETICS .VS. “CLASSICAL” GENETICSEPIGENETICS .VS. “CLASSICAL” GENETICS
• MAINTAINED IN SOMATIC CELL REPLICATIONMAINTAINED IN SOMATIC CELL REPLICATION
• MAYMAY BE MAINTAINED DURING MEIOSIS, OR MODIFIED, OR COMPLETELYBE MAINTAINED DURING MEIOSIS, OR MODIFIED, OR COMPLETELY
REMOVEDREMOVED
• SUBJECT TO RANDOM ORSUBJECT TO RANDOM OR STOCHASTICSTOCHASTIC EFFECTSEFFECTS
• MODIFIABLE BY ENVIRONMENTAL FACTORS, SUCH AS NUTRITION,MODIFIABLE BY ENVIRONMENTAL FACTORS, SUCH AS NUTRITION,
SUBSTANCES OR HORMONESSUBSTANCES OR HORMONES
• MODIFICATIONSMODIFICATIONS (EPIMUTATIONS)(EPIMUTATIONS) MAY “REGRESS TO THE MEAN” WITHMAY “REGRESS TO THE MEAN” WITH
AGEAGE
AN EPIGENETIC MODEL OFAN EPIGENETIC MODEL OF
SCHIZOPHRENIASCHIZOPHRENIA (PETRONIS, 2004)(PETRONIS, 2004)
PHENOMENA THAT MAY BE EXPLAINED BYPHENOMENA THAT MAY BE EXPLAINED BY
EPIGENETICS IN PSYCHOSISEPIGENETICS IN PSYCHOSIS
• FAMILIAL AND SPORADIC CASESFAMILIAL AND SPORADIC CASES
• DISCORDANCE IN MONOZYGOTIC TWINSDISCORDANCE IN MONOZYGOTIC TWINS
• COURSE AND RESOLUTION OF THE ILLNESSCOURSE AND RESOLUTION OF THE ILLNESS
• EFFECTS OF GENDEREFFECTS OF GENDER
• PERSISTENCE OF THE ILLNESS DESPITE EVOLUTIONARYPERSISTENCE OF THE ILLNESS DESPITE EVOLUTIONARY
DISADVANTAGESDISADVANTAGES
• NON-REPLICABILITY OF “CLASSICAL” STUDIESNON-REPLICABILITY OF “CLASSICAL” STUDIES
• ANTICIPATION AND PARENT-OF-ORIGIN EFFECTSANTICIPATION AND PARENT-OF-ORIGIN EFFECTS
IMPRINTINGIMPRINTING
 PATERNAL AND MATERNAL COPIES OF THE SAME GENE UNDERGOPATERNAL AND MATERNAL COPIES OF THE SAME GENE UNDERGO
EPIGENETIC MODIFICATIONS.EPIGENETIC MODIFICATIONS.
 THIS PROCESS IS CALLEDTHIS PROCESS IS CALLED IMPRINTINGIMPRINTING, AND LEADS TO DIFFERENTIAL, AND LEADS TO DIFFERENTIAL
EXPRESSION OF GENES IN THE OFFSPRING DEPENDING ON WHICHEXPRESSION OF GENES IN THE OFFSPRING DEPENDING ON WHICH
COPY IS INHERITED.COPY IS INHERITED.
 THIS CAN LEAD TO DIFFERENCES IN ILLNESS EXPRESSION – E.G.THIS CAN LEAD TO DIFFERENCES IN ILLNESS EXPRESSION – E.G.
PRADER-WILLIPRADER-WILLI ANDAND ANGELMANANGELMAN SYNDROMES HAVE THE SAMESYNDROMES HAVE THE SAME
GENETIC MUTATION, BUT DIFFERENT SYMPTOMSGENETIC MUTATION, BUT DIFFERENT SYMPTOMS
GENETIC MODELSGENETIC MODELS
• MENDELIANMENDELIAN
• MENDELIANMENDELIAN WITH VARIABLE PENETRANCEWITH VARIABLE PENETRANCE
• MENDELIANMENDELIAN WITHWITH IMPRINTINGIMPRINTING
• OLIGOGENIC –OLIGOGENIC – A SMALL NUMBER OF KEY GENES INTERACTINGA SMALL NUMBER OF KEY GENES INTERACTING
• MIXED –MIXED – A SINGLE MAJOR GENE + OLIGOGENESA SINGLE MAJOR GENE + OLIGOGENES
• POLYGENIC –POLYGENIC – MULTIPLE GENES OF SMALL EFFECTMULTIPLE GENES OF SMALL EFFECT
HERITABILITYHERITABILITY
TECHNIQUES UTILIZED IN GENETIC STUDIESTECHNIQUES UTILIZED IN GENETIC STUDIES
• CLEAVAGE OF DNA AT SPECIFIC SITES BYCLEAVAGE OF DNA AT SPECIFIC SITES BY RESTRICTIONRESTRICTION
ENDONUCLEASESENDONUCLEASES
• USINGUSING MARKERS –MARKERS – RFLPS, SNPS, TRINUCLEOTIDE REPEATSRFLPS, SNPS, TRINUCLEOTIDE REPEATS
• HYBRIDIZATIONHYBRIDIZATION OF MARKERS AND COMPLEMENTARY SEQUENCES –OF MARKERS AND COMPLEMENTARY SEQUENCES –
FLUORESCENT, IMMUNE, ETC.FLUORESCENT, IMMUNE, ETC.
• KARYOTYPINGKARYOTYPING AND OTHER CYTOGENETIC METHODSAND OTHER CYTOGENETIC METHODS
• EXAMINING SEQUENCES OF DNA THAT HAVE BEEN CONSERVEDEXAMINING SEQUENCES OF DNA THAT HAVE BEEN CONSERVED
EVOLUTIONARILY, OREVOLUTIONARILY, OR HAPLOTYPESHAPLOTYPES
TECHNIQUES UTILIZED IN GENETIC STUDIESTECHNIQUES UTILIZED IN GENETIC STUDIES
• THETHE POLYMERASE CHAIN REACTIONPOLYMERASE CHAIN REACTION – USING BACTERIAL DNA– USING BACTERIAL DNA
POLYMERASE TO AMPLIFY SEQUENCESPOLYMERASE TO AMPLIFY SEQUENCES
• RECOMBINANT DNA TECHNOLOGYRECOMBINANT DNA TECHNOLOGY TO EXAMINE GENE EXPRESSIONTO EXAMINE GENE EXPRESSION
AND PRODUCTSAND PRODUCTS
• KNOCK-OUTKNOCK-OUT ANDAND TRANSGENICTRANSGENIC ANIMAL MODELS TO STUDY THEANIMAL MODELS TO STUDY THE
EFFECTS OF A SINGLE GENE OR GENE PRODUCTEFFECTS OF A SINGLE GENE OR GENE PRODUCT
• USING THE MAP OF THE HUMAN GENOME FROM THEUSING THE MAP OF THE HUMAN GENOME FROM THE HUMANHUMAN
GENOME PROJECTGENOME PROJECT
• MICRO-ARRAYMICRO-ARRAY TECHNIQUES, WHICH USE SEMICONDUCTORTECHNIQUES, WHICH USE SEMICONDUCTOR
TECHNIQUES OR ROBOTICS TO AMPLIFY AND EXAMINE MARKERS,TECHNIQUES OR ROBOTICS TO AMPLIFY AND EXAMINE MARKERS,
AND TO MEASURE MRNA LEVELSAND TO MEASURE MRNA LEVELS
• POSTMORTEMPOSTMORTEM STUDIES ON HUMAN BRAINSSTUDIES ON HUMAN BRAINS
• NEWER STATISTICAL METHODS -NEWER STATISTICAL METHODS - BIOINFORMATICSBIOINFORMATICS
CLASSICAL PSYCHIATRIC GENETICSCLASSICAL PSYCHIATRIC GENETICS
DOES THE DISORDER RUN IN FAMILIES?
Family studies – establish familiality
IS FAMILIALITY DUE TO GENES OR THE ENVIRONMENT?
Twin studies – examine concordance rates in twin pairs
HOW MUCH DO GENES AND THE ENVIRONMENT CONTRIBUTE?
Adoption studies – separate genetic and environmental contributions
WHICH GENES ARE INVOLVED?
Linkage and association studies
HOW DO THE GENES PRODUCE THE DISEASE?
Molecular genetics
MORE RECENT CONCEPTSMORE RECENT CONCEPTS
• ENDOPHENOTYPE APPROACHESENDOPHENOTYPE APPROACHES
• ANIMAL MODELS – KNOCKOUT MICE, ETC.ANIMAL MODELS – KNOCKOUT MICE, ETC.
• PHARMACOGENETICS AND PHARMACOGENOMICSPHARMACOGENETICS AND PHARMACOGENOMICS
THE FIRST STEP: FAMILY STUDIESTHE FIRST STEP: FAMILY STUDIES
• FAMILY STUDIES ESTABLISH THAT A GIVEN DISORDER RUNS IN FAMILIES.FAMILY STUDIES ESTABLISH THAT A GIVEN DISORDER RUNS IN FAMILIES.
• HOWEVER, THEY DO NOT DIRECTLY SHOW WHETHER THIS IS DUE TOHOWEVER, THEY DO NOT DIRECTLY SHOW WHETHER THIS IS DUE TO
GENES OR ENVIRONMENTAL FACTORS.GENES OR ENVIRONMENTAL FACTORS.
• IN FAMILY STUDIES, AFFECTED INDIVIDUALSIN FAMILY STUDIES, AFFECTED INDIVIDUALS (PROBANDS)(PROBANDS) ARE SELECTED,ARE SELECTED,
AND THEIR FAMILIES ARE EXAMINED FOR A GIVEN DISORDER.AND THEIR FAMILIES ARE EXAMINED FOR A GIVEN DISORDER.
• THEIR RATES OF THE DISORDER ARE THEN COMPARED WITH EITHER ATHEIR RATES OF THE DISORDER ARE THEN COMPARED WITH EITHER A
CONTROL GROUP OR THE POPULATION.CONTROL GROUP OR THE POPULATION.
TWO TYPES OF FAMILY STUDIESTWO TYPES OF FAMILY STUDIES
• FAMILY HISTORY METHOD:FAMILY HISTORY METHOD: THE PROBAND ISTHE PROBAND IS
INTERVIEWED, AND INFORMATION ABOUT MENTALINTERVIEWED, AND INFORMATION ABOUT MENTAL
ILLNESS IN RELATIVES IS COLLECTED. SIMPLER, BUT LESSILLNESS IN RELATIVES IS COLLECTED. SIMPLER, BUT LESS
RELIABLE; UNDERESTIMATES TRUE RATES.RELIABLE; UNDERESTIMATES TRUE RATES.
• FAMILY STUDY METHOD:FAMILY STUDY METHOD: ALL AVAILABLE RELATIVES AREALL AVAILABLE RELATIVES ARE
INTERVIEWED DIRECTLY. TIME-CONSUMING, BUT MOREINTERVIEWED DIRECTLY. TIME-CONSUMING, BUT MORE
RELIABLE.RELIABLE.
GENETIC DISTANCEGENETIC DISTANCE
• FAMILY STUDIES CANNOT DIRECTLY GIVE ESTIMATES OF GENETICFAMILY STUDIES CANNOT DIRECTLY GIVE ESTIMATES OF GENETIC
CONTRIBUTIONS.CONTRIBUTIONS.
• HOWEVER, IF THE RATE OF DISORDERS FALLS AS THE AMOUNT OFHOWEVER, IF THE RATE OF DISORDERS FALLS AS THE AMOUNT OF
SHARED DNA BETWEEN RELATIVES DECREASES (INCREASEDSHARED DNA BETWEEN RELATIVES DECREASES (INCREASED GENETICGENETIC
DISTANCEDISTANCE), A GENETIC COMPONENT IS LIKELY.), A GENETIC COMPONENT IS LIKELY.
• A FAMILY STUDY OF OCD FOUND RATES OF 7% IN FIRST-DEGREEA FAMILY STUDY OF OCD FOUND RATES OF 7% IN FIRST-DEGREE
RELATIVES, AND 2% IN SECOND-DEGREE RELATIVES.RELATIVES, AND 2% IN SECOND-DEGREE RELATIVES.
• THE POPULATION RATE IS 2-3%.THE POPULATION RATE IS 2-3%.
• THIS SUGGESTS THAT:THIS SUGGESTS THAT:
1. OCD IS FAMILIAL.1. OCD IS FAMILIAL.
2. A GENETIC CONTRIBUTION IS LIKELY.2. A GENETIC CONTRIBUTION IS LIKELY.
TWIN STUDIESTWIN STUDIES
• MONOZYGOTIC (MZ) TWINS SHARE 100% GENETIC MATERIAL, WHILE DIZYGOTICMONOZYGOTIC (MZ) TWINS SHARE 100% GENETIC MATERIAL, WHILE DIZYGOTIC
(DZ) TWINS SHARE AS MUCH AS BROTHERS OR SISTERS (50%)(DZ) TWINS SHARE AS MUCH AS BROTHERS OR SISTERS (50%)
• CONCORDANCECONCORDANCE IS DEFINED AS THE POSSIBILITY THAT BOTH MEMBERS OF AIS DEFINED AS THE POSSIBILITY THAT BOTH MEMBERS OF A
TWIN PAIR WILL HAVE THE DISORDER BEING STUDIED.TWIN PAIR WILL HAVE THE DISORDER BEING STUDIED.
• IT IS ASSUMED THAT MZ AND DZ TWINS GROW UP IN SIMILAR ENVIRONMENTSIT IS ASSUMED THAT MZ AND DZ TWINS GROW UP IN SIMILAR ENVIRONMENTS
(THE(THE “EQUAL-ENVIRONMENT ASSUMPTION”“EQUAL-ENVIRONMENT ASSUMPTION”))
• IF A DISORDER IS DETERMINED BY ENVIRONMENTAL FACTORS, CONCORDANCEIF A DISORDER IS DETERMINED BY ENVIRONMENTAL FACTORS, CONCORDANCE
RATES IN MZ AND DZ TWINS SHOULD BE SIMILAR.RATES IN MZ AND DZ TWINS SHOULD BE SIMILAR.
• ON THE OTHER HAND, IF IT IS GENETICALLY DETERMINED, CONCORDANCEON THE OTHER HAND, IF IT IS GENETICALLY DETERMINED, CONCORDANCE
SHOULD BE MORE IN MZ THAN IN DZ TWINS.SHOULD BE MORE IN MZ THAN IN DZ TWINS.
• THE EXTENT OF CONCORDANCE PROVIDES AN ESTIMATE OF THE GENETICTHE EXTENT OF CONCORDANCE PROVIDES AN ESTIMATE OF THE GENETIC
CONTRIBUTION.CONTRIBUTION.
AN EXAMPLE OF TWIN STUDIESAN EXAMPLE OF TWIN STUDIES
• A STUDY FINDS THAT THE CONCORDANCE FOR BIPOLAR DISORDER INA STUDY FINDS THAT THE CONCORDANCE FOR BIPOLAR DISORDER IN
MZ TWINS IS 60%, AND IN DZ TWINS 20%MZ TWINS IS 60%, AND IN DZ TWINS 20%
• THIS INDICATES THAT GENETIC FACTORS ARE LIKELY MORE IMPORTANTTHIS INDICATES THAT GENETIC FACTORS ARE LIKELY MORE IMPORTANT
(NUMERICALLY) THAN ENVIRONMENTAL FACTORS IN BIPOLAR(NUMERICALLY) THAN ENVIRONMENTAL FACTORS IN BIPOLAR
DISORDER.DISORDER.
• HOWEVER, THE <100% CONCORDANCE INDICATES THAT THERE IS STILLHOWEVER, THE <100% CONCORDANCE INDICATES THAT THERE IS STILL
A 40% CONTRIBUTION FROM ENVIRONMENTAL FACTORS.A 40% CONTRIBUTION FROM ENVIRONMENTAL FACTORS.
ADOPTION STUDIESADOPTION STUDIES
• ADOPTION STUDIES BROADLY SEEK TO DETERMINE WHETHER HEREDITY (NATURE)ADOPTION STUDIES BROADLY SEEK TO DETERMINE WHETHER HEREDITY (NATURE)
OR ENVIRONMENT (NURTURE) ARE MORE IMPORTANT IN A GIVEN DISORDER.OR ENVIRONMENT (NURTURE) ARE MORE IMPORTANT IN A GIVEN DISORDER.
• THEY RELY ON THE ASSUMPTION OFTHEY RELY ON THE ASSUMPTION OF “NO SELECTIVE PLACEMENT”“NO SELECTIVE PLACEMENT” - THAT IS, THAT- THAT IS, THAT
THE ENVIRONMENT PROVIDED BY ADOPTIVE PARENTS IS ONLY RANDOMLYTHE ENVIRONMENT PROVIDED BY ADOPTIVE PARENTS IS ONLY RANDOMLY
SIMILAR TO THAT OF THE BIOLOGICAL PARENTS.SIMILAR TO THAT OF THE BIOLOGICAL PARENTS.
• CONSIDER TWO GROUPS OF ADOPTED CHILDREN, NAMED A AND B.CONSIDER TWO GROUPS OF ADOPTED CHILDREN, NAMED A AND B.
• GROUP A ARE CHILDREN OF PATIENTS WITH A GIVEN DISORDER (SAYGROUP A ARE CHILDREN OF PATIENTS WITH A GIVEN DISORDER (SAY
DEPRESSION).DEPRESSION).
• GROUP B ARE CHILDREN WHOSE ADOPTIVE PARENTS HAVE THE GIVENGROUP B ARE CHILDREN WHOSE ADOPTIVE PARENTS HAVE THE GIVEN
DISORDER, OR CONTROLS.DISORDER, OR CONTROLS.
• WE NOW COMPARE THE RATES OF DEPRESSION IN GROUPS A AND B, AS WELLWE NOW COMPARE THE RATES OF DEPRESSION IN GROUPS A AND B, AS WELL
AS THE AGREEMENT BETWEEN THEIR DIAGNOSES AND THOSE OF BIOLOGICALAS THE AGREEMENT BETWEEN THEIR DIAGNOSES AND THOSE OF BIOLOGICAL
AND ADOPTED PARENTS.AND ADOPTED PARENTS.
ADOPTION STUDIESADOPTION STUDIES
• IN OUR EXAMPLE, GROUP A HAVE A (PRESUMED) GENETIC LIABILITYIN OUR EXAMPLE, GROUP A HAVE A (PRESUMED) GENETIC LIABILITY
TO DEPRESSION, BUT NO ENVIRONMENTAL LOADING.TO DEPRESSION, BUT NO ENVIRONMENTAL LOADING.
• THE OPPOSITE HOLDS GOOD FOR GROUP B.THE OPPOSITE HOLDS GOOD FOR GROUP B.
• MEASURING THE RATES OF THE DISORDER IN GROUPS WOULD GIVEMEASURING THE RATES OF THE DISORDER IN GROUPS WOULD GIVE
US A MEASURE OF WHETHER ENVIRONMENTAL OR GENETICUS A MEASURE OF WHETHER ENVIRONMENTAL OR GENETIC
VULNERABILITY PLAYS A GREATER ROLE.VULNERABILITY PLAYS A GREATER ROLE.
AN EXAMPLE OF ADOPTION STUDYAN EXAMPLE OF ADOPTION STUDY
• A STUDY IS DONE EXAMINING 50 CHILDREN OF ALCOHOLICS WHOA STUDY IS DONE EXAMINING 50 CHILDREN OF ALCOHOLICS WHO
ARE ADOPTED, AND 50 CHILDREN WHOSE ADOPTIVE PARENTS HAVEARE ADOPTED, AND 50 CHILDREN WHOSE ADOPTIVE PARENTS HAVE
ALCOHOLISM.ALCOHOLISM.
• THE STUDY FINDS THAT RATES OF ALCOHOLISM ARE 12% IN THE FIRSTTHE STUDY FINDS THAT RATES OF ALCOHOLISM ARE 12% IN THE FIRST
GROUP, AND 6% IN THE SECOND GROUP.GROUP, AND 6% IN THE SECOND GROUP.
• THE GREATER AGREEMENT WITH THE BIOLOGICAL PARENTS'THE GREATER AGREEMENT WITH THE BIOLOGICAL PARENTS'
DIAGNOSIS POINTS TO A GENETIC COMPONENT.DIAGNOSIS POINTS TO A GENETIC COMPONENT.
FINDING THE GENESFINDING THE GENES
• ONCE THE FAMILIALITY AND GENETIC COMPONENT OF A GIVEN DISORDER AREONCE THE FAMILIALITY AND GENETIC COMPONENT OF A GIVEN DISORDER ARE
ESTABLISHED, THE GENE OR GENES RESPONSIBLE MUST BE IDENTIFIED.ESTABLISHED, THE GENE OR GENES RESPONSIBLE MUST BE IDENTIFIED.
• THIS IS DONE BY MEANS OF FOUR METHODS:THIS IS DONE BY MEANS OF FOUR METHODS:
1. LINKAGE ANALYSIS1. LINKAGE ANALYSIS
2. ASSOCIATION ANALYSIS2. ASSOCIATION ANALYSIS
3. CANDIDATE GENE ANALYSIS3. CANDIDATE GENE ANALYSIS
4. CYTOGENETIC ANALYSIS4. CYTOGENETIC ANALYSIS
LINKAGE STUDIESLINKAGE STUDIES
PARAMETRIC LINKAGE STUDIESPARAMETRIC LINKAGE STUDIES
NONPARAMETRIC LINKAGE STUDIESNONPARAMETRIC LINKAGE STUDIES
• ALSO KNOWN AS THE AFFECTED SIBLING PAIR (ASP)ALSO KNOWN AS THE AFFECTED SIBLING PAIR (ASP)
METHODMETHOD
• IN THIS DISORDER, THE FREQUENCY WITH WHICH THEIN THIS DISORDER, THE FREQUENCY WITH WHICH THE
GIVEN GENETIC MARKER IS INHERITED FROM A PARENTGIVEN GENETIC MARKER IS INHERITED FROM A PARENT
IS MEASURED.IS MEASURED.
• IF THIS FREQUENCY EXCEEDS 50% IN AFFECTED PAIRSIF THIS FREQUENCY EXCEEDS 50% IN AFFECTED PAIRS
OF SIBLINGS, LINKAGE IS LIKELY (I.E. THE DISEASE GENEOF SIBLINGS, LINKAGE IS LIKELY (I.E. THE DISEASE GENE
AND THE INHERITED MARKER ARE IN LINKAGE.)AND THE INHERITED MARKER ARE IN LINKAGE.)
ASSOCIATION STUDIESASSOCIATION STUDIES
• SIMPLER THAN LINKAGE STUDIES.SIMPLER THAN LINKAGE STUDIES.
• IN THIS METHOD, THE FREQUENCY OF MARKERS IS COMPARED ININ THIS METHOD, THE FREQUENCY OF MARKERS IS COMPARED IN
AFFECTED AND UNAFFECTED SUBJECTS.AFFECTED AND UNAFFECTED SUBJECTS.
• A CHI-SQUARE TEST IS USED TO COMPARE FREQUENCIES OF THE MARKERA CHI-SQUARE TEST IS USED TO COMPARE FREQUENCIES OF THE MARKER
IN BOTH GROUPS, AND THE RELATIVE RISK CAN BE CALCULATED.IN BOTH GROUPS, AND THE RELATIVE RISK CAN BE CALCULATED.
• IN SUCH STUDIES, POPULATIONS MUST IDEALLY BE AS GENETICALLYIN SUCH STUDIES, POPULATIONS MUST IDEALLY BE AS GENETICALLY
HOMOGENEOUS AS POSSIBLE.HOMOGENEOUS AS POSSIBLE.
HOW DO WE FIND THE GENES ONCEHOW DO WE FIND THE GENES ONCE
LINKAGE IS ESTABLISHED?LINKAGE IS ESTABLISHED?
• USE A CANDIDATE APPROACH – THAT IS, CONCENTRATE ON THOSEUSE A CANDIDATE APPROACH – THAT IS, CONCENTRATE ON THOSE
MARKERS CLOSE TO GENES THAT MAY BE RELEVANT.MARKERS CLOSE TO GENES THAT MAY BE RELEVANT.
• IF THESE ARE NOT KNOWN, SYSTEMATICALLY SEARCH THE REGION CLOSEIF THESE ARE NOT KNOWN, SYSTEMATICALLY SEARCH THE REGION CLOSE
TO THE MARKER.TO THE MARKER.
• IDEALLY, AN ENTIRE GENOME SCAN FOR LINKAGE DISEQUILIBRIUMIDEALLY, AN ENTIRE GENOME SCAN FOR LINKAGE DISEQUILIBRIUM
SHOULD BE DONE – THIS IS TIME-CONSUMING, BUT MODERNSHOULD BE DONE – THIS IS TIME-CONSUMING, BUT MODERN
TECHNOLOGIES HELP.TECHNOLOGIES HELP.
CANDIDATE GENE STUDIESCANDIDATE GENE STUDIES
 IN THESE STUDIES, GENES THAT CODE FOR PROTEINS BELIEVED TO BEIN THESE STUDIES, GENES THAT CODE FOR PROTEINS BELIEVED TO BE
IMPORTANT IN A GIVEN DISORDER ARE STUDIED IN AFFECTED ANDIMPORTANT IN A GIVEN DISORDER ARE STUDIED IN AFFECTED AND
UNAFFECTED PATIENTS.UNAFFECTED PATIENTS.
 SINCE THE PATHOPHYSIOLOGY OF PSYCHIATRIC ILLNESS IS NOTSINCE THE PATHOPHYSIOLOGY OF PSYCHIATRIC ILLNESS IS NOT
GENERALLY KNOWN, THESE GENES HAVE TO BE “GUESSED AT” - E.GGENERALLY KNOWN, THESE GENES HAVE TO BE “GUESSED AT” - E.G
DOPAMINE RECEPTORS IN SCHIZOPHRENIA.DOPAMINE RECEPTORS IN SCHIZOPHRENIA.
 COMPARING FREQUENCIES OF DIFFERENT GENE POLYMORPHISMS MAYCOMPARING FREQUENCIES OF DIFFERENT GENE POLYMORPHISMS MAY
SHOW ASSOCIATIONS BETWEEN A GENE AND A GIVEN DISORDERSHOW ASSOCIATIONS BETWEEN A GENE AND A GIVEN DISORDER..
 IF ONE POLYMORPHISM IS MORE THEN SUSPECT A CANDIDATE.IF ONE POLYMORPHISM IS MORE THEN SUSPECT A CANDIDATE.
CYTOGENETIC STUDIESCYTOGENETIC STUDIES
• THESE ARE USED WHEN DISORDERS IN CHROMOSOME NUMBER ORTHESE ARE USED WHEN DISORDERS IN CHROMOSOME NUMBER OR
STRUCTURE ARE SUSPECTED.STRUCTURE ARE SUSPECTED.
• THEY ARE MORE USEFUL IN STUDYINGTHEY ARE MORE USEFUL IN STUDYING INHERITED NEUROPSYCHIATRICINHERITED NEUROPSYCHIATRIC
SYNDROMESSYNDROMES WHERE ANEUPLOIDY OR STRUCTURAL DEFICITS AREWHERE ANEUPLOIDY OR STRUCTURAL DEFICITS ARE
DIAGNOSTICDIAGNOSTIC
• EXAMPLES: DOWN'S SYNDROME, TURNER'S SYNDROME, FRAGILE XEXAMPLES: DOWN'S SYNDROME, TURNER'S SYNDROME, FRAGILE X
SYNDROMESYNDROME
FINDINGS IN COMMON DISORDERSFINDINGS IN COMMON DISORDERS
• SCHIZOPHRENIASCHIZOPHRENIA
• BIPOLAR DISORDERBIPOLAR DISORDER
• DEPRESSIONDEPRESSION
• OCDOCD
• PANIC DISORDERPANIC DISORDER
• ALCOHOL DEPENDENCE SYNDROMEALCOHOL DEPENDENCE SYNDROME
GENETIC CONTRIBUTIONS ACROSSGENETIC CONTRIBUTIONS ACROSS
DISORDERSDISORDERS
(MERIKANGAS AND RISCH, 2003)(MERIKANGAS AND RISCH, 2003)
HERITABILITY ESTIMATES FOR COMMONHERITABILITY ESTIMATES FOR COMMON
DISORDERSDISORDERS
(HILL AND SAHHAR, 2006)(HILL AND SAHHAR, 2006)
SCHIZOPHRENIASCHIZOPHRENIA
SCHIZOPHRENIASCHIZOPHRENIA
• FAMILY STUDIES HAVE FOUND HIGH ODDS RATIOS FOR AFFECTED RELATIVES,FAMILY STUDIES HAVE FOUND HIGH ODDS RATIOS FOR AFFECTED RELATIVES,
UP TO 9-14.UP TO 9-14.
• RATES ARE HIGHER IN FIRST THAN IN SECOND DEGREE RELATIVES, ANDRATES ARE HIGHER IN FIRST THAN IN SECOND DEGREE RELATIVES, AND
APPROACH POPULATION RATES FOR THIRD DEGREE RELATIVES.APPROACH POPULATION RATES FOR THIRD DEGREE RELATIVES.
• FAMILIALITY SEEMS TO BE STRONGER IN THE CASE OF EARLY ONSETFAMILIALITY SEEMS TO BE STRONGER IN THE CASE OF EARLY ONSET
SCHIZOPHRENIA (DEFINED AS <25 YEARS IN GENETIC STUDIES)SCHIZOPHRENIA (DEFINED AS <25 YEARS IN GENETIC STUDIES)
• CONCORDANCE FOR MONOZYGOTIC TWINS IS 47-53%, AS OPPOSED TOCONCORDANCE FOR MONOZYGOTIC TWINS IS 47-53%, AS OPPOSED TO
AROUND 4-15% FOR DIZYGOTIC TWINSAROUND 4-15% FOR DIZYGOTIC TWINS
• RISK OF SCHIZOPHRENIA IN THE OFFSPRING OF UNAFFECTED TWINS IS EQUALRISK OF SCHIZOPHRENIA IN THE OFFSPRING OF UNAFFECTED TWINS IS EQUAL
TO THAT IN THE OFFSPRING OF AFFECTED TWINS.TO THAT IN THE OFFSPRING OF AFFECTED TWINS.
• RATES OF SCHIZOAFFECTIVE DISORDER AND OTHER NONAFFECTIVERATES OF SCHIZOAFFECTIVE DISORDER AND OTHER NONAFFECTIVE
PSYCHOSES ARE ALSO HIGHER IN TWINS.PSYCHOSES ARE ALSO HIGHER IN TWINS.
SCHIZOPHRENIASCHIZOPHRENIA
• ADOPTION STUDIES HAVE SHOWN CLOSER CONCORDANCE FORADOPTION STUDIES HAVE SHOWN CLOSER CONCORDANCE FOR
BIOLOGICAL THAN ADOPTIVE PARENTS AND RELATIVES.BIOLOGICAL THAN ADOPTIVE PARENTS AND RELATIVES.
• THERE IS SOME EVIDENCE FOR SHARED GENETIC LIABILITY TOTHERE IS SOME EVIDENCE FOR SHARED GENETIC LIABILITY TO
SCHIZOPHRENIA AND BIPOLAR DISORDER (COMMON LINKAGES AT 6Q,SCHIZOPHRENIA AND BIPOLAR DISORDER (COMMON LINKAGES AT 6Q,
10Q, 13Q AND 22Q)10Q, 13Q AND 22Q)
• THERE IS ALSO A LINK WITH PSYCHOTIC MOOD DISORDERS ANDTHERE IS ALSO A LINK WITH PSYCHOTIC MOOD DISORDERS AND
PERSONALITY DISORDERS, ESPECIALLY CLUSTER A PERSONALITY.PERSONALITY DISORDERS, ESPECIALLY CLUSTER A PERSONALITY.
GENES IMPLICATED IN SCHIZOPHRENIAGENES IMPLICATED IN SCHIZOPHRENIA
• CATECHOL O-METHYL TRANSFERASE (COMT) – 22QCATECHOL O-METHYL TRANSFERASE (COMT) – 22Q
• PROLINE DEHYDROGENASE (PRODH) – 22QPROLINE DEHYDROGENASE (PRODH) – 22Q
• NEUREGULIN (NRG1) – 8PNEUREGULIN (NRG1) – 8P
• CALCINEURIN A GAMMA (PPP3CC) – 8PCALCINEURIN A GAMMA (PPP3CC) – 8P
• DYSTROBREVIN BINDING PROTEIN – 6PDYSTROBREVIN BINDING PROTEIN – 6P
• DAAO AND G72 – EPISTASIS – 13QDAAO AND G72 – EPISTASIS – 13Q
• CHOLINERGIC ALPHA-7 RECEPTOR – 15QCHOLINERGIC ALPHA-7 RECEPTOR – 15Q
• DOPAMINE BETA-HYDROXYLASE AND NMDA RECEPTOR SUBUNIT - 9QDOPAMINE BETA-HYDROXYLASE AND NMDA RECEPTOR SUBUNIT - 9Q
• DISC GENEDISC GENE
BIPOLAR DISORDERBIPOLAR DISORDER
• FAMILY STUDIES FIND AN ODDS RATIO OF 5-10 FOR FIRST-DEGREEFAMILY STUDIES FIND AN ODDS RATIO OF 5-10 FOR FIRST-DEGREE
RELATIVES.RELATIVES.
• THIS EFFECT IS STRONGER FOR EARLY-ONSET BIPOLAR DISORDER.THIS EFFECT IS STRONGER FOR EARLY-ONSET BIPOLAR DISORDER.
• MONOZYGOTIC TWIN CONCORDANCE IS 67%, AND DIZYGOTIC TWINMONOZYGOTIC TWIN CONCORDANCE IS 67%, AND DIZYGOTIC TWIN
CONCORDANCE IS 20%CONCORDANCE IS 20%
• TWO ADOPTION STUDIES FOUND HIGHER RATES IN BIOLOGICAL PARENTS,TWO ADOPTION STUDIES FOUND HIGHER RATES IN BIOLOGICAL PARENTS,
AND NORMAL RATES IN ADOPTIVE PARENTS.AND NORMAL RATES IN ADOPTIVE PARENTS.
• LINK TO UNIPOLAR DEPRESSION IN ONE DIRECTION – BIPOLAR PROBANDSLINK TO UNIPOLAR DEPRESSION IN ONE DIRECTION – BIPOLAR PROBANDS
HAVE MORE RELATIVES WITH UNIPOLAR DISORDER, BUT NOT VICE VERSA.HAVE MORE RELATIVES WITH UNIPOLAR DISORDER, BUT NOT VICE VERSA.
• SIGNIFICANT ASSOCIATION WITH SUBSTANCE USE DISORDERS ANDSIGNIFICANT ASSOCIATION WITH SUBSTANCE USE DISORDERS AND
CONDUCT DISORDERS IN FAMILY STUDIES.CONDUCT DISORDERS IN FAMILY STUDIES.
• LINKAGE WITH SCHIZOPHRENIA / SCHIZOAFFECTIVE AS DISCUSSED ABOVE.LINKAGE WITH SCHIZOPHRENIA / SCHIZOAFFECTIVE AS DISCUSSED ABOVE.
GENES IN BIPOLAR DISORDERGENES IN BIPOLAR DISORDER
• BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) – 11PBRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) – 11P
• G-PROTEIN RECEPTOR KINASE (GSK-3) – 22QG-PROTEIN RECEPTOR KINASE (GSK-3) – 22Q
• G72 (MODULATES NMDA RECEPTORS) – 13QG72 (MODULATES NMDA RECEPTORS) – 13Q
• OTHERS – GSK-3 BETA, CLOCK GENESOTHERS – GSK-3 BETA, CLOCK GENES
DEPRESSIONDEPRESSION
DEPRESSIONDEPRESSION
• WINOKUR PROPOSED THE CONCEPT OF THE DEPRESSIVE SPECTRUM,WINOKUR PROPOSED THE CONCEPT OF THE DEPRESSIVE SPECTRUM,
INCLUDING ALCOHOLISM, ANTISOCIAL BEHAVIOUR ANDINCLUDING ALCOHOLISM, ANTISOCIAL BEHAVIOUR AND
SOMATIZATION / CONVERSION.SOMATIZATION / CONVERSION.
• ON THE WHOLE, THE HERITABILITY OF DEPRESSION IS LOWER THANON THE WHOLE, THE HERITABILITY OF DEPRESSION IS LOWER THAN
THAT OF BPAD.THAT OF BPAD.
• BPAD PROBANDS HAVE MORE RELATIVES WITH UNIPOLARBPAD PROBANDS HAVE MORE RELATIVES WITH UNIPOLAR
DEPRESSION THAN CONTROLS.DEPRESSION THAN CONTROLS.
GENES IN DEPRESSIONGENES IN DEPRESSION
• FEW IDENTIFIED:FEW IDENTIFIED:
1. BDNF ON 11P1. BDNF ON 11P
2. CYCLIC AMP RESPONSE ELEMENT BINDING PROTEIN (CREB) ON2. CYCLIC AMP RESPONSE ELEMENT BINDING PROTEIN (CREB) ON
CHROMOSOME 2CHROMOSOME 2
3. SEROTONIN TRANSPORTER (5HTT) POLYMORPHISM - 17Q3. SEROTONIN TRANSPORTER (5HTT) POLYMORPHISM - 17Q
4. MONOAMINE OXIDASE A - XP4. MONOAMINE OXIDASE A - XP
OCDOCD
PANIC DISORDERPANIC DISORDER
• FAMILIARITY SHOWN IN FAMILY STUDIES, MORE IN THE CASE OFFAMILIARITY SHOWN IN FAMILY STUDIES, MORE IN THE CASE OF
FEMALE RELATIVESFEMALE RELATIVES..
• SOME GENETIC OVERLAP WITH GENERALIZED ANXIETY DISORDER ANDSOME GENETIC OVERLAP WITH GENERALIZED ANXIETY DISORDER AND
MAJOR DEPRESSION.MAJOR DEPRESSION.
• 2-3 FOLD HIGHER CONCORDANCE IN MONOZYGOTIC TWINS2-3 FOLD HIGHER CONCORDANCE IN MONOZYGOTIC TWINS
COMPARED TO DIZYGOTIC TWINSCOMPARED TO DIZYGOTIC TWINS
• SIGNIFICANT OVERLAP WITH ALCOHOL DEPENDENCE IN FIRST-DEGREESIGNIFICANT OVERLAP WITH ALCOHOL DEPENDENCE IN FIRST-DEGREE
RELATIVES, MORE SO IN WOMEN WITH PANIC DISORDER.RELATIVES, MORE SO IN WOMEN WITH PANIC DISORDER.
ALCOHOLISMALCOHOLISM
• EARLY-ONSET ALCOHOLISM (<25 YEARS, TYPE II)EARLY-ONSET ALCOHOLISM (<25 YEARS, TYPE II) HAS A STRONG GENETICHAS A STRONG GENETIC
COMPONENT.COMPONENT.
• ASSOCIATION WITH EXTERNALIZING DISORDERS AND ADULT ANTISOCIALASSOCIATION WITH EXTERNALIZING DISORDERS AND ADULT ANTISOCIAL
BEHAVIOUR.BEHAVIOUR.
• ASSOCIATION WITH MOOD DISORDERS, BOTH UNIPOLAR AND BIPOLAR.ASSOCIATION WITH MOOD DISORDERS, BOTH UNIPOLAR AND BIPOLAR.
• TWIN AND ADOPTION STUDIES SUPPORT A GENETIC AETIOLOGY FORTWIN AND ADOPTION STUDIES SUPPORT A GENETIC AETIOLOGY FOR
ALCOHOLISM, ESPECIALLY IN MEN.ALCOHOLISM, ESPECIALLY IN MEN.
• THERE MAY BE AN INTERACTION BETWEEN GENOTYPE AND GENDER –THERE MAY BE AN INTERACTION BETWEEN GENOTYPE AND GENDER –
WOMEN REQUIRE MORE LOADINGWOMEN REQUIRE MORE LOADING
• POLYGENIC MODELS HAVE THE BEST SUPPORT.POLYGENIC MODELS HAVE THE BEST SUPPORT.
• LINKAGE TO CHROMOSOMES 1, 7 AND 2.LINKAGE TO CHROMOSOMES 1, 7 AND 2.
• POSSIBLE PROTECTIVE EFFECT OF ALCOHOL DEHYDROGENASE ONPOSSIBLE PROTECTIVE EFFECT OF ALCOHOL DEHYDROGENASE ON
CHROMOSOME 4CHROMOSOME 4
• SEROTONIN, GABA-A AND DOPAMINE RECEPTOR GENES ALSOSEROTONIN, GABA-A AND DOPAMINE RECEPTOR GENES ALSO
IMPLICATED
LIMITATIONS OF GENETIC STUDIES INLIMITATIONS OF GENETIC STUDIES IN
PSYCHIATRYPSYCHIATRY
• DIAGNOSES ARE HETEROGENOUS, AND DO NOT MATCH TO CLEARDIAGNOSES ARE HETEROGENOUS, AND DO NOT MATCH TO CLEAR
PHENOTYPESPHENOTYPES
• RELIABILITY / VALIDITY IN IDENTIFYING CASESRELIABILITY / VALIDITY IN IDENTIFYING CASES
• THE PROBLEM OF “BROAD DEFINITIONS”THE PROBLEM OF “BROAD DEFINITIONS”
• GENETIC HETEROGENEITY AND PHENOCOPIESGENETIC HETEROGENEITY AND PHENOCOPIES
• SIMPLIFYING ASSUMPTIONSSIMPLIFYING ASSUMPTIONS
• EFFECT OF POPULATION INTERBREEDING, MIGRATIONEFFECT OF POPULATION INTERBREEDING, MIGRATION
• METHODOLOGICAL ISSUES AND FLAWSMETHODOLOGICAL ISSUES AND FLAWS
• COMPLEX GENETICS – NOT FITTING INTO SIMPLE MODELSCOMPLEX GENETICS – NOT FITTING INTO SIMPLE MODELS
• GENETIC PLEIOTROPY – ONE GENE MANIFESTING IN DIFFERENT WAYSGENETIC PLEIOTROPY – ONE GENE MANIFESTING IN DIFFERENT WAYS
• OTHER EFFECTS, SUCH AS EPIGENETIC MODIFICATIONOTHER EFFECTS, SUCH AS EPIGENETIC MODIFICATION
• STATISTICAL ERRORS DUE TO MULTIPLE COMPARISONSSTATISTICAL ERRORS DUE TO MULTIPLE COMPARISONS
PHENOCOPIESPHENOCOPIES
PERVASIVE
HYPERACTIVITY
(phenotype)
ADHD
Conduct
disorder
Anxiety disorder
Learning
disability
Developmental
disorders
Abuse and PTSD
OVERCOMING HURDLESOVERCOMING HURDLES
• ONE WAY OF AVOIDING THESE PROBLEMS IS IN IDENTIFYING A “PURER”ONE WAY OF AVOIDING THESE PROBLEMS IS IN IDENTIFYING A “PURER”
AND MORE VALID AND RELIABLE PHENOTYPE.AND MORE VALID AND RELIABLE PHENOTYPE.
• IDEALLY, IT SHOULD BE MEASURABLE BY A LABORATORY TEST OR OTHERIDEALLY, IT SHOULD BE MEASURABLE BY A LABORATORY TEST OR OTHER
OBJECTIVE PROCEDURE.OBJECTIVE PROCEDURE.
• THIS “INTERMEDIATE PHENOTYPE” APPROACH GAVE RISE TO THETHIS “INTERMEDIATE PHENOTYPE” APPROACH GAVE RISE TO THE
CONCEPT OFCONCEPT OF ENDOPHENOTYPES.ENDOPHENOTYPES.
ENDOPHENOTYPESENDOPHENOTYPES
• COINED BY BERNARD JOHN AND KENNETH R. LEWIS IN A 1966 PAPER
ATTEMPTING TO EXPLAIN THE GEOGRAPHIC
DISTRIBUTION OF GRASSHOPPERS
• ENDOPHENOTYPES ARE “INTERNAL PHENOTYPES” DISCOVERABLE BY AENDOPHENOTYPES ARE “INTERNAL PHENOTYPES” DISCOVERABLE BY A
LABORATORY TEST.LABORATORY TEST.
• THEY INTERACT WITH ENVIRONMENTAL FACTORS TO PRODUCE ATHEY INTERACT WITH ENVIRONMENTAL FACTORS TO PRODUCE A
COMPLEX PHENOTYPE, OR DISORDER.COMPLEX PHENOTYPE, OR DISORDER.
• BECAUSE OF THEIR GREATER SIMPLICITY, VALIDITY AND RELIABILITY, IT ISBECAUSE OF THEIR GREATER SIMPLICITY, VALIDITY AND RELIABILITY, IT IS
EASIER TO STUDY THEM IN FAMILIES AND ASSOCIATE THEM WITHEASIER TO STUDY THEM IN FAMILIES AND ASSOCIATE THEM WITH
CANDIDATE GENES.CANDIDATE GENES.
CRITERIA FOR AN ENDOPHENOTYPECRITERIA FOR AN ENDOPHENOTYPE
(GOTTESMAN AND SHIELDS, 2003)(GOTTESMAN AND SHIELDS, 2003)
• AN ENDOPHENOTYPE MUST SEGREGATE WITH ILLNESS IN THE
POPULATION.
• AN ENDOPHENOTYPE MUST BE HERITABLE.
• AN ENDOPHENOTYPE MUST BE STATE-INDEPENDENT (I.E., MANIFESTS
WHETHER ILLNESS IS ACTIVE OR IN REMISSION).
• AN ENDOPHENOTYPE MUST CO-SEGREGATE WITH ILLNESS WITHIN
FAMILIES.
• AN ENDOPHENOTYPE MUST BE PRESENT AT A HIGHER RATE WITHIN
AFFECTED FAMILIES THAN IN THE POPULATION.
• AN ENDOPHENOTYPE MUST BE AMENABLE TO RELIABLE
MEASUREMENT, AND BE SPECIFIC TO THE ILLNESS OF INTEREST.
TYPES OF ENDOPHENOTYPETYPES OF ENDOPHENOTYPE
• STRUCTURAL ANATOMICALSTRUCTURAL ANATOMICAL
• FUNCTIONAL NEUROANATOMICALFUNCTIONAL NEUROANATOMICAL
• PHYSICAL FINDINGPHYSICAL FINDING
• BIOCHEMICALBIOCHEMICAL
• NEUROENDOCRINENEUROENDOCRINE
• NEUROPSYCHOLOGICALNEUROPSYCHOLOGICAL
EXAMPLES OF ENDOPHENOTYPESEXAMPLES OF ENDOPHENOTYPES
• SENSORY GATING ANOMALIES IN SCHIZOPHRENIA.SENSORY GATING ANOMALIES IN SCHIZOPHRENIA.
• EYE TRACKING ABNORMALITIES IN SCHIZOPHRENIA.EYE TRACKING ABNORMALITIES IN SCHIZOPHRENIA.
• NEUROPSYCHOLOGICAL DEFICITS IN BIPOLAR DISORDER,NEUROPSYCHOLOGICAL DEFICITS IN BIPOLAR DISORDER,
SCHIZOPHRENIA AND POSSIBLY OCD.SCHIZOPHRENIA AND POSSIBLY OCD.
PHARMACOGENETICS ANDPHARMACOGENETICS AND
PHARMACOGENOMICSPHARMACOGENOMICS
• PHARMACOGENETICS IS THE STUDY OF INHERITED GENETIC DIFFERENCES IN
DRUG METABOLIC PATHWAYS WHICH CAN AFFECT INDIVIDUAL RESPONSES TO
DRUGS, BOTH IN TERMS OF THERAPEUTIC EFFECT AS WELL AS ADVERSE EFFECTS.
(KLOTZ, 2007)
• PHARMACOGENOMICS IS THE STUDY OF THE ROLE OF GENETICS IN DRUG
RESPONSE. IT DEALS WITH THE INFLUENCE OF ACQUIRED AND
INHERITED GENETIC VARIATION ON DRUG RESPONSE IN PATIENTS BY
CORRELATING GENE EXPRESSION OR SINGLE-NUCLEOTIDE
POLYMORPHISMS WITH
DRUG ABSORPTION, DISTRIBUTION, METABOLISM AND ELIMINATION, AS WELL AS
DRUG RECEPTOR TARGET EFFECTS. (JOHNSON, 2003)
• PHARMACOGENETICS FOCUSES ON SINGLE DRUG-GENE INTERACTIONS, WHILE
PHARMACOGENOMICS ENCOMPASSES A MORE GENOME-WIDE ASSOCIATION
APPROACH, INCORPORATING GENOMICS AND EPIGENETICS WHILE DEALING
WITH THE EFFECTS OF MULTIPLE GENES ON DRUG RESPONSE
PHARMACOGENETICS ANDPHARMACOGENETICS AND
PHARMACOGENOMICSPHARMACOGENOMICS
• THOUGH EFFECTIVE DRUGS EXIST FOR MANY PSYCHIATRIC DISORDERS, THEY ARETHOUGH EFFECTIVE DRUGS EXIST FOR MANY PSYCHIATRIC DISORDERS, THEY ARE
NOT CURATIVE.NOT CURATIVE.
• THEIR EXACT MECHANISMS OF ACTION ARE UNCLEAR.THEIR EXACT MECHANISMS OF ACTION ARE UNCLEAR.
• RESPONSE RATES ARE GENERALLY AROUND 50-60%.RESPONSE RATES ARE GENERALLY AROUND 50-60%.
• ATTEMPTS TO PREDICT RESPONSE BASED ON CLINICAL PARAMETERS ARE NOTATTEMPTS TO PREDICT RESPONSE BASED ON CLINICAL PARAMETERS ARE NOT
ALWAYS SUCCESSFUL.ALWAYS SUCCESSFUL.
• INITIALLY, ATTENTION WAS DEVOTED TO IDENTIFYING GENETIC DIFFERENCES ININITIALLY, ATTENTION WAS DEVOTED TO IDENTIFYING GENETIC DIFFERENCES IN
DRUG METABOLISM.DRUG METABOLISM.
• LATER, THIS GENERALIZED TO FINDING GENES THAT COULD BE ASSOCIATED WITHLATER, THIS GENERALIZED TO FINDING GENES THAT COULD BE ASSOCIATED WITH
DRUG RESPONSE, OR WITH SPECIFIC ADVERSE EFFECTS.DRUG RESPONSE, OR WITH SPECIFIC ADVERSE EFFECTS.
• THE LATEST ADVANCE HAS BEEN GENOME SCANNING TO IDENTIFY THE EFFECTSTHE LATEST ADVANCE HAS BEEN GENOME SCANNING TO IDENTIFY THE EFFECTS
OF DRUGS ON GENE EXPRESSION AND PROTEIN SYNTHESISOF DRUGS ON GENE EXPRESSION AND PROTEIN SYNTHESIS
EXAMPLES OFEXAMPLES OF
PHARMACOGENETIC/GENOMIC FINDINGS:PHARMACOGENETIC/GENOMIC FINDINGS:
GENETIC COUNSELINGGENETIC COUNSELING
REFERENCESREFERENCES
• GRAFEN, ALAN; RIDLEY, MARK (2006). RICHARD DAWKINS: HOW A SCIENTIST CHANGED THE WAY WE THINK. NEW YORK, NEW YORK: OXFORDGRAFEN, ALAN; RIDLEY, MARK (2006). RICHARD DAWKINS: HOW A SCIENTIST CHANGED THE WAY WE THINK. NEW YORK, NEW YORK: OXFORD
UNIVERSITY PRESS. P. 69. ISBN 0-19-929116-0.UNIVERSITY PRESS. P. 69. ISBN 0-19-929116-0.
• WIO, S. HORACIO, DEZA, R. ROBERTO & LOPEZ, M. JUAN (2012). AN INTRODUCTION TO STOCHASTIC PROCESSES AND NONEQUILIBRIUM STATISTICALWIO, S. HORACIO, DEZA, R. ROBERTO & LOPEZ, M. JUAN (2012). AN INTRODUCTION TO STOCHASTIC PROCESSES AND NONEQUILIBRIUM STATISTICAL
PHYSICS. WORLD SCIENTIFIC PUBLISHING. ISBN 978-981-4374-78-1.PHYSICS. WORLD SCIENTIFIC PUBLISHING. ISBN 978-981-4374-78-1.
• THE ORIGIN OF SCHIZOPHRENIA: GENETIC THESIS, EPIGENETIC ANTITHESIS, AND RESOLVING SYNTHESIS.ARTURAS PETRONIS. BIOL PSYCHIATRY. 2004THE ORIGIN OF SCHIZOPHRENIA: GENETIC THESIS, EPIGENETIC ANTITHESIS, AND RESOLVING SYNTHESIS.ARTURAS PETRONIS. BIOL PSYCHIATRY. 2004
MAY 15; 55(10): 965–970. DOI: 10.1016/J.BIOPSYCH.2004.02.005MAY 15; 55(10): 965–970. DOI: 10.1016/J.BIOPSYCH.2004.02.005
• BURMEISTER M, MCINNIS MG, ZÖLLNER S (2008). "PSYCHIATRIC GENETICS: PROGRESS AMID CONTROVERSY". NAT REV GENET 9 (7): 527–40.BURMEISTER M, MCINNIS MG, ZÖLLNER S (2008). "PSYCHIATRIC GENETICS: PROGRESS AMID CONTROVERSY". NAT REV GENET 9 (7): 527–40.
DOI:10.1038/NRG2381. PMID 18560438.DOI:10.1038/NRG2381. PMID 18560438.
• GOTTESMAN II, GOULD TD (APRIL 2003). "THE ENDOPHENOTYPE CONCEPT IN PSYCHIATRY: ETYMOLOGY AND STRATEGIC INTENTIONS". AM JGOTTESMAN II, GOULD TD (APRIL 2003). "THE ENDOPHENOTYPE CONCEPT IN PSYCHIATRY: ETYMOLOGY AND STRATEGIC INTENTIONS". AM J
PSYCHIATRY 160 (4): 636–45. DOI:10.1176/APPI.AJP.160.4.636. PMID 12668349.PSYCHIATRY 160 (4): 636–45. DOI:10.1176/APPI.AJP.160.4.636. PMID 12668349.
• KLOTZ, U. (2007). "THE ROLE OF PHARMACOGENETICS IN THE METABOLISM OF ANTIEPILEPTIC DRUGS: PHARMACOKINETIC AND THERAPEUTICKLOTZ, U. (2007). "THE ROLE OF PHARMACOGENETICS IN THE METABOLISM OF ANTIEPILEPTIC DRUGS: PHARMACOKINETIC AND THERAPEUTIC
IMPLICATIONS.". CLIN PHARMACOKINET 46 (4): 271–9. DOI:10.2165/00003088-200746040-00001. PMID 17375979.IMPLICATIONS.". CLIN PHARMACOKINET 46 (4): 271–9. DOI:10.2165/00003088-200746040-00001. PMID 17375979.
• JOHNSON JA (NOVEMBER 2003). "PHARMACOGENETICS: POTENTIAL FOR INDIVIDUALIZED DRUG THERAPY THROUGH GENETICS.". TRENDS GENET 19JOHNSON JA (NOVEMBER 2003). "PHARMACOGENETICS: POTENTIAL FOR INDIVIDUALIZED DRUG THERAPY THROUGH GENETICS.". TRENDS GENET 19
(11): 660–6. DOI:10.1016/J.TIG.2003.09.008. PMID 14585618.(11): 660–6. DOI:10.1016/J.TIG.2003.09.008. PMID 14585618.
• HTTP://WWW.NSGC.ORG/ABOUT/FAQSDEFINITIONS/TABID/97/DEFAULT.ASPXHTTP://WWW.NSGC.ORG/ABOUT/FAQSDEFINITIONS/TABID/97/DEFAULT.ASPX
THANK YOUTHANK YOU

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Genetics in Psychiatry

  • 1. GENETICS IN PSYCHIATRYGENETICS IN PSYCHIATRY PRESENTER – DR. SRIRAM.R, FINAL YEAR MDPRESENTER – DR. SRIRAM.R, FINAL YEAR MD PG PSYCHIATRYPG PSYCHIATRY CHAIRPERSON – DR. R.RAJKUMAR,CHAIRPERSON – DR. R.RAJKUMAR, ASSOCIATE PROF OF PSYCHIATRYASSOCIATE PROF OF PSYCHIATRY
  • 5. GENETIC TERMS USED IN PSYCHIATRY  Concordance: the probability that a pair of individuals will both have a certain characteristic, given that one of the pair has the characteristic. For example, twins are concordant when both have or both lack a given trait. (Lewontin,1982)  Heritability: proportion of the variance of a phenotype (disease,trait) that is due to genes, estimated from risks to twins and other relatives  Mendelian disease: caused by a (usually rare) change(mutation) in DNA sequence on one(dominant) or both(recessive) of an individual’s pair of chromosomes  Complex disease: caused by an interaction of multiple genetic and/or environmental factors  Allele: A variant of the similar DNA sequence located at a given locus is called an allele.  Haplotype: collection of specific alleles in a cluster of tightly-linked genes on a chromosome that are likely to be inherited together
  • 6.  Locus: a locus (plural loci) is the specific location of a gene, DNA sequence, or position on a chromosome. Each chromosome carries many genes; humans' estimated 'haploid' protein coding genes are 20,000-25,000, on the 23 different chromosomes.  Eg. The chromosomal locus of a gene might be written "6p21.3". Because "21" refers to "region 2, band 1" this is read as "two one", not as "twenty-one". So the entire locus is "six P two one point three"
  • 7.  Genetic map: The ordered list of loci known for a particular genome is called a genetic map.   Gene mapping: Gene mapping is the process of determining the locus for a particular biological trait.  Genetic linkage is the tendency of alleles that are located close together on a chromosome to be inherited together during meiosis. Genes whose loci are nearer to each other are less likely to be separated onto different chromatids during chromosomal crossover, and are therefore said to be genetically linked. In other words, the nearer two genes are on a chromosome, the lower is the chance of a swap occurring between them, and the more likely they are to be inherited together.  Linkage disequilibrium(LD): non-random association of alleles at two or more loci that descend from single, ancestral chromosomes (Reich, 2001)  A variant that is highly correlated with a truly causal variant will show a similar statistical association to phenotype.  If the LD is widespread, many fewer markers will need to be assayed (Psychiatric GWAS consortium coordinating committee 2009)
  • 8.  Mutation is a permanent change of the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA or other genetic elements  SNP pronounced “snip”( Single nucleotide polymorphism)  DNA sequence variation occurring commonly within a population (e.g. 1%) in which a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes  Common SNPs: ≥5% frequency ~10million in the genome- targets of the GWAS  Rare SNPs: <1% frequency
  • 9.  Copy-number variations (CNVs)—a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal or, for certain genes, a normal variation in the number of copies of one or more sections of the DNA.  CNVs correspond to relatively large regions of the genome that have been deleted (fewer than the normal number) or duplicated (more than the normal number) on certain chromosomes.  For example, the chromosome that normally has sections in order as A-B-C-D might instead have sections A-B-C-C-D (a duplication of "C") or A-B-D (a deletion of "C").  This variation accounts for roughly 13% of human genomic DNA and each variation may range from about one kilobase (1,000 nucleotide bases) to several megabases in size (Pawel et al, 2010)
  • 10.  Genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS) or common-variant association study (CVAS), is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait.  GWAS typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major diseases.  compare the DNA of two groups of participants: people with the disease (cases) and similar people without (controls). Each person gives a sample of DNA, from which millions of genetic variants are read using SNP arrays.  If one type of the variant (one allele) is more frequent in people with the disease, the SNP is said to be "associated" with the disease.  A polygene, multiple factor, multiple gene inheritance, or quantitative gene is a group of non-allelic genes that together influence a phenotypic trait. The precise loci or identities of the non-allelic genes are often unknown to biologists.
  • 11.  The common disease-common variant (often abbreviated CD-CV) hypothesis predicts that common disease-causing alleles, or variants, will be found in all human populations which manifest a given disease.  Common variants (not necessarily disease-causing) are known to exist in coding and regulatory sequences of genes.  According to the CD-CV hypothesis, some of those variants lead to susceptibility to complex polygenic diseases.  Each variant at each gene influencing a complex disease will have a small additive or multiplicative effect on the disease phenotype  Pleiotropy occurs when one gene influences multiple, seemingly unrelated phenotypic traits, an example being phenylketonuria, which is a human disease that affects multiple systems but is caused by one gene defect.
  • 13. TOPICS IN PSYCHIATRIC GENETICSTOPICS IN PSYCHIATRIC GENETICS • UNDERLYING CONCEPTSUNDERLYING CONCEPTS • TECHNICAL ASPECTSTECHNICAL ASPECTS • STUDY PRINCIPLES AND METHODSSTUDY PRINCIPLES AND METHODS • FINDINGS IN INDIVIDUAL DISORDERSFINDINGS IN INDIVIDUAL DISORDERS • LIMITATIONS AND CONTROVERSIESLIMITATIONS AND CONTROVERSIES • ENDOPHENOTYPESENDOPHENOTYPES • PREDICTING RESPONSE: PHARMACOGENOMICSPREDICTING RESPONSE: PHARMACOGENOMICS • WHAT WE KNOW: GENETIC COUNSELLINGWHAT WE KNOW: GENETIC COUNSELLING
  • 14. UNDERLYING CONCEPTSUNDERLYING CONCEPTS • THE BIOPSYCHOSOCIAL HYPOTHESISTHE BIOPSYCHOSOCIAL HYPOTHESIS • GENE – ENVIRONMENT INTERACTIONGENE – ENVIRONMENT INTERACTION • MENDELIAN GENETICS AND BEYONDMENDELIAN GENETICS AND BEYOND • GENETIC MODELSGENETIC MODELS
  • 15. THE BIOPSYCHOSOCIAL HYPOTHESISTHE BIOPSYCHOSOCIAL HYPOTHESIS BIOLOGICAL CONTRIBUTION Often genetically related PSYCHOLOGICAL FACTORS Traits, coping, defenses ENVIRONMENTAL FACTORS Family, social, cultural, substances, adverse life events MENTAL ILLNESS
  • 16. GENE-ENVIRONMENT INTERACTIONGENE-ENVIRONMENT INTERACTION • THE RELATIONSHIP BETWEEN GENES AND ENVIRONMENT IS NON-THE RELATIONSHIP BETWEEN GENES AND ENVIRONMENT IS NON- LINEAR.LINEAR. • OFTEN, IT IS THE INTERACTION OF ONE OR MORE GENETICOFTEN, IT IS THE INTERACTION OF ONE OR MORE GENETIC VULNERABILITIES WITH ENVIRONMENTAL FACTORS THAT DETERMINESVULNERABILITIES WITH ENVIRONMENTAL FACTORS THAT DETERMINES ILLNESS.ILLNESS. • IN OTHER WORDS, BOTH ARE NECESSARY, BUT MAY NOT BEIN OTHER WORDS, BOTH ARE NECESSARY, BUT MAY NOT BE SUFFICIENT TO PRODUCE THE ILLNESS.SUFFICIENT TO PRODUCE THE ILLNESS.
  • 17. GENE-ENVIRONMENT INTERACTION:GENE-ENVIRONMENT INTERACTION: AN EXAMPLEAN EXAMPLE (CASPI ET AL., 2003)(CASPI ET AL., 2003) GENETIC CODE Polymorphism of the serotonin transporter (5-HTT) LIFE STRESSORS Adverse life events in early life DEPRESSION in adult life
  • 18. GENE-ENVIRONMENT INTERACTION:GENE-ENVIRONMENT INTERACTION: A MORE COMPLEX EXAMPLEA MORE COMPLEX EXAMPLE GENETIC CODE Family history of schizophrenia (Gene – COMT? NR1? CHRNA7? CNR1?) PERSONALITY schizotypal, “schizotaxia” CANNABIS USE “SELF- MEDICATION?” FIRST- EPISODE PSYCHOSIS
  • 19. OTHER EXAMPLESOTHER EXAMPLES • HPA AXIS GENES AND STRESS IN ALCOHOLISM – ACTS AS AHPA AXIS GENES AND STRESS IN ALCOHOLISM – ACTS AS A MAINTAINING FACTOR AND CAUSE FOR RELAPSEMAINTAINING FACTOR AND CAUSE FOR RELAPSE • THE DOPAMINE D2 RECEPTOR AND SEROTONIN TRANSPORTER GENES INTHE DOPAMINE D2 RECEPTOR AND SEROTONIN TRANSPORTER GENES IN PTSD – ASSOCIATED WITH VULNERABILITYPTSD – ASSOCIATED WITH VULNERABILITY • MONOAMINE OXIDASE A (MAOMONOAMINE OXIDASE A (MAOAA) GENES AND EARLY LIFE ADVERSITY –) GENES AND EARLY LIFE ADVERSITY – ASSOCIATED WITH ADULT ANTISOCIAL BEHAVIOURASSOCIATED WITH ADULT ANTISOCIAL BEHAVIOUR
  • 20. MENDELIAN GENETICSMENDELIAN GENETICS • MORE APPLICABLE TOMORE APPLICABLE TO SINGLE-GENESINGLE-GENE DISORDERSDISORDERS • PRINCIPLES OFPRINCIPLES OF DOMINANTDOMINANT ANDAND RECESSIVERECESSIVE GENESGENES • ALLELESALLELES OF A GENEOF A GENE • GENOTYPEGENOTYPE ANDAND PHENOTYPEPHENOTYPE • PRINCIPLE OFPRINCIPLE OF SEGREGATIONSEGREGATION • PRINCIPLE OFPRINCIPLE OF INDEPENDENT ASSORTMENTINDEPENDENT ASSORTMENT • COMMONLY APPLIED IN NEUROPSYCHIATRIC DISORDERSCOMMONLY APPLIED IN NEUROPSYCHIATRIC DISORDERS
  • 21. MENDELIAN DISORDERS IN PSYCHIATRYMENDELIAN DISORDERS IN PSYCHIATRY • AUTOSOMAL DOMINANTAUTOSOMAL DOMINANT HUNTINGTON'S DISEASEHUNTINGTON'S DISEASE FAMILIAL ALZHEIMER'SFAMILIAL ALZHEIMER'S • AUTOSOMAL RECESSIVEAUTOSOMAL RECESSIVE WILSON'S DISEASEWILSON'S DISEASE LYSOSOMAL DISORDERSLYSOSOMAL DISORDERS PHENYLKETONURIAPHENYLKETONURIA
  • 22. LATER MODIFICATIONS OF MENDEL'SLATER MODIFICATIONS OF MENDEL'S CONCEPTSCONCEPTS • LINKAGELINKAGE • CO-DOMINANCECO-DOMINANCE • PENETRANCEPENETRANCE • EPISTASISEPISTASIS • HARDY-WEINBERG EQUILIBRIUMHARDY-WEINBERG EQUILIBRIUM • TRINUCLEOTIDE REPEATSTRINUCLEOTIDE REPEATS ANDAND ANTICIPATIONANTICIPATION • EPIGENETICSEPIGENETICS ANDAND IMPRINTINGIMPRINTING
  • 23. LINKAGELINKAGE • AS PER MENDEL'S PRINCIPLES, GENES ARE INHERITED INDEPENDENTLYAS PER MENDEL'S PRINCIPLES, GENES ARE INHERITED INDEPENDENTLY (ONE BY ONE) AND NOT IN BLOCKS.(ONE BY ONE) AND NOT IN BLOCKS. • HOWEVER, IT HAS BEEN FOUND THAT CERTAIN TRAITS MAY BE INHERITEDHOWEVER, IT HAS BEEN FOUND THAT CERTAIN TRAITS MAY BE INHERITED TOGETHER AND NOT SHOW INDEPENDENT ASSORTMENT.TOGETHER AND NOT SHOW INDEPENDENT ASSORTMENT. • THIS IS DUE TO THEIR PROXIMITY ON THE RELEVANT SEGMENT OF THETHIS IS DUE TO THEIR PROXIMITY ON THE RELEVANT SEGMENT OF THE CHROMOSOME.CHROMOSOME. • THIS PHENOMENON IS CALLED LINKAGE.THIS PHENOMENON IS CALLED LINKAGE.
  • 24. LINKAGE DISEQUILBRIUMLINKAGE DISEQUILBRIUM • WE DO NOT KNOW WHICH GENES CAUSE PSYCHIATRIC DISORDERS.WE DO NOT KNOW WHICH GENES CAUSE PSYCHIATRIC DISORDERS. • INSTEAD, WE USE MARKERS SPACED EVENLY ALONG THE GENOTYPEINSTEAD, WE USE MARKERS SPACED EVENLY ALONG THE GENOTYPE TO LOCALIZE THEM.TO LOCALIZE THEM. • THESE MARKERS MAY BE:THESE MARKERS MAY BE: RESTRICTION FRAGMENT LENGTHRESTRICTION FRAGMENT LENGTH POLYMORPHISMS ANDPOLYMORPHISMS AND SINGLE NUCLEOTIDE POLYMORPHISMSSINGLE NUCLEOTIDE POLYMORPHISMS • MARKERS THAT ARE CLOSE TO A POSSIBLE DISEASE GENE WILL BEMARKERS THAT ARE CLOSE TO A POSSIBLE DISEASE GENE WILL BE INHERITED ALONG WITH IT – THEY SHOW LINKAGEINHERITED ALONG WITH IT – THEY SHOW LINKAGE • THIS IMPLIES THAT IF THE FREQUENCY OF A PARTICULAR MARKER ISTHIS IMPLIES THAT IF THE FREQUENCY OF A PARTICULAR MARKER IS HIGHER IN AFFECTED SUBJECTS THAN CONTROLS, A DISEASE GENEHIGHER IN AFFECTED SUBJECTS THAN CONTROLS, A DISEASE GENE MAY BE CLOSE TO IT.MAY BE CLOSE TO IT. • THIS PHENOMENON IS CALLED LINKAGE DISEQUILBRIUM, BECAUSE INTHIS PHENOMENON IS CALLED LINKAGE DISEQUILBRIUM, BECAUSE IN A NORMAL POPULATION, WE WOULD EXPECT EQUAL FREQUENCIES.A NORMAL POPULATION, WE WOULD EXPECT EQUAL FREQUENCIES.
  • 25. CO-DOMINANCECO-DOMINANCE • IN MENDEL'S MODEL, GENES EXIST AS DOMINANT AND RECESSIVE FORMSIN MENDEL'S MODEL, GENES EXIST AS DOMINANT AND RECESSIVE FORMS OR ALLELESOR ALLELES • HOWEVER, OTHER MODELS EXIST WHEREIN BOTH GENES MAY BOTH BEHOWEVER, OTHER MODELS EXIST WHEREIN BOTH GENES MAY BOTH BE EXPRESSED EQUALLY, OR AT LEAST CONCURRENTLY.EXPRESSED EQUALLY, OR AT LEAST CONCURRENTLY. • THIS PHENOMENON IS KNOWN AS CO-DOMINANCE: A COMMONTHIS PHENOMENON IS KNOWN AS CO-DOMINANCE: A COMMON EXAMPLE WOULD BE THE ABO BLOOD GROUP GENES.EXAMPLE WOULD BE THE ABO BLOOD GROUP GENES.
  • 26. PENETRANCEPENETRANCE • IN MENDEL'S MODEL, A GENE EITHER MANIFESTS AS A GIVEN PHENOTYPEIN MENDEL'S MODEL, A GENE EITHER MANIFESTS AS A GIVEN PHENOTYPE (1) OR NOT (0).(1) OR NOT (0). • HOWEVER, SOME AUTOSOMAL DOMINANT HUMAN DISORDERS SHOWHOWEVER, SOME AUTOSOMAL DOMINANT HUMAN DISORDERS SHOW MARKED VARIANCE IN PHENOTYPE, EVEN WHEN THE SAME GENE ISMARKED VARIANCE IN PHENOTYPE, EVEN WHEN THE SAME GENE IS PRESENT.PRESENT. • THIS IS KNOWN ASTHIS IS KNOWN AS PENETRANCEPENETRANCE, AND CAN CONFOUND GENETIC, AND CAN CONFOUND GENETIC STUDIES BY OBSCURING THE PATTERN OF INHERITANCE.STUDIES BY OBSCURING THE PATTERN OF INHERITANCE.
  • 27. EPISTASISEPISTASIS • SOMETIMES, MORE THAN ONE GENE MAY BE REQUIRED FOR A GIVENSOMETIMES, MORE THAN ONE GENE MAY BE REQUIRED FOR A GIVEN PHENOTYPE.PHENOTYPE. • THESE TWO GENES ARE AT DIFFERENT LOCI.THESE TWO GENES ARE AT DIFFERENT LOCI. • THEIR EFFECTS ARE INTERACTIVE, BUT NOT ADDITIVE.THEIR EFFECTS ARE INTERACTIVE, BUT NOT ADDITIVE. • IN OTHER WORDS, GENES A AND B AT DIFFERENT LOCI LEAD TOIN OTHER WORDS, GENES A AND B AT DIFFERENT LOCI LEAD TO PHENOTYPE C; NEITHER A NOR B ALONE LEAD TO C.PHENOTYPE C; NEITHER A NOR B ALONE LEAD TO C. • THIS IS KNOWN AS GENE-GENE INTERACTION, OR EPISTASIS.THIS IS KNOWN AS GENE-GENE INTERACTION, OR EPISTASIS.
  • 28. HARDY-WEINBERG EQUILIBRIUMHARDY-WEINBERG EQUILIBRIUM • SUPPOSE THAT TWO ALLELES P AND Q OF A GENE EXIST, AND THEIRSUPPOSE THAT TWO ALLELES P AND Q OF A GENE EXIST, AND THEIR RELATIVE FREQUENCIES IN A POPULATION ARERELATIVE FREQUENCIES IN A POPULATION ARE PP ANDAND Q.Q. • THE SUM OFTHE SUM OF PP ANDAND QQ IS 1.IS 1. • IT CAN BE SHOWN THAT THE FREQUENCY OF GENOTYPES IN THEIT CAN BE SHOWN THAT THE FREQUENCY OF GENOTYPES IN THE POPULATION WOULD BEPOPULATION WOULD BE PP22 + 2PQ + Q+ 2PQ + Q22 • THIS IS KNOWN ASTHIS IS KNOWN AS HARDY-WEINBERGHARDY-WEINBERG EQUILIBRIUM.EQUILIBRIUM.
  • 29. AN EXAMPLEAN EXAMPLE • CONSIDER A GENE M FOR MUSICAL TALENT.CONSIDER A GENE M FOR MUSICAL TALENT. • FORMFORM PP (MORE TALENT) IS PRESENT IN 60%(MORE TALENT) IS PRESENT IN 60% (0.6)(0.6) OF A GIVEN POPULATION.OF A GIVEN POPULATION. PP ANDAND QQ ARE CO-DOMINANT.ARE CO-DOMINANT. • Q = 1 – P = 0.4Q = 1 – P = 0.4 • IF HARDY-WEINBERG EQUILIBRIUM HOLDS, THE FREQUENCIES WOULD BE:IF HARDY-WEINBERG EQUILIBRIUM HOLDS, THE FREQUENCIES WOULD BE: PP22 : 0.36 (0.6 X 0.6) – VERY TALENTED: 0.36 (0.6 X 0.6) – VERY TALENTED 2PQ : 0.48 (2 X 0.6 X 0.4) – FAIR TALENT2PQ : 0.48 (2 X 0.6 X 0.4) – FAIR TALENT QQ22 : 0.16 (0.4 X 0.4) – LEAST TALENT: 0.16 (0.4 X 0.4) – LEAST TALENT
  • 30. ASSUMPTIONS IN THE HARDY-WEINBERGASSUMPTIONS IN THE HARDY-WEINBERG EQUILIBRIUMEQUILIBRIUM • MATING IS RANDOM – IF GOOD MUSICIANSMATING IS RANDOM – IF GOOD MUSICIANS (PP)(PP) SELECTIVELYSELECTIVELY MARRY GOOD MUSICIANSMARRY GOOD MUSICIANS (PP)(PP), THIS ASSUMPTION DOES NOT, THIS ASSUMPTION DOES NOT HOLD.HOLD. • THERE IS NO SELECTION – IF GOOD MUSICIANS HAVE ATHERE IS NO SELECTION – IF GOOD MUSICIANS HAVE A SHORTER LIFE SPAN OR REDUCED REPRODUCTIVE CAPACITY,SHORTER LIFE SPAN OR REDUCED REPRODUCTIVE CAPACITY, PPPP WOULD BE SELECTED OUT.WOULD BE SELECTED OUT. • THERE IS NO EMIGRATION – IF POOR MUSICIANS MIGRATE TOTHERE IS NO EMIGRATION – IF POOR MUSICIANS MIGRATE TO THE U.S., THE FREQUENCY OFTHE U.S., THE FREQUENCY OF QQQQ IN INDIA WOULD FALLIN INDIA WOULD FALL • THERE ARE NO MUTATIONS (FOR EXAMPLE, CREATING A NEWTHERE ARE NO MUTATIONS (FOR EXAMPLE, CREATING A NEW ALLELEALLELE RR THAT CONFERS MORE TALENT)THAT CONFERS MORE TALENT)
  • 31. TRINUCLEOTIDETRINUCLEOTIDE REPEATSREPEATS • CERTAIN GENES ARE NOTICED TO CONTAIN REPEATING SEQUENCES OFCERTAIN GENES ARE NOTICED TO CONTAIN REPEATING SEQUENCES OF TRINUCLEOTIDE BASES, SUCH AS CAG OR CGG.TRINUCLEOTIDE BASES, SUCH AS CAG OR CGG. • THE NUMBER OF THESE REPEATS AFFECTS THE FUNCTIONING OF THE GENETHE NUMBER OF THESE REPEATS AFFECTS THE FUNCTIONING OF THE GENE AND MAY LEAD TO DISEASE.AND MAY LEAD TO DISEASE. • THESE DISORDERS ARE KNOWN ASTHESE DISORDERS ARE KNOWN AS TRINUCLEOTIDE REPEAT DISORDERSTRINUCLEOTIDE REPEAT DISORDERS..
  • 32. EXAMPLES OF TRINUCLEOTIDE REPEATEXAMPLES OF TRINUCLEOTIDE REPEAT DISORDERSDISORDERS • HUNTINGTON'S DISEASE –HUNTINGTON'S DISEASE – CAG REPEATS IN THE HUNTINGTIN GENE ONCAG REPEATS IN THE HUNTINGTIN GENE ON CHROMOSOME 4.CHROMOSOME 4. • SPINOCEREBELLAR ATAXIA –SPINOCEREBELLAR ATAXIA – CAG REPEATS ON VARIOUS CHROMOSOMES (6, 12, 16)CAG REPEATS ON VARIOUS CHROMOSOMES (6, 12, 16) • FRAGILE X SYNDROME –FRAGILE X SYNDROME – CGG REPEATS ON THE LONG ARM OF CHROMOSOME X.CGG REPEATS ON THE LONG ARM OF CHROMOSOME X. • ? SCHIZOPHRENIA –? SCHIZOPHRENIA – ONE GENETIC MODEL OF SCHIZOPHRENIA INVOLVES CAGONE GENETIC MODEL OF SCHIZOPHRENIA INVOLVES CAG REPEATS AT 6P, 8P AND 22Q, AND PERHAPS OTHER AREASREPEATS AT 6P, 8P AND 22Q, AND PERHAPS OTHER AREAS
  • 33. NUMBERS AND SEVERITYNUMBERS AND SEVERITY • THE NUMBER OF REPEATS OFTEN CORRELATES WITH THE PHENOTYPE.THE NUMBER OF REPEATS OFTEN CORRELATES WITH THE PHENOTYPE. • FOR EXAMPLE, IN HUNTINGTON'S DISEASE, CLINICAL SYMPTOMSFOR EXAMPLE, IN HUNTINGTON'S DISEASE, CLINICAL SYMPTOMS USUALLY APPEAR WHEN THEREUSUALLY APPEAR WHEN THERE ARE >38 CAGARE >38 CAG REPEATS.REPEATS. • IN FRAGILE X SYNDROME,IN FRAGILE X SYNDROME, <43 CGG REPEATS ARE NORMAL, 43-200 ARE<43 CGG REPEATS ARE NORMAL, 43-200 ARE CARRIERS, AND >200 HAVE THE CLINICAL SYNDROMECARRIERS, AND >200 HAVE THE CLINICAL SYNDROME..
  • 34. ANTICIPATIONANTICIPATION • WHEN A TRINUCLEOTIDE REPEAT DISEASE GENE IS TRANSMITTED TOWHEN A TRINUCLEOTIDE REPEAT DISEASE GENE IS TRANSMITTED TO OFFSPRING, THE NUMBER OF REPEATS MAY UNDERGO EXPANSION.OFFSPRING, THE NUMBER OF REPEATS MAY UNDERGO EXPANSION. • THIS MAY BE RELATED TO THE ORIGIN OF THE GENE – IN HUNTINGTON'S,THIS MAY BE RELATED TO THE ORIGIN OF THE GENE – IN HUNTINGTON'S, PATERNAL GENES ARE MORE LIKELY TO EXPAND.PATERNAL GENES ARE MORE LIKELY TO EXPAND. • THIS LEADS TO OFFSPRING DEVELOPING THE ILLNESS AT AN EARLIER AGETHIS LEADS TO OFFSPRING DEVELOPING THE ILLNESS AT AN EARLIER AGE AND WITH GREATER SEVERITY; THIS PROCESS IS KNOWN ASAND WITH GREATER SEVERITY; THIS PROCESS IS KNOWN AS ANTICIPATIONANTICIPATION..
  • 35. EPIGENETICSEPIGENETICS • THUS FAR, WE HAVE CONSIDERED THE DNA SEQUENCE OF GENES AS BEING OFTHUS FAR, WE HAVE CONSIDERED THE DNA SEQUENCE OF GENES AS BEING OF PRIME IMPORTANCE.PRIME IMPORTANCE. • HOWEVER, GENES IN DNA EXIST IN CHROMOSOMES, ASSOCIATED WITHHOWEVER, GENES IN DNA EXIST IN CHROMOSOMES, ASSOCIATED WITH PROTEINSPROTEINS (HISTONES)(HISTONES).. • THE CHEMICAL STRUCTURE OF DNA CAN UNDERGO MODIFICATIONS, SUCH ASTHE CHEMICAL STRUCTURE OF DNA CAN UNDERGO MODIFICATIONS, SUCH AS METHYLATION, PHOSPHORYLATION, ACETYLATION, ETCMETHYLATION, PHOSPHORYLATION, ACETYLATION, ETC • THE AMINO ACIDS OF HISTONES CAN ALSO UNDERGO SUCH MODIFICATIONS.THE AMINO ACIDS OF HISTONES CAN ALSO UNDERGO SUCH MODIFICATIONS. • THESE CHANGES DOTHESE CHANGES DO NOTNOT ALTER THE SEQUENCE OF NUCLEOTIDES IN GENES.ALTER THE SEQUENCE OF NUCLEOTIDES IN GENES. • HOWEVER, THEY MAY AFFECT THE ACTIVATION AND LEVEL OF EXPRESSION OFHOWEVER, THEY MAY AFFECT THE ACTIVATION AND LEVEL OF EXPRESSION OF THE RESPECTIVE GENES.THE RESPECTIVE GENES. • THESE PROCESSES ARE COLLECTIVELY CALLEDTHESE PROCESSES ARE COLLECTIVELY CALLED EPIGENETIC MODIFICATIONSEPIGENETIC MODIFICATIONS,, AND SHARE CERTAIN INTERESTING PROPERTIESAND SHARE CERTAIN INTERESTING PROPERTIES
  • 36. EPIGENETICS .VS. “CLASSICAL” GENETICSEPIGENETICS .VS. “CLASSICAL” GENETICS • MAINTAINED IN SOMATIC CELL REPLICATIONMAINTAINED IN SOMATIC CELL REPLICATION • MAYMAY BE MAINTAINED DURING MEIOSIS, OR MODIFIED, OR COMPLETELYBE MAINTAINED DURING MEIOSIS, OR MODIFIED, OR COMPLETELY REMOVEDREMOVED • SUBJECT TO RANDOM ORSUBJECT TO RANDOM OR STOCHASTICSTOCHASTIC EFFECTSEFFECTS • MODIFIABLE BY ENVIRONMENTAL FACTORS, SUCH AS NUTRITION,MODIFIABLE BY ENVIRONMENTAL FACTORS, SUCH AS NUTRITION, SUBSTANCES OR HORMONESSUBSTANCES OR HORMONES • MODIFICATIONSMODIFICATIONS (EPIMUTATIONS)(EPIMUTATIONS) MAY “REGRESS TO THE MEAN” WITHMAY “REGRESS TO THE MEAN” WITH AGEAGE
  • 37. AN EPIGENETIC MODEL OFAN EPIGENETIC MODEL OF SCHIZOPHRENIASCHIZOPHRENIA (PETRONIS, 2004)(PETRONIS, 2004)
  • 38. PHENOMENA THAT MAY BE EXPLAINED BYPHENOMENA THAT MAY BE EXPLAINED BY EPIGENETICS IN PSYCHOSISEPIGENETICS IN PSYCHOSIS • FAMILIAL AND SPORADIC CASESFAMILIAL AND SPORADIC CASES • DISCORDANCE IN MONOZYGOTIC TWINSDISCORDANCE IN MONOZYGOTIC TWINS • COURSE AND RESOLUTION OF THE ILLNESSCOURSE AND RESOLUTION OF THE ILLNESS • EFFECTS OF GENDEREFFECTS OF GENDER • PERSISTENCE OF THE ILLNESS DESPITE EVOLUTIONARYPERSISTENCE OF THE ILLNESS DESPITE EVOLUTIONARY DISADVANTAGESDISADVANTAGES • NON-REPLICABILITY OF “CLASSICAL” STUDIESNON-REPLICABILITY OF “CLASSICAL” STUDIES • ANTICIPATION AND PARENT-OF-ORIGIN EFFECTSANTICIPATION AND PARENT-OF-ORIGIN EFFECTS
  • 39. IMPRINTINGIMPRINTING  PATERNAL AND MATERNAL COPIES OF THE SAME GENE UNDERGOPATERNAL AND MATERNAL COPIES OF THE SAME GENE UNDERGO EPIGENETIC MODIFICATIONS.EPIGENETIC MODIFICATIONS.  THIS PROCESS IS CALLEDTHIS PROCESS IS CALLED IMPRINTINGIMPRINTING, AND LEADS TO DIFFERENTIAL, AND LEADS TO DIFFERENTIAL EXPRESSION OF GENES IN THE OFFSPRING DEPENDING ON WHICHEXPRESSION OF GENES IN THE OFFSPRING DEPENDING ON WHICH COPY IS INHERITED.COPY IS INHERITED.  THIS CAN LEAD TO DIFFERENCES IN ILLNESS EXPRESSION – E.G.THIS CAN LEAD TO DIFFERENCES IN ILLNESS EXPRESSION – E.G. PRADER-WILLIPRADER-WILLI ANDAND ANGELMANANGELMAN SYNDROMES HAVE THE SAMESYNDROMES HAVE THE SAME GENETIC MUTATION, BUT DIFFERENT SYMPTOMSGENETIC MUTATION, BUT DIFFERENT SYMPTOMS
  • 40. GENETIC MODELSGENETIC MODELS • MENDELIANMENDELIAN • MENDELIANMENDELIAN WITH VARIABLE PENETRANCEWITH VARIABLE PENETRANCE • MENDELIANMENDELIAN WITHWITH IMPRINTINGIMPRINTING • OLIGOGENIC –OLIGOGENIC – A SMALL NUMBER OF KEY GENES INTERACTINGA SMALL NUMBER OF KEY GENES INTERACTING • MIXED –MIXED – A SINGLE MAJOR GENE + OLIGOGENESA SINGLE MAJOR GENE + OLIGOGENES • POLYGENIC –POLYGENIC – MULTIPLE GENES OF SMALL EFFECTMULTIPLE GENES OF SMALL EFFECT
  • 42. TECHNIQUES UTILIZED IN GENETIC STUDIESTECHNIQUES UTILIZED IN GENETIC STUDIES • CLEAVAGE OF DNA AT SPECIFIC SITES BYCLEAVAGE OF DNA AT SPECIFIC SITES BY RESTRICTIONRESTRICTION ENDONUCLEASESENDONUCLEASES • USINGUSING MARKERS –MARKERS – RFLPS, SNPS, TRINUCLEOTIDE REPEATSRFLPS, SNPS, TRINUCLEOTIDE REPEATS • HYBRIDIZATIONHYBRIDIZATION OF MARKERS AND COMPLEMENTARY SEQUENCES –OF MARKERS AND COMPLEMENTARY SEQUENCES – FLUORESCENT, IMMUNE, ETC.FLUORESCENT, IMMUNE, ETC. • KARYOTYPINGKARYOTYPING AND OTHER CYTOGENETIC METHODSAND OTHER CYTOGENETIC METHODS • EXAMINING SEQUENCES OF DNA THAT HAVE BEEN CONSERVEDEXAMINING SEQUENCES OF DNA THAT HAVE BEEN CONSERVED EVOLUTIONARILY, OREVOLUTIONARILY, OR HAPLOTYPESHAPLOTYPES
  • 43. TECHNIQUES UTILIZED IN GENETIC STUDIESTECHNIQUES UTILIZED IN GENETIC STUDIES • THETHE POLYMERASE CHAIN REACTIONPOLYMERASE CHAIN REACTION – USING BACTERIAL DNA– USING BACTERIAL DNA POLYMERASE TO AMPLIFY SEQUENCESPOLYMERASE TO AMPLIFY SEQUENCES • RECOMBINANT DNA TECHNOLOGYRECOMBINANT DNA TECHNOLOGY TO EXAMINE GENE EXPRESSIONTO EXAMINE GENE EXPRESSION AND PRODUCTSAND PRODUCTS • KNOCK-OUTKNOCK-OUT ANDAND TRANSGENICTRANSGENIC ANIMAL MODELS TO STUDY THEANIMAL MODELS TO STUDY THE EFFECTS OF A SINGLE GENE OR GENE PRODUCTEFFECTS OF A SINGLE GENE OR GENE PRODUCT • USING THE MAP OF THE HUMAN GENOME FROM THEUSING THE MAP OF THE HUMAN GENOME FROM THE HUMANHUMAN GENOME PROJECTGENOME PROJECT • MICRO-ARRAYMICRO-ARRAY TECHNIQUES, WHICH USE SEMICONDUCTORTECHNIQUES, WHICH USE SEMICONDUCTOR TECHNIQUES OR ROBOTICS TO AMPLIFY AND EXAMINE MARKERS,TECHNIQUES OR ROBOTICS TO AMPLIFY AND EXAMINE MARKERS, AND TO MEASURE MRNA LEVELSAND TO MEASURE MRNA LEVELS • POSTMORTEMPOSTMORTEM STUDIES ON HUMAN BRAINSSTUDIES ON HUMAN BRAINS • NEWER STATISTICAL METHODS -NEWER STATISTICAL METHODS - BIOINFORMATICSBIOINFORMATICS
  • 44. CLASSICAL PSYCHIATRIC GENETICSCLASSICAL PSYCHIATRIC GENETICS DOES THE DISORDER RUN IN FAMILIES? Family studies – establish familiality IS FAMILIALITY DUE TO GENES OR THE ENVIRONMENT? Twin studies – examine concordance rates in twin pairs HOW MUCH DO GENES AND THE ENVIRONMENT CONTRIBUTE? Adoption studies – separate genetic and environmental contributions WHICH GENES ARE INVOLVED? Linkage and association studies HOW DO THE GENES PRODUCE THE DISEASE? Molecular genetics
  • 45. MORE RECENT CONCEPTSMORE RECENT CONCEPTS • ENDOPHENOTYPE APPROACHESENDOPHENOTYPE APPROACHES • ANIMAL MODELS – KNOCKOUT MICE, ETC.ANIMAL MODELS – KNOCKOUT MICE, ETC. • PHARMACOGENETICS AND PHARMACOGENOMICSPHARMACOGENETICS AND PHARMACOGENOMICS
  • 46. THE FIRST STEP: FAMILY STUDIESTHE FIRST STEP: FAMILY STUDIES • FAMILY STUDIES ESTABLISH THAT A GIVEN DISORDER RUNS IN FAMILIES.FAMILY STUDIES ESTABLISH THAT A GIVEN DISORDER RUNS IN FAMILIES. • HOWEVER, THEY DO NOT DIRECTLY SHOW WHETHER THIS IS DUE TOHOWEVER, THEY DO NOT DIRECTLY SHOW WHETHER THIS IS DUE TO GENES OR ENVIRONMENTAL FACTORS.GENES OR ENVIRONMENTAL FACTORS. • IN FAMILY STUDIES, AFFECTED INDIVIDUALSIN FAMILY STUDIES, AFFECTED INDIVIDUALS (PROBANDS)(PROBANDS) ARE SELECTED,ARE SELECTED, AND THEIR FAMILIES ARE EXAMINED FOR A GIVEN DISORDER.AND THEIR FAMILIES ARE EXAMINED FOR A GIVEN DISORDER. • THEIR RATES OF THE DISORDER ARE THEN COMPARED WITH EITHER ATHEIR RATES OF THE DISORDER ARE THEN COMPARED WITH EITHER A CONTROL GROUP OR THE POPULATION.CONTROL GROUP OR THE POPULATION.
  • 47. TWO TYPES OF FAMILY STUDIESTWO TYPES OF FAMILY STUDIES • FAMILY HISTORY METHOD:FAMILY HISTORY METHOD: THE PROBAND ISTHE PROBAND IS INTERVIEWED, AND INFORMATION ABOUT MENTALINTERVIEWED, AND INFORMATION ABOUT MENTAL ILLNESS IN RELATIVES IS COLLECTED. SIMPLER, BUT LESSILLNESS IN RELATIVES IS COLLECTED. SIMPLER, BUT LESS RELIABLE; UNDERESTIMATES TRUE RATES.RELIABLE; UNDERESTIMATES TRUE RATES. • FAMILY STUDY METHOD:FAMILY STUDY METHOD: ALL AVAILABLE RELATIVES AREALL AVAILABLE RELATIVES ARE INTERVIEWED DIRECTLY. TIME-CONSUMING, BUT MOREINTERVIEWED DIRECTLY. TIME-CONSUMING, BUT MORE RELIABLE.RELIABLE.
  • 48. GENETIC DISTANCEGENETIC DISTANCE • FAMILY STUDIES CANNOT DIRECTLY GIVE ESTIMATES OF GENETICFAMILY STUDIES CANNOT DIRECTLY GIVE ESTIMATES OF GENETIC CONTRIBUTIONS.CONTRIBUTIONS. • HOWEVER, IF THE RATE OF DISORDERS FALLS AS THE AMOUNT OFHOWEVER, IF THE RATE OF DISORDERS FALLS AS THE AMOUNT OF SHARED DNA BETWEEN RELATIVES DECREASES (INCREASEDSHARED DNA BETWEEN RELATIVES DECREASES (INCREASED GENETICGENETIC DISTANCEDISTANCE), A GENETIC COMPONENT IS LIKELY.), A GENETIC COMPONENT IS LIKELY. • A FAMILY STUDY OF OCD FOUND RATES OF 7% IN FIRST-DEGREEA FAMILY STUDY OF OCD FOUND RATES OF 7% IN FIRST-DEGREE RELATIVES, AND 2% IN SECOND-DEGREE RELATIVES.RELATIVES, AND 2% IN SECOND-DEGREE RELATIVES. • THE POPULATION RATE IS 2-3%.THE POPULATION RATE IS 2-3%. • THIS SUGGESTS THAT:THIS SUGGESTS THAT: 1. OCD IS FAMILIAL.1. OCD IS FAMILIAL. 2. A GENETIC CONTRIBUTION IS LIKELY.2. A GENETIC CONTRIBUTION IS LIKELY.
  • 49. TWIN STUDIESTWIN STUDIES • MONOZYGOTIC (MZ) TWINS SHARE 100% GENETIC MATERIAL, WHILE DIZYGOTICMONOZYGOTIC (MZ) TWINS SHARE 100% GENETIC MATERIAL, WHILE DIZYGOTIC (DZ) TWINS SHARE AS MUCH AS BROTHERS OR SISTERS (50%)(DZ) TWINS SHARE AS MUCH AS BROTHERS OR SISTERS (50%) • CONCORDANCECONCORDANCE IS DEFINED AS THE POSSIBILITY THAT BOTH MEMBERS OF AIS DEFINED AS THE POSSIBILITY THAT BOTH MEMBERS OF A TWIN PAIR WILL HAVE THE DISORDER BEING STUDIED.TWIN PAIR WILL HAVE THE DISORDER BEING STUDIED. • IT IS ASSUMED THAT MZ AND DZ TWINS GROW UP IN SIMILAR ENVIRONMENTSIT IS ASSUMED THAT MZ AND DZ TWINS GROW UP IN SIMILAR ENVIRONMENTS (THE(THE “EQUAL-ENVIRONMENT ASSUMPTION”“EQUAL-ENVIRONMENT ASSUMPTION”)) • IF A DISORDER IS DETERMINED BY ENVIRONMENTAL FACTORS, CONCORDANCEIF A DISORDER IS DETERMINED BY ENVIRONMENTAL FACTORS, CONCORDANCE RATES IN MZ AND DZ TWINS SHOULD BE SIMILAR.RATES IN MZ AND DZ TWINS SHOULD BE SIMILAR. • ON THE OTHER HAND, IF IT IS GENETICALLY DETERMINED, CONCORDANCEON THE OTHER HAND, IF IT IS GENETICALLY DETERMINED, CONCORDANCE SHOULD BE MORE IN MZ THAN IN DZ TWINS.SHOULD BE MORE IN MZ THAN IN DZ TWINS. • THE EXTENT OF CONCORDANCE PROVIDES AN ESTIMATE OF THE GENETICTHE EXTENT OF CONCORDANCE PROVIDES AN ESTIMATE OF THE GENETIC CONTRIBUTION.CONTRIBUTION.
  • 50. AN EXAMPLE OF TWIN STUDIESAN EXAMPLE OF TWIN STUDIES • A STUDY FINDS THAT THE CONCORDANCE FOR BIPOLAR DISORDER INA STUDY FINDS THAT THE CONCORDANCE FOR BIPOLAR DISORDER IN MZ TWINS IS 60%, AND IN DZ TWINS 20%MZ TWINS IS 60%, AND IN DZ TWINS 20% • THIS INDICATES THAT GENETIC FACTORS ARE LIKELY MORE IMPORTANTTHIS INDICATES THAT GENETIC FACTORS ARE LIKELY MORE IMPORTANT (NUMERICALLY) THAN ENVIRONMENTAL FACTORS IN BIPOLAR(NUMERICALLY) THAN ENVIRONMENTAL FACTORS IN BIPOLAR DISORDER.DISORDER. • HOWEVER, THE <100% CONCORDANCE INDICATES THAT THERE IS STILLHOWEVER, THE <100% CONCORDANCE INDICATES THAT THERE IS STILL A 40% CONTRIBUTION FROM ENVIRONMENTAL FACTORS.A 40% CONTRIBUTION FROM ENVIRONMENTAL FACTORS.
  • 51. ADOPTION STUDIESADOPTION STUDIES • ADOPTION STUDIES BROADLY SEEK TO DETERMINE WHETHER HEREDITY (NATURE)ADOPTION STUDIES BROADLY SEEK TO DETERMINE WHETHER HEREDITY (NATURE) OR ENVIRONMENT (NURTURE) ARE MORE IMPORTANT IN A GIVEN DISORDER.OR ENVIRONMENT (NURTURE) ARE MORE IMPORTANT IN A GIVEN DISORDER. • THEY RELY ON THE ASSUMPTION OFTHEY RELY ON THE ASSUMPTION OF “NO SELECTIVE PLACEMENT”“NO SELECTIVE PLACEMENT” - THAT IS, THAT- THAT IS, THAT THE ENVIRONMENT PROVIDED BY ADOPTIVE PARENTS IS ONLY RANDOMLYTHE ENVIRONMENT PROVIDED BY ADOPTIVE PARENTS IS ONLY RANDOMLY SIMILAR TO THAT OF THE BIOLOGICAL PARENTS.SIMILAR TO THAT OF THE BIOLOGICAL PARENTS. • CONSIDER TWO GROUPS OF ADOPTED CHILDREN, NAMED A AND B.CONSIDER TWO GROUPS OF ADOPTED CHILDREN, NAMED A AND B. • GROUP A ARE CHILDREN OF PATIENTS WITH A GIVEN DISORDER (SAYGROUP A ARE CHILDREN OF PATIENTS WITH A GIVEN DISORDER (SAY DEPRESSION).DEPRESSION). • GROUP B ARE CHILDREN WHOSE ADOPTIVE PARENTS HAVE THE GIVENGROUP B ARE CHILDREN WHOSE ADOPTIVE PARENTS HAVE THE GIVEN DISORDER, OR CONTROLS.DISORDER, OR CONTROLS. • WE NOW COMPARE THE RATES OF DEPRESSION IN GROUPS A AND B, AS WELLWE NOW COMPARE THE RATES OF DEPRESSION IN GROUPS A AND B, AS WELL AS THE AGREEMENT BETWEEN THEIR DIAGNOSES AND THOSE OF BIOLOGICALAS THE AGREEMENT BETWEEN THEIR DIAGNOSES AND THOSE OF BIOLOGICAL AND ADOPTED PARENTS.AND ADOPTED PARENTS.
  • 52. ADOPTION STUDIESADOPTION STUDIES • IN OUR EXAMPLE, GROUP A HAVE A (PRESUMED) GENETIC LIABILITYIN OUR EXAMPLE, GROUP A HAVE A (PRESUMED) GENETIC LIABILITY TO DEPRESSION, BUT NO ENVIRONMENTAL LOADING.TO DEPRESSION, BUT NO ENVIRONMENTAL LOADING. • THE OPPOSITE HOLDS GOOD FOR GROUP B.THE OPPOSITE HOLDS GOOD FOR GROUP B. • MEASURING THE RATES OF THE DISORDER IN GROUPS WOULD GIVEMEASURING THE RATES OF THE DISORDER IN GROUPS WOULD GIVE US A MEASURE OF WHETHER ENVIRONMENTAL OR GENETICUS A MEASURE OF WHETHER ENVIRONMENTAL OR GENETIC VULNERABILITY PLAYS A GREATER ROLE.VULNERABILITY PLAYS A GREATER ROLE.
  • 53. AN EXAMPLE OF ADOPTION STUDYAN EXAMPLE OF ADOPTION STUDY • A STUDY IS DONE EXAMINING 50 CHILDREN OF ALCOHOLICS WHOA STUDY IS DONE EXAMINING 50 CHILDREN OF ALCOHOLICS WHO ARE ADOPTED, AND 50 CHILDREN WHOSE ADOPTIVE PARENTS HAVEARE ADOPTED, AND 50 CHILDREN WHOSE ADOPTIVE PARENTS HAVE ALCOHOLISM.ALCOHOLISM. • THE STUDY FINDS THAT RATES OF ALCOHOLISM ARE 12% IN THE FIRSTTHE STUDY FINDS THAT RATES OF ALCOHOLISM ARE 12% IN THE FIRST GROUP, AND 6% IN THE SECOND GROUP.GROUP, AND 6% IN THE SECOND GROUP. • THE GREATER AGREEMENT WITH THE BIOLOGICAL PARENTS'THE GREATER AGREEMENT WITH THE BIOLOGICAL PARENTS' DIAGNOSIS POINTS TO A GENETIC COMPONENT.DIAGNOSIS POINTS TO A GENETIC COMPONENT.
  • 54. FINDING THE GENESFINDING THE GENES • ONCE THE FAMILIALITY AND GENETIC COMPONENT OF A GIVEN DISORDER AREONCE THE FAMILIALITY AND GENETIC COMPONENT OF A GIVEN DISORDER ARE ESTABLISHED, THE GENE OR GENES RESPONSIBLE MUST BE IDENTIFIED.ESTABLISHED, THE GENE OR GENES RESPONSIBLE MUST BE IDENTIFIED. • THIS IS DONE BY MEANS OF FOUR METHODS:THIS IS DONE BY MEANS OF FOUR METHODS: 1. LINKAGE ANALYSIS1. LINKAGE ANALYSIS 2. ASSOCIATION ANALYSIS2. ASSOCIATION ANALYSIS 3. CANDIDATE GENE ANALYSIS3. CANDIDATE GENE ANALYSIS 4. CYTOGENETIC ANALYSIS4. CYTOGENETIC ANALYSIS
  • 57. NONPARAMETRIC LINKAGE STUDIESNONPARAMETRIC LINKAGE STUDIES • ALSO KNOWN AS THE AFFECTED SIBLING PAIR (ASP)ALSO KNOWN AS THE AFFECTED SIBLING PAIR (ASP) METHODMETHOD • IN THIS DISORDER, THE FREQUENCY WITH WHICH THEIN THIS DISORDER, THE FREQUENCY WITH WHICH THE GIVEN GENETIC MARKER IS INHERITED FROM A PARENTGIVEN GENETIC MARKER IS INHERITED FROM A PARENT IS MEASURED.IS MEASURED. • IF THIS FREQUENCY EXCEEDS 50% IN AFFECTED PAIRSIF THIS FREQUENCY EXCEEDS 50% IN AFFECTED PAIRS OF SIBLINGS, LINKAGE IS LIKELY (I.E. THE DISEASE GENEOF SIBLINGS, LINKAGE IS LIKELY (I.E. THE DISEASE GENE AND THE INHERITED MARKER ARE IN LINKAGE.)AND THE INHERITED MARKER ARE IN LINKAGE.)
  • 58. ASSOCIATION STUDIESASSOCIATION STUDIES • SIMPLER THAN LINKAGE STUDIES.SIMPLER THAN LINKAGE STUDIES. • IN THIS METHOD, THE FREQUENCY OF MARKERS IS COMPARED ININ THIS METHOD, THE FREQUENCY OF MARKERS IS COMPARED IN AFFECTED AND UNAFFECTED SUBJECTS.AFFECTED AND UNAFFECTED SUBJECTS. • A CHI-SQUARE TEST IS USED TO COMPARE FREQUENCIES OF THE MARKERA CHI-SQUARE TEST IS USED TO COMPARE FREQUENCIES OF THE MARKER IN BOTH GROUPS, AND THE RELATIVE RISK CAN BE CALCULATED.IN BOTH GROUPS, AND THE RELATIVE RISK CAN BE CALCULATED. • IN SUCH STUDIES, POPULATIONS MUST IDEALLY BE AS GENETICALLYIN SUCH STUDIES, POPULATIONS MUST IDEALLY BE AS GENETICALLY HOMOGENEOUS AS POSSIBLE.HOMOGENEOUS AS POSSIBLE.
  • 59. HOW DO WE FIND THE GENES ONCEHOW DO WE FIND THE GENES ONCE LINKAGE IS ESTABLISHED?LINKAGE IS ESTABLISHED? • USE A CANDIDATE APPROACH – THAT IS, CONCENTRATE ON THOSEUSE A CANDIDATE APPROACH – THAT IS, CONCENTRATE ON THOSE MARKERS CLOSE TO GENES THAT MAY BE RELEVANT.MARKERS CLOSE TO GENES THAT MAY BE RELEVANT. • IF THESE ARE NOT KNOWN, SYSTEMATICALLY SEARCH THE REGION CLOSEIF THESE ARE NOT KNOWN, SYSTEMATICALLY SEARCH THE REGION CLOSE TO THE MARKER.TO THE MARKER. • IDEALLY, AN ENTIRE GENOME SCAN FOR LINKAGE DISEQUILIBRIUMIDEALLY, AN ENTIRE GENOME SCAN FOR LINKAGE DISEQUILIBRIUM SHOULD BE DONE – THIS IS TIME-CONSUMING, BUT MODERNSHOULD BE DONE – THIS IS TIME-CONSUMING, BUT MODERN TECHNOLOGIES HELP.TECHNOLOGIES HELP.
  • 60. CANDIDATE GENE STUDIESCANDIDATE GENE STUDIES  IN THESE STUDIES, GENES THAT CODE FOR PROTEINS BELIEVED TO BEIN THESE STUDIES, GENES THAT CODE FOR PROTEINS BELIEVED TO BE IMPORTANT IN A GIVEN DISORDER ARE STUDIED IN AFFECTED ANDIMPORTANT IN A GIVEN DISORDER ARE STUDIED IN AFFECTED AND UNAFFECTED PATIENTS.UNAFFECTED PATIENTS.  SINCE THE PATHOPHYSIOLOGY OF PSYCHIATRIC ILLNESS IS NOTSINCE THE PATHOPHYSIOLOGY OF PSYCHIATRIC ILLNESS IS NOT GENERALLY KNOWN, THESE GENES HAVE TO BE “GUESSED AT” - E.GGENERALLY KNOWN, THESE GENES HAVE TO BE “GUESSED AT” - E.G DOPAMINE RECEPTORS IN SCHIZOPHRENIA.DOPAMINE RECEPTORS IN SCHIZOPHRENIA.  COMPARING FREQUENCIES OF DIFFERENT GENE POLYMORPHISMS MAYCOMPARING FREQUENCIES OF DIFFERENT GENE POLYMORPHISMS MAY SHOW ASSOCIATIONS BETWEEN A GENE AND A GIVEN DISORDERSHOW ASSOCIATIONS BETWEEN A GENE AND A GIVEN DISORDER..  IF ONE POLYMORPHISM IS MORE THEN SUSPECT A CANDIDATE.IF ONE POLYMORPHISM IS MORE THEN SUSPECT A CANDIDATE.
  • 61. CYTOGENETIC STUDIESCYTOGENETIC STUDIES • THESE ARE USED WHEN DISORDERS IN CHROMOSOME NUMBER ORTHESE ARE USED WHEN DISORDERS IN CHROMOSOME NUMBER OR STRUCTURE ARE SUSPECTED.STRUCTURE ARE SUSPECTED. • THEY ARE MORE USEFUL IN STUDYINGTHEY ARE MORE USEFUL IN STUDYING INHERITED NEUROPSYCHIATRICINHERITED NEUROPSYCHIATRIC SYNDROMESSYNDROMES WHERE ANEUPLOIDY OR STRUCTURAL DEFICITS AREWHERE ANEUPLOIDY OR STRUCTURAL DEFICITS ARE DIAGNOSTICDIAGNOSTIC • EXAMPLES: DOWN'S SYNDROME, TURNER'S SYNDROME, FRAGILE XEXAMPLES: DOWN'S SYNDROME, TURNER'S SYNDROME, FRAGILE X SYNDROMESYNDROME
  • 62. FINDINGS IN COMMON DISORDERSFINDINGS IN COMMON DISORDERS • SCHIZOPHRENIASCHIZOPHRENIA • BIPOLAR DISORDERBIPOLAR DISORDER • DEPRESSIONDEPRESSION • OCDOCD • PANIC DISORDERPANIC DISORDER • ALCOHOL DEPENDENCE SYNDROMEALCOHOL DEPENDENCE SYNDROME
  • 63. GENETIC CONTRIBUTIONS ACROSSGENETIC CONTRIBUTIONS ACROSS DISORDERSDISORDERS (MERIKANGAS AND RISCH, 2003)(MERIKANGAS AND RISCH, 2003)
  • 64. HERITABILITY ESTIMATES FOR COMMONHERITABILITY ESTIMATES FOR COMMON DISORDERSDISORDERS (HILL AND SAHHAR, 2006)(HILL AND SAHHAR, 2006)
  • 66. SCHIZOPHRENIASCHIZOPHRENIA • FAMILY STUDIES HAVE FOUND HIGH ODDS RATIOS FOR AFFECTED RELATIVES,FAMILY STUDIES HAVE FOUND HIGH ODDS RATIOS FOR AFFECTED RELATIVES, UP TO 9-14.UP TO 9-14. • RATES ARE HIGHER IN FIRST THAN IN SECOND DEGREE RELATIVES, ANDRATES ARE HIGHER IN FIRST THAN IN SECOND DEGREE RELATIVES, AND APPROACH POPULATION RATES FOR THIRD DEGREE RELATIVES.APPROACH POPULATION RATES FOR THIRD DEGREE RELATIVES. • FAMILIALITY SEEMS TO BE STRONGER IN THE CASE OF EARLY ONSETFAMILIALITY SEEMS TO BE STRONGER IN THE CASE OF EARLY ONSET SCHIZOPHRENIA (DEFINED AS <25 YEARS IN GENETIC STUDIES)SCHIZOPHRENIA (DEFINED AS <25 YEARS IN GENETIC STUDIES) • CONCORDANCE FOR MONOZYGOTIC TWINS IS 47-53%, AS OPPOSED TOCONCORDANCE FOR MONOZYGOTIC TWINS IS 47-53%, AS OPPOSED TO AROUND 4-15% FOR DIZYGOTIC TWINSAROUND 4-15% FOR DIZYGOTIC TWINS • RISK OF SCHIZOPHRENIA IN THE OFFSPRING OF UNAFFECTED TWINS IS EQUALRISK OF SCHIZOPHRENIA IN THE OFFSPRING OF UNAFFECTED TWINS IS EQUAL TO THAT IN THE OFFSPRING OF AFFECTED TWINS.TO THAT IN THE OFFSPRING OF AFFECTED TWINS. • RATES OF SCHIZOAFFECTIVE DISORDER AND OTHER NONAFFECTIVERATES OF SCHIZOAFFECTIVE DISORDER AND OTHER NONAFFECTIVE PSYCHOSES ARE ALSO HIGHER IN TWINS.PSYCHOSES ARE ALSO HIGHER IN TWINS.
  • 67. SCHIZOPHRENIASCHIZOPHRENIA • ADOPTION STUDIES HAVE SHOWN CLOSER CONCORDANCE FORADOPTION STUDIES HAVE SHOWN CLOSER CONCORDANCE FOR BIOLOGICAL THAN ADOPTIVE PARENTS AND RELATIVES.BIOLOGICAL THAN ADOPTIVE PARENTS AND RELATIVES. • THERE IS SOME EVIDENCE FOR SHARED GENETIC LIABILITY TOTHERE IS SOME EVIDENCE FOR SHARED GENETIC LIABILITY TO SCHIZOPHRENIA AND BIPOLAR DISORDER (COMMON LINKAGES AT 6Q,SCHIZOPHRENIA AND BIPOLAR DISORDER (COMMON LINKAGES AT 6Q, 10Q, 13Q AND 22Q)10Q, 13Q AND 22Q) • THERE IS ALSO A LINK WITH PSYCHOTIC MOOD DISORDERS ANDTHERE IS ALSO A LINK WITH PSYCHOTIC MOOD DISORDERS AND PERSONALITY DISORDERS, ESPECIALLY CLUSTER A PERSONALITY.PERSONALITY DISORDERS, ESPECIALLY CLUSTER A PERSONALITY.
  • 68. GENES IMPLICATED IN SCHIZOPHRENIAGENES IMPLICATED IN SCHIZOPHRENIA • CATECHOL O-METHYL TRANSFERASE (COMT) – 22QCATECHOL O-METHYL TRANSFERASE (COMT) – 22Q • PROLINE DEHYDROGENASE (PRODH) – 22QPROLINE DEHYDROGENASE (PRODH) – 22Q • NEUREGULIN (NRG1) – 8PNEUREGULIN (NRG1) – 8P • CALCINEURIN A GAMMA (PPP3CC) – 8PCALCINEURIN A GAMMA (PPP3CC) – 8P • DYSTROBREVIN BINDING PROTEIN – 6PDYSTROBREVIN BINDING PROTEIN – 6P • DAAO AND G72 – EPISTASIS – 13QDAAO AND G72 – EPISTASIS – 13Q • CHOLINERGIC ALPHA-7 RECEPTOR – 15QCHOLINERGIC ALPHA-7 RECEPTOR – 15Q • DOPAMINE BETA-HYDROXYLASE AND NMDA RECEPTOR SUBUNIT - 9QDOPAMINE BETA-HYDROXYLASE AND NMDA RECEPTOR SUBUNIT - 9Q • DISC GENEDISC GENE
  • 69. BIPOLAR DISORDERBIPOLAR DISORDER • FAMILY STUDIES FIND AN ODDS RATIO OF 5-10 FOR FIRST-DEGREEFAMILY STUDIES FIND AN ODDS RATIO OF 5-10 FOR FIRST-DEGREE RELATIVES.RELATIVES. • THIS EFFECT IS STRONGER FOR EARLY-ONSET BIPOLAR DISORDER.THIS EFFECT IS STRONGER FOR EARLY-ONSET BIPOLAR DISORDER. • MONOZYGOTIC TWIN CONCORDANCE IS 67%, AND DIZYGOTIC TWINMONOZYGOTIC TWIN CONCORDANCE IS 67%, AND DIZYGOTIC TWIN CONCORDANCE IS 20%CONCORDANCE IS 20% • TWO ADOPTION STUDIES FOUND HIGHER RATES IN BIOLOGICAL PARENTS,TWO ADOPTION STUDIES FOUND HIGHER RATES IN BIOLOGICAL PARENTS, AND NORMAL RATES IN ADOPTIVE PARENTS.AND NORMAL RATES IN ADOPTIVE PARENTS. • LINK TO UNIPOLAR DEPRESSION IN ONE DIRECTION – BIPOLAR PROBANDSLINK TO UNIPOLAR DEPRESSION IN ONE DIRECTION – BIPOLAR PROBANDS HAVE MORE RELATIVES WITH UNIPOLAR DISORDER, BUT NOT VICE VERSA.HAVE MORE RELATIVES WITH UNIPOLAR DISORDER, BUT NOT VICE VERSA. • SIGNIFICANT ASSOCIATION WITH SUBSTANCE USE DISORDERS ANDSIGNIFICANT ASSOCIATION WITH SUBSTANCE USE DISORDERS AND CONDUCT DISORDERS IN FAMILY STUDIES.CONDUCT DISORDERS IN FAMILY STUDIES. • LINKAGE WITH SCHIZOPHRENIA / SCHIZOAFFECTIVE AS DISCUSSED ABOVE.LINKAGE WITH SCHIZOPHRENIA / SCHIZOAFFECTIVE AS DISCUSSED ABOVE.
  • 70. GENES IN BIPOLAR DISORDERGENES IN BIPOLAR DISORDER • BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) – 11PBRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) – 11P • G-PROTEIN RECEPTOR KINASE (GSK-3) – 22QG-PROTEIN RECEPTOR KINASE (GSK-3) – 22Q • G72 (MODULATES NMDA RECEPTORS) – 13QG72 (MODULATES NMDA RECEPTORS) – 13Q • OTHERS – GSK-3 BETA, CLOCK GENESOTHERS – GSK-3 BETA, CLOCK GENES
  • 72. DEPRESSIONDEPRESSION • WINOKUR PROPOSED THE CONCEPT OF THE DEPRESSIVE SPECTRUM,WINOKUR PROPOSED THE CONCEPT OF THE DEPRESSIVE SPECTRUM, INCLUDING ALCOHOLISM, ANTISOCIAL BEHAVIOUR ANDINCLUDING ALCOHOLISM, ANTISOCIAL BEHAVIOUR AND SOMATIZATION / CONVERSION.SOMATIZATION / CONVERSION. • ON THE WHOLE, THE HERITABILITY OF DEPRESSION IS LOWER THANON THE WHOLE, THE HERITABILITY OF DEPRESSION IS LOWER THAN THAT OF BPAD.THAT OF BPAD. • BPAD PROBANDS HAVE MORE RELATIVES WITH UNIPOLARBPAD PROBANDS HAVE MORE RELATIVES WITH UNIPOLAR DEPRESSION THAN CONTROLS.DEPRESSION THAN CONTROLS.
  • 73. GENES IN DEPRESSIONGENES IN DEPRESSION • FEW IDENTIFIED:FEW IDENTIFIED: 1. BDNF ON 11P1. BDNF ON 11P 2. CYCLIC AMP RESPONSE ELEMENT BINDING PROTEIN (CREB) ON2. CYCLIC AMP RESPONSE ELEMENT BINDING PROTEIN (CREB) ON CHROMOSOME 2CHROMOSOME 2 3. SEROTONIN TRANSPORTER (5HTT) POLYMORPHISM - 17Q3. SEROTONIN TRANSPORTER (5HTT) POLYMORPHISM - 17Q 4. MONOAMINE OXIDASE A - XP4. MONOAMINE OXIDASE A - XP
  • 75. PANIC DISORDERPANIC DISORDER • FAMILIARITY SHOWN IN FAMILY STUDIES, MORE IN THE CASE OFFAMILIARITY SHOWN IN FAMILY STUDIES, MORE IN THE CASE OF FEMALE RELATIVESFEMALE RELATIVES.. • SOME GENETIC OVERLAP WITH GENERALIZED ANXIETY DISORDER ANDSOME GENETIC OVERLAP WITH GENERALIZED ANXIETY DISORDER AND MAJOR DEPRESSION.MAJOR DEPRESSION. • 2-3 FOLD HIGHER CONCORDANCE IN MONOZYGOTIC TWINS2-3 FOLD HIGHER CONCORDANCE IN MONOZYGOTIC TWINS COMPARED TO DIZYGOTIC TWINSCOMPARED TO DIZYGOTIC TWINS • SIGNIFICANT OVERLAP WITH ALCOHOL DEPENDENCE IN FIRST-DEGREESIGNIFICANT OVERLAP WITH ALCOHOL DEPENDENCE IN FIRST-DEGREE RELATIVES, MORE SO IN WOMEN WITH PANIC DISORDER.RELATIVES, MORE SO IN WOMEN WITH PANIC DISORDER.
  • 76. ALCOHOLISMALCOHOLISM • EARLY-ONSET ALCOHOLISM (<25 YEARS, TYPE II)EARLY-ONSET ALCOHOLISM (<25 YEARS, TYPE II) HAS A STRONG GENETICHAS A STRONG GENETIC COMPONENT.COMPONENT. • ASSOCIATION WITH EXTERNALIZING DISORDERS AND ADULT ANTISOCIALASSOCIATION WITH EXTERNALIZING DISORDERS AND ADULT ANTISOCIAL BEHAVIOUR.BEHAVIOUR. • ASSOCIATION WITH MOOD DISORDERS, BOTH UNIPOLAR AND BIPOLAR.ASSOCIATION WITH MOOD DISORDERS, BOTH UNIPOLAR AND BIPOLAR. • TWIN AND ADOPTION STUDIES SUPPORT A GENETIC AETIOLOGY FORTWIN AND ADOPTION STUDIES SUPPORT A GENETIC AETIOLOGY FOR ALCOHOLISM, ESPECIALLY IN MEN.ALCOHOLISM, ESPECIALLY IN MEN. • THERE MAY BE AN INTERACTION BETWEEN GENOTYPE AND GENDER –THERE MAY BE AN INTERACTION BETWEEN GENOTYPE AND GENDER – WOMEN REQUIRE MORE LOADINGWOMEN REQUIRE MORE LOADING • POLYGENIC MODELS HAVE THE BEST SUPPORT.POLYGENIC MODELS HAVE THE BEST SUPPORT. • LINKAGE TO CHROMOSOMES 1, 7 AND 2.LINKAGE TO CHROMOSOMES 1, 7 AND 2. • POSSIBLE PROTECTIVE EFFECT OF ALCOHOL DEHYDROGENASE ONPOSSIBLE PROTECTIVE EFFECT OF ALCOHOL DEHYDROGENASE ON CHROMOSOME 4CHROMOSOME 4 • SEROTONIN, GABA-A AND DOPAMINE RECEPTOR GENES ALSOSEROTONIN, GABA-A AND DOPAMINE RECEPTOR GENES ALSO IMPLICATED
  • 77. LIMITATIONS OF GENETIC STUDIES INLIMITATIONS OF GENETIC STUDIES IN PSYCHIATRYPSYCHIATRY • DIAGNOSES ARE HETEROGENOUS, AND DO NOT MATCH TO CLEARDIAGNOSES ARE HETEROGENOUS, AND DO NOT MATCH TO CLEAR PHENOTYPESPHENOTYPES • RELIABILITY / VALIDITY IN IDENTIFYING CASESRELIABILITY / VALIDITY IN IDENTIFYING CASES • THE PROBLEM OF “BROAD DEFINITIONS”THE PROBLEM OF “BROAD DEFINITIONS” • GENETIC HETEROGENEITY AND PHENOCOPIESGENETIC HETEROGENEITY AND PHENOCOPIES • SIMPLIFYING ASSUMPTIONSSIMPLIFYING ASSUMPTIONS • EFFECT OF POPULATION INTERBREEDING, MIGRATIONEFFECT OF POPULATION INTERBREEDING, MIGRATION • METHODOLOGICAL ISSUES AND FLAWSMETHODOLOGICAL ISSUES AND FLAWS • COMPLEX GENETICS – NOT FITTING INTO SIMPLE MODELSCOMPLEX GENETICS – NOT FITTING INTO SIMPLE MODELS • GENETIC PLEIOTROPY – ONE GENE MANIFESTING IN DIFFERENT WAYSGENETIC PLEIOTROPY – ONE GENE MANIFESTING IN DIFFERENT WAYS • OTHER EFFECTS, SUCH AS EPIGENETIC MODIFICATIONOTHER EFFECTS, SUCH AS EPIGENETIC MODIFICATION • STATISTICAL ERRORS DUE TO MULTIPLE COMPARISONSSTATISTICAL ERRORS DUE TO MULTIPLE COMPARISONS
  • 79. OVERCOMING HURDLESOVERCOMING HURDLES • ONE WAY OF AVOIDING THESE PROBLEMS IS IN IDENTIFYING A “PURER”ONE WAY OF AVOIDING THESE PROBLEMS IS IN IDENTIFYING A “PURER” AND MORE VALID AND RELIABLE PHENOTYPE.AND MORE VALID AND RELIABLE PHENOTYPE. • IDEALLY, IT SHOULD BE MEASURABLE BY A LABORATORY TEST OR OTHERIDEALLY, IT SHOULD BE MEASURABLE BY A LABORATORY TEST OR OTHER OBJECTIVE PROCEDURE.OBJECTIVE PROCEDURE. • THIS “INTERMEDIATE PHENOTYPE” APPROACH GAVE RISE TO THETHIS “INTERMEDIATE PHENOTYPE” APPROACH GAVE RISE TO THE CONCEPT OFCONCEPT OF ENDOPHENOTYPES.ENDOPHENOTYPES.
  • 80. ENDOPHENOTYPESENDOPHENOTYPES • COINED BY BERNARD JOHN AND KENNETH R. LEWIS IN A 1966 PAPER ATTEMPTING TO EXPLAIN THE GEOGRAPHIC DISTRIBUTION OF GRASSHOPPERS • ENDOPHENOTYPES ARE “INTERNAL PHENOTYPES” DISCOVERABLE BY AENDOPHENOTYPES ARE “INTERNAL PHENOTYPES” DISCOVERABLE BY A LABORATORY TEST.LABORATORY TEST. • THEY INTERACT WITH ENVIRONMENTAL FACTORS TO PRODUCE ATHEY INTERACT WITH ENVIRONMENTAL FACTORS TO PRODUCE A COMPLEX PHENOTYPE, OR DISORDER.COMPLEX PHENOTYPE, OR DISORDER. • BECAUSE OF THEIR GREATER SIMPLICITY, VALIDITY AND RELIABILITY, IT ISBECAUSE OF THEIR GREATER SIMPLICITY, VALIDITY AND RELIABILITY, IT IS EASIER TO STUDY THEM IN FAMILIES AND ASSOCIATE THEM WITHEASIER TO STUDY THEM IN FAMILIES AND ASSOCIATE THEM WITH CANDIDATE GENES.CANDIDATE GENES.
  • 81. CRITERIA FOR AN ENDOPHENOTYPECRITERIA FOR AN ENDOPHENOTYPE (GOTTESMAN AND SHIELDS, 2003)(GOTTESMAN AND SHIELDS, 2003) • AN ENDOPHENOTYPE MUST SEGREGATE WITH ILLNESS IN THE POPULATION. • AN ENDOPHENOTYPE MUST BE HERITABLE. • AN ENDOPHENOTYPE MUST BE STATE-INDEPENDENT (I.E., MANIFESTS WHETHER ILLNESS IS ACTIVE OR IN REMISSION). • AN ENDOPHENOTYPE MUST CO-SEGREGATE WITH ILLNESS WITHIN FAMILIES. • AN ENDOPHENOTYPE MUST BE PRESENT AT A HIGHER RATE WITHIN AFFECTED FAMILIES THAN IN THE POPULATION. • AN ENDOPHENOTYPE MUST BE AMENABLE TO RELIABLE MEASUREMENT, AND BE SPECIFIC TO THE ILLNESS OF INTEREST.
  • 82. TYPES OF ENDOPHENOTYPETYPES OF ENDOPHENOTYPE • STRUCTURAL ANATOMICALSTRUCTURAL ANATOMICAL • FUNCTIONAL NEUROANATOMICALFUNCTIONAL NEUROANATOMICAL • PHYSICAL FINDINGPHYSICAL FINDING • BIOCHEMICALBIOCHEMICAL • NEUROENDOCRINENEUROENDOCRINE • NEUROPSYCHOLOGICALNEUROPSYCHOLOGICAL
  • 83. EXAMPLES OF ENDOPHENOTYPESEXAMPLES OF ENDOPHENOTYPES • SENSORY GATING ANOMALIES IN SCHIZOPHRENIA.SENSORY GATING ANOMALIES IN SCHIZOPHRENIA. • EYE TRACKING ABNORMALITIES IN SCHIZOPHRENIA.EYE TRACKING ABNORMALITIES IN SCHIZOPHRENIA. • NEUROPSYCHOLOGICAL DEFICITS IN BIPOLAR DISORDER,NEUROPSYCHOLOGICAL DEFICITS IN BIPOLAR DISORDER, SCHIZOPHRENIA AND POSSIBLY OCD.SCHIZOPHRENIA AND POSSIBLY OCD.
  • 84. PHARMACOGENETICS ANDPHARMACOGENETICS AND PHARMACOGENOMICSPHARMACOGENOMICS • PHARMACOGENETICS IS THE STUDY OF INHERITED GENETIC DIFFERENCES IN DRUG METABOLIC PATHWAYS WHICH CAN AFFECT INDIVIDUAL RESPONSES TO DRUGS, BOTH IN TERMS OF THERAPEUTIC EFFECT AS WELL AS ADVERSE EFFECTS. (KLOTZ, 2007) • PHARMACOGENOMICS IS THE STUDY OF THE ROLE OF GENETICS IN DRUG RESPONSE. IT DEALS WITH THE INFLUENCE OF ACQUIRED AND INHERITED GENETIC VARIATION ON DRUG RESPONSE IN PATIENTS BY CORRELATING GENE EXPRESSION OR SINGLE-NUCLEOTIDE POLYMORPHISMS WITH DRUG ABSORPTION, DISTRIBUTION, METABOLISM AND ELIMINATION, AS WELL AS DRUG RECEPTOR TARGET EFFECTS. (JOHNSON, 2003) • PHARMACOGENETICS FOCUSES ON SINGLE DRUG-GENE INTERACTIONS, WHILE PHARMACOGENOMICS ENCOMPASSES A MORE GENOME-WIDE ASSOCIATION APPROACH, INCORPORATING GENOMICS AND EPIGENETICS WHILE DEALING WITH THE EFFECTS OF MULTIPLE GENES ON DRUG RESPONSE
  • 85. PHARMACOGENETICS ANDPHARMACOGENETICS AND PHARMACOGENOMICSPHARMACOGENOMICS • THOUGH EFFECTIVE DRUGS EXIST FOR MANY PSYCHIATRIC DISORDERS, THEY ARETHOUGH EFFECTIVE DRUGS EXIST FOR MANY PSYCHIATRIC DISORDERS, THEY ARE NOT CURATIVE.NOT CURATIVE. • THEIR EXACT MECHANISMS OF ACTION ARE UNCLEAR.THEIR EXACT MECHANISMS OF ACTION ARE UNCLEAR. • RESPONSE RATES ARE GENERALLY AROUND 50-60%.RESPONSE RATES ARE GENERALLY AROUND 50-60%. • ATTEMPTS TO PREDICT RESPONSE BASED ON CLINICAL PARAMETERS ARE NOTATTEMPTS TO PREDICT RESPONSE BASED ON CLINICAL PARAMETERS ARE NOT ALWAYS SUCCESSFUL.ALWAYS SUCCESSFUL. • INITIALLY, ATTENTION WAS DEVOTED TO IDENTIFYING GENETIC DIFFERENCES ININITIALLY, ATTENTION WAS DEVOTED TO IDENTIFYING GENETIC DIFFERENCES IN DRUG METABOLISM.DRUG METABOLISM. • LATER, THIS GENERALIZED TO FINDING GENES THAT COULD BE ASSOCIATED WITHLATER, THIS GENERALIZED TO FINDING GENES THAT COULD BE ASSOCIATED WITH DRUG RESPONSE, OR WITH SPECIFIC ADVERSE EFFECTS.DRUG RESPONSE, OR WITH SPECIFIC ADVERSE EFFECTS. • THE LATEST ADVANCE HAS BEEN GENOME SCANNING TO IDENTIFY THE EFFECTSTHE LATEST ADVANCE HAS BEEN GENOME SCANNING TO IDENTIFY THE EFFECTS OF DRUGS ON GENE EXPRESSION AND PROTEIN SYNTHESISOF DRUGS ON GENE EXPRESSION AND PROTEIN SYNTHESIS
  • 86. EXAMPLES OFEXAMPLES OF PHARMACOGENETIC/GENOMIC FINDINGS:PHARMACOGENETIC/GENOMIC FINDINGS:
  • 88. REFERENCESREFERENCES • GRAFEN, ALAN; RIDLEY, MARK (2006). RICHARD DAWKINS: HOW A SCIENTIST CHANGED THE WAY WE THINK. NEW YORK, NEW YORK: OXFORDGRAFEN, ALAN; RIDLEY, MARK (2006). RICHARD DAWKINS: HOW A SCIENTIST CHANGED THE WAY WE THINK. NEW YORK, NEW YORK: OXFORD UNIVERSITY PRESS. P. 69. ISBN 0-19-929116-0.UNIVERSITY PRESS. P. 69. ISBN 0-19-929116-0. • WIO, S. HORACIO, DEZA, R. ROBERTO & LOPEZ, M. JUAN (2012). AN INTRODUCTION TO STOCHASTIC PROCESSES AND NONEQUILIBRIUM STATISTICALWIO, S. HORACIO, DEZA, R. ROBERTO & LOPEZ, M. JUAN (2012). AN INTRODUCTION TO STOCHASTIC PROCESSES AND NONEQUILIBRIUM STATISTICAL PHYSICS. WORLD SCIENTIFIC PUBLISHING. ISBN 978-981-4374-78-1.PHYSICS. WORLD SCIENTIFIC PUBLISHING. ISBN 978-981-4374-78-1. • THE ORIGIN OF SCHIZOPHRENIA: GENETIC THESIS, EPIGENETIC ANTITHESIS, AND RESOLVING SYNTHESIS.ARTURAS PETRONIS. BIOL PSYCHIATRY. 2004THE ORIGIN OF SCHIZOPHRENIA: GENETIC THESIS, EPIGENETIC ANTITHESIS, AND RESOLVING SYNTHESIS.ARTURAS PETRONIS. BIOL PSYCHIATRY. 2004 MAY 15; 55(10): 965–970. DOI: 10.1016/J.BIOPSYCH.2004.02.005MAY 15; 55(10): 965–970. DOI: 10.1016/J.BIOPSYCH.2004.02.005 • BURMEISTER M, MCINNIS MG, ZÖLLNER S (2008). "PSYCHIATRIC GENETICS: PROGRESS AMID CONTROVERSY". NAT REV GENET 9 (7): 527–40.BURMEISTER M, MCINNIS MG, ZÖLLNER S (2008). "PSYCHIATRIC GENETICS: PROGRESS AMID CONTROVERSY". NAT REV GENET 9 (7): 527–40. DOI:10.1038/NRG2381. PMID 18560438.DOI:10.1038/NRG2381. PMID 18560438. • GOTTESMAN II, GOULD TD (APRIL 2003). "THE ENDOPHENOTYPE CONCEPT IN PSYCHIATRY: ETYMOLOGY AND STRATEGIC INTENTIONS". AM JGOTTESMAN II, GOULD TD (APRIL 2003). "THE ENDOPHENOTYPE CONCEPT IN PSYCHIATRY: ETYMOLOGY AND STRATEGIC INTENTIONS". AM J PSYCHIATRY 160 (4): 636–45. DOI:10.1176/APPI.AJP.160.4.636. PMID 12668349.PSYCHIATRY 160 (4): 636–45. DOI:10.1176/APPI.AJP.160.4.636. PMID 12668349. • KLOTZ, U. (2007). "THE ROLE OF PHARMACOGENETICS IN THE METABOLISM OF ANTIEPILEPTIC DRUGS: PHARMACOKINETIC AND THERAPEUTICKLOTZ, U. (2007). "THE ROLE OF PHARMACOGENETICS IN THE METABOLISM OF ANTIEPILEPTIC DRUGS: PHARMACOKINETIC AND THERAPEUTIC IMPLICATIONS.". CLIN PHARMACOKINET 46 (4): 271–9. DOI:10.2165/00003088-200746040-00001. PMID 17375979.IMPLICATIONS.". CLIN PHARMACOKINET 46 (4): 271–9. DOI:10.2165/00003088-200746040-00001. PMID 17375979. • JOHNSON JA (NOVEMBER 2003). "PHARMACOGENETICS: POTENTIAL FOR INDIVIDUALIZED DRUG THERAPY THROUGH GENETICS.". TRENDS GENET 19JOHNSON JA (NOVEMBER 2003). "PHARMACOGENETICS: POTENTIAL FOR INDIVIDUALIZED DRUG THERAPY THROUGH GENETICS.". TRENDS GENET 19 (11): 660–6. DOI:10.1016/J.TIG.2003.09.008. PMID 14585618.(11): 660–6. DOI:10.1016/J.TIG.2003.09.008. PMID 14585618. • HTTP://WWW.NSGC.ORG/ABOUT/FAQSDEFINITIONS/TABID/97/DEFAULT.ASPXHTTP://WWW.NSGC.ORG/ABOUT/FAQSDEFINITIONS/TABID/97/DEFAULT.ASPX