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Genetics in schizophrenia

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Genetics in schizophrenia

  1. 1. 16/1/2012
  2. 2. GENETICS IN SCHIZOPHRENIA 6/1/2012 2
  3. 3.  Rationale for genetic study in Schizophrenia Common definitions Sub-fields in genetics Family studies Twin studies Adoption studies Linkage studies Association studies and GWAS Chromosomal aberrations and CNVs Challenges and future of genetics in schizophrenia Take home message GENETICS IN SCHIZOPHRENIA 6/1/2012 3
  4. 4.  SCZ- schizophrenia MZ- monozygotic DZ- dizygotic GWAS- Genome-wide Association Studies LD- Linkage Disequilibrium ISC- International Schizophrenia Consortium MGS- Molecular Genetics of Schizophrenia SGENE- Schizophrenia Genetics Consortium GENETICS IN SCHIZOPHRENIA 6/1/2012 4
  5. 5.  Overall, psychiatric diseases are › First-rank public health problems › Cause enormous morbidity, mortality and personal/societal cost › Mostly idiopathic › Despite considerable research, little known for certain about the disease etiology Genetic knowledge of SCZ › Can give a definite biological basis for distinguishing affected from non-affected (Sullivan 2010)  Can guide for newer treatments GENETICS IN SCHIZOPHRENIA 6/1/2012 5
  6. 6.  Concordance: proportion of co-twins who are also affected or the proportion of twin pairs where both twins are affected 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 GENETICS IN SCHIZOPHRENIA 6/1/2012 6
  7. 7.  Complex disease: caused by an interaction of multiple genetic and/or environmental factors Linkage disequilibrium(LD): nonrandom association of alleles at the adjacent loci › 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) GENETICS IN SCHIZOPHRENIA 6/1/2012 7
  8. 8.  SNP “snips”( Single nucleotide polymorphism): specific position(among 3.2billion in the genome) where chromosomes carry different nucleic acids Common SNPs: ≥5% frequency ~10million in the genome- targets of the GWAS Rare SNPs: <1% frequency Copy number variant(CNV): chromosomal segment where DNA has been deleted or duplicated GENETICS IN SCHIZOPHRENIA 6/1/2012 8
  9. 9.  Genomewide Association Study(GWAS): a systematic search for the common SNPs that influence a disease or trait, using a genomewide SNP array for typing a cohort of individuals Common-disease common-variant hypothesis: many different common SNPs have small effects on each disease Pleiotropy: The single gene controlling or influencing multiple (and possibly unrelated) phenotypic traits. GENETICS IN SCHIZOPHRENIA 6/1/2012 9
  10. 10.  Biochemical genetics: biochemical reactions by which genetic determinants are replicated and produce their effects Developmental genetics: how the expression of normal genes controls growth and developmental processes Molecular genetics: structure and functioning of genes at molecular level. Cytogenetics: chromosomes GENETICS IN SCHIZOPHRENIA 6/1/2012 10
  11. 11.  Population genetics: mathematical properties of genetic transmission in families and populations- evolutionary genetics, genetic demography, quantitative genetics, genetic epidemiology Quantitative genetics: goal is to partition the observed variation of phenotypes into genetic and environmental components Genetic epidemiology: understanding the causes, distribution and control of disease in groups of relatives and the multifactorial causes of disease in populations GENETICS IN SCHIZOPHRENIA 6/1/2012 11
  12. 12. 12GENETICS IN SCHIZOPHRENIA 6/1/2012
  13. 13.  FAMILY STUDIES TWIN STUDIES ADOPTION STUDIES LINKAGE STUDIES ASSOCIATION STUDIES GENOMEWIDE ASSOCIATION STUDIES CHROMOSOMAL ABERRATIONS AND COPY NUMBER VARIANTS GENETICS IN SCHIZOPHRENIA 6/1/2012 13
  14. 14. 14GENETICS IN SCHIZOPHRENIA 6/1/2012
  15. 15.  Study of families of probands to see if the relatives of the probands have increased risk of developing the disease Ernst Rudin(1916): first systematic family study Other prominent researchers: Edith Zerbin-Rudin, Irving I. Gottesman, Franz Kallmann, Manfred Bleuler GENETICS IN SCHIZOPHRENIA 6/1/2012 15
  16. 16.  Data showed the familial basis of schizophrenia with increased risk of developing schizophrenia in the relatives of schizophrenic patients Bezugsziffer: an age-adjusted size of the sample which takes into account the fact that younger persons have not passed through the full period of risk- traditionally 15-39yrs Average lifetime prevalence risk of 10% in siblings and children GENETICS IN SCHIZOPHRENIA 6/1/2012 16
  17. 17. GENETICS IN SCHIZOPHRENIA 6/1/2012 17
  18. 18.  General population:  Siblings(parents well): 1% 9.6% First cousins,  Siblings(one parent uncles/aunts: 2.4% schizophrenic): 16.7% Nephew/nieces: 3%  Children: 12.8% Grandchildren: 3.7%  Children with both Half siblings: 4.2% parents Parents: 5.6% schizophrenic: 46.3% All siblings: 10.1% (Kirov G 2009) GENETICS IN SCHIZOPHRENIA 6/1/2012 18
  19. 19.  Lower risk among parents explained by the reduced reproductive fitness associated with schizophrenia and the possibility of de novo mutations causing the illness in the offspring* Earlier studies questioned on the methodological grounds: no control groups, diagnoses not made blind, no structured interviews or operationalized diagnostic criteria used GENETICS IN SCHIZOPHRENIA 6/1/2012 19
  20. 20. GENETICS IN SCHIZOPHRENIA 20 ((Kirov G,2009)6/1/2012
  21. 21.  No major difference in the findings of newer studies as compared to that of older ones Significant difference for parents(5.6% in older ones vs. 2.3% in newer) could be due to application of more stringent diagnostic criteria* Confirmed the higher risk of SCZ in the relatives of the probands but did not delineate the role of shared genetic or environmental factors in this difference GENETICS IN SCHIZOPHRENIA 6/1/2012 21
  22. 22. 22GENETICS IN SCHIZOPHRENIA 6/1/2012
  23. 23.  Compare the concordance rates in Monozygotic(MZ) and Dizygotic(DZ) twins MZ twins share all their genes while DZ twins share on average 50% of their genes Principle: assuming twins share common environment, › higher concordance in MZ twins than in DZ implies genetic origin › Concordance of less than 100% in MZ twins indicate the role of environment GENETICS IN SCHIZOPHRENIA 6/1/2012 23
  24. 24.  Allow for the estimation of: › Proportion of variance due to shared environmental factors(c2)- › Proportion of variance due to non-shared environmental effects(e2) [shared environment- the effects of those non-genetic factors that make both twins more likely to have similar phenotypes] [non-shared environment- the effects of factors that make twins different] GENETICS IN SCHIZOPHRENIA 6/1/2012 24
  25. 25.  Pairwise concordance: simply the number of concordant pairs divided by the total number of pairs Probandwise concordance: each of the concordant twin is counted i.e. the pair is counted twice and is ascertained by › number of affected co-twins/ the number of probands › Gives the risk for the twin of a person suffering from SCZ to become ill him/her-self › Preferred by geneticists- technically more correct and directly comparable to population risks reported in family studies GENETICS IN SCHIZOPHRENIA 6/1/2012 25
  26. 26. (Kirov G,2009)GENETICS IN SCHIZOPHRENIA 6/1/2012 26
  27. 27.  Probandwise concordance in MZ twins: 25%(n=8)(Essen-Moller,1970) 78%(n=245)(Kallmann,1946) Probandwise concordance in same-sex DZ twins: 0%(n=50)(Cardno,1998)- 28% (n=25)(Franzek and Beckmann,1998) Heritability: 41%- 90%- very similar estimates with both the methodologically superior and inferior studies(Sullivan) GENETICS IN SCHIZOPHRENIA 6/1/2012 27
  28. 28.  Meta-analyses of heritability: › Sullivan- 81% (Sullivan, 2007) › Cardno and Gottesmann- 88% (Cardno, 2000) High agreement between studies conducted in different countries over nearly a century Calculation based on assumptions: › Polygenic multifactorial threshold model › Similar risk of SCZ in twins as in general population › DZ and MZ twins share similar environment GENETICS IN SCHIZOPHRENIA 6/1/2012 28
  29. 29.  Identical twins reared apart: theoretically nullifies the effects of shared environment › 9/14( Gottesmann and Shields)=64% Possible explanations for the discordance in MZ twins: › Affected co-twin suffers from an environmentally determined form of the disorder › Both twins inherited the same genetic liability but only expressed in the affected twin Explained by the study of risk in the offspring of discordant SCZ twins GENETICS IN SCHIZOPHRENIA 6/1/2012 29
  30. 30.  First study › 11 SCZ twins, 47 offspring with 6 developing SCZ 16.8% › 6 unaffected twins, 24 offspring with 4 developing SCZ 17.4% Second study › 28 offspring of SCZ twins with 3 developing SCZ 10.7% › 45 offspring of unaffected twins with 1 developing SCZ 2.2% Combined: › risk among offspring of SCZ twins, 9/75=12% › Risk among offspring of unaffected, 5/69= 7.2% (P=0.38)no significant difference similar morbidity risk consistent with unexpressed risk (Kirov , 2009) GENETICS IN SCHIZOPHRENIA 6/1/2012 30
  31. 31. 31GENETICS IN SCHIZOPHRENIA 6/1/2012
  32. 32.  Allow dissection of genetic from environmental contributions in ways that twin studies cannot Principle: › if there is a genetic component to the disorder, the similarity between the adopted children and their biological parents should be higher than the similarity between adopted children and their adoptive parents › Adoption itself does not increase the risk for developing SCZ among adopted children GENETICS IN SCHIZOPHRENIA 6/1/2012 32
  33. 33.  Leonard Heston, 1966: › 47 adopted children of mothers suffering from SCZ and other psychoses, separated within 3days of birth- by age 36, 5 developed SCZ(10.6%) › None out of 50 children in the control group had SCZ David Rosenthal, 1971: › Studied 5500 adoptees › 14/52(26.9%) children of SCZ parents had SCZ- spectrum d/o › 12/67 control(17.9%) had illness of similar spectrum (Kirov, 2009) GENETICS IN SCHIZOPHRENIA 6/1/2012 33
  34. 34.  M. W. Higgins, 1976: › 50 children of SCZ mothers › 4/23(17.9%) children reared by SCZ mothers had SCZ › Of 25 children adopted away, 4(16%) SCZ Seymour S. Kety and colleagues, 1994 › 14/279(5%) biological relatives of SCZ adoptees had chronic SCZ › None out of 111 adoptive relatives had SCZ › 1/351(0.3%) biological + adoptive relatives of unaffected adoptees had SCZ GENETICS IN SCHIZOPHRENIA 6/1/2012 34
  35. 35.  Pekka Tienari, 2000: › 164 adopted children of mothers suffering from SCZ or paranoid d/o  SCZ- 11(6.7%)  Schizoaffective- 1(0.6%)  Schizotypal personality d/o- 4(2.4%)  Overall narrow spectrum SCZ d/o- 10.4% › 197 control adoptees  SCZ - 4(2%) GENETICS IN SCHIZOPHRENIA 6/1/2012 35
  36. 36.  CONCLUSION: › Overall at least 10% risk of developing SCZ and other narrow-spectrum SCZ disorders in adopted away children of SCZ parents › Risk similar to that in offspring in family studies  genetic basis of transmission of SCZ GENETICS IN SCHIZOPHRENIA 6/1/2012 36
  37. 37. 37GENETICS IN SCHIZOPHRENIA 6/1/2012
  38. 38.  A statistical procedure by which pedigree data are examined to determine whether a disease phenotype is cosegregating with a genetic marker of known chromosomal location Demonstration of linkage between a putative disease susceptibility locus and one or more genetic markers determines in which chromosomal region the disease locus lies GENETICS IN SCHIZOPHRENIA 6/1/2012 38
  39. 39.  Use of large number of small families containing individuals who are definitely affected rather than large, multigenerational pedigrees At least 27 whole genome studies that analyzed between 1 to 294 pedigree containing between 32 to 669 patients of SCZ J. A. Badner and E.S. Gershon- susceptibility genes on chromosomes › 8p, 13q and 22q Cathryn M. Lewis and colleagues- › Strong evidence for 2q › 1q, 3p, 5p, 6p, 8p, 11q, 14q, 20q and 22q GENETICS IN SCHIZOPHRENIA 6/1/2012 39
  40. 40.  Meta-analysis by Sullivan- › Only 42%, 35%, 14%, 6% and 3% of all known genes were implicated by zero, one, two, three and four linkage studies imprecise tool Possible explanations for the varied linkage findings: › Different genes operate in different populations › SCZ is caused by the effect of many genes of small effect, so studies had no power to detect the loci GENETICS IN SCHIZOPHRENIA 6/1/2012 40
  41. 41. GENETICS IN SCHIZOPHRENIA 6/1/2012 41
  42. 42.  Hypotheses regarding genetic background of common diseases including SCZ: › Common disease/common variant hypothesis:  Common diseases caused by common variants  Joint action of several common genetic variants, each has a small effect on disease susceptibility, together with environmental factors  Could range into thousands GENETICS IN SCHIZOPHRENIA 6/1/2012 42
  43. 43.  Multiple rare variants in different genes, which have low population frequencies, operate in different individuals: › lack of families with clear cut Mendelian Inheritance › Inability of linkage studies to find any causative mutation › Mathematical modeling is inconsistent with single gene of large effect › A small number of cases of SCZ could be due to rare chromosomal aberrations with high penetrance GENETICS IN SCHIZOPHRENIA 6/1/2012 43
  44. 44. 44GENETICS IN SCHIZOPHRENIA 6/1/2012
  45. 45.  Principle: › association studies implicate a specific gene by identifying a correlation between a disease and alleles at a specific genetic locus › Compares the frequency of marker genotypes in cases with an appropriate control group › SNPs are the most common source of genetic measurement in association studies GENETICS IN SCHIZOPHRENIA 6/1/2012 45
  46. 46.  Dystrobrevin-binding protein1(DTNBP1)/ dysbindin › First reported by Richard E. Straub and colleagues in 2002 › On chromosome 6p22.3 › Konrad Talbot(2004)- presynaptic dystrobrevin-independent fraction reduced in SCZ brain within certain glutamatergic neurones in the hippocampus  associated with increased expression of vesicular glutamate transporter type 1alteration in presynaptic glutamate function GENETICS IN SCHIZOPHRENIA 6/1/2012 46
  47. 47.  DTNBP1… › Significant associations found between SCZ and several SNPs and multimarker haplotypes spanning DTNBP1 › Support from other large studies as well- at least 10 studies › Some studies showing no association › Inconsistencies indicative of presence of multiple susceptibility and protective alleles GENETICS IN SCHIZOPHRENIA 6/1/2012 47
  48. 48.  Neuregulin 1(NRG1) › Encodes multiple proteins with diverse range of functions in the brain  Cell-cell signaling  ErbB receptor interactions  Axon guidance  Synaptogenesis  Glial differentiation  Myelination  Neurotransmission › Located on 8p21-22 GENETICS IN SCHIZOPHRENIA 6/1/2012 48
  49. 49.  NRG1… › First implicated from linkage study in Icelandic sample › Further positive findings supported by studies from UK, Irish, Chinese, Bulgarian and South African samples › Only 3 other studies replicating the specific haplotype  differences in linkage disequilibrium GENETICS IN SCHIZOPHRENIA 6/1/2012 49
  50. 50.  Other genes: › Catechol-O-Methyltransferase (COMT) › Proline Dehydrogenase (PRODH) › Regulator of G-protein signaling4 (RGS4) › D-Amino-acid oxidase (DAO) › D-Amino-acid oxidase activator (DAOA) › G72/G30 › CAPON › AKT1 GENETICS IN SCHIZOPHRENIA 6/1/2012 50
  51. 51. 51GENETICS IN SCHIZOPHRENIA 6/1/2012
  52. 52.  Common variant SNPs: › minor allele frequency of SNPs>0.05 The effect sizes of the associations likely to be very small  hundreds and even thousands of genes might contribute small effects to the pathogenesis of SCZ GENETICS IN SCHIZOPHRENIA 6/1/2012 52
  53. 53.  RELN gene: › Relin protein- a serine protease important in corticogenesis (Hong et al, 2000) › Implicated in neurotransmitter-related GSK3β signaling and regulation of NMDA receptor activation (Herz, 2006) › Polymorphism in RELN associated with neurocognitive endophenotypes of SCZ(working memory and executive functioning) (Wedenoja, 2008) GENETICS IN SCHIZOPHRENIA 6/1/2012 53
  54. 54.  Genome-pooling based study › rs11064768 in intron 1 of CCDC60 on 12q24.23 › rs11782269 on 8p23.1 › RBP1 on 3q23- implicated in SCZ pathogenesis › Not replicated in other studies and no genome-wide significance Suggestive of neurodevelopmental hypothesis of SCZ (Keshavan et al 2004) GENETICS IN SCHIZOPHRENIA 6/1/2012 54
  55. 55.  Zinc finger protein 804A(ZNF804A) › Located on 2q32.1 › Putative transcription factor › Shown to be associated with disturbed connectivity between the dorsolateral prefrontal cortex(DLPFC) & the hippocampus; between rt. and lt. hemisphere (Esslinger et al 2009) › Strong association with SCZ and BPAD › Supported by replication in other large studies as well GENETICS IN SCHIZOPHRENIA 6/1/2012 55
  56. 56.  Major histocompatibility complex(MHC): › Significant association shown by the meta- analysis of the three major GWAS (ISC, MGS, and SGENE) at the MHC region on chromosome 6 › Genes in the MHC region have different functions immune function predominate › Histones regulate DNA transcription by chromatin modification and have role as antimicrobial agent genetic variation in histones might underlie differential placental susceptibility to infection susceptibility to SCZ* (Gejman et al 2010) GENETICS IN SCHIZOPHRENIA 6/1/2012 56
  57. 57.  MHC… › Danish study registry  increased risk of autoimmune diseases for schizophrenics and a history of any autoimmune d/o(n=29) associated with 45% increase in the risk for SCZ (Eaton et al, 2006) Neurogranin(NRGN): › On chromosome 11 › Encodes a postsynaptic protein kinase substrate that binds calmodulin, mediating NMDA receptor signaling  important for learning & memory, relevant to proposed glutamate pathophysiology of SCZ(Wang et al, 2008) GENETICS IN SCHIZOPHRENIA 6/1/2012 57
  58. 58.  Transcription factor 4 (TCF4): › On chromosome 18 › Neuronal transcriptional factor essential for brain development, esp. neurogenesis › Mutations cause Pitt-Hopkins syndrome, a neuro-developmental d/o GENETICS IN SCHIZOPHRENIA 6/1/2012 58
  59. 59.  International Schizophrenia Consortium ( ISC) conclusion: › Thousands of common polygenic variants with very small individual effects explain about 1/3rd of the total variation in genetic liability to SCZ (Purcell et al, 2009) › The remaining heritability is still missing even after the well powered GWAS studies GENETICS IN SCHIZOPHRENIA 6/1/2012 59
  60. 60. (Gejman,2010)GENETICS IN SCHIZOPHRENIA 6/1/2012 60
  61. 61. 61GENETICS IN SCHIZOPHRENIA 6/1/2012
  62. 62.  CNVs: › are stretches of genomic deletions & duplications ranging from 1kb to several Mb › Likely to have larger phenotypic effects than SNPs › Only rare(<1%) and large(>100kb) CNVs have been implicated in SCZ › Chromosome 22q11.21 deletion syndrome  Velocardiofacial syndrome  Increased risk for SCZ >30% carriers develop psychosis,80% of which as SCZ  Largest known individual risk factor for SCZ second only to having an identical twin with SCZ GENETICS IN SCHIZOPHRENIA 6/1/2012 62
  63. 63.  CNV: › 2p16.3 Neurexin1(NRXN1) deletion  NRXN presynaptic cell adhesion molecule  Interact with post synaptic cell adhesion molecules including neuroligins  Believed to play important role in release of neurotransmitter from presynaptic vesicles and together with neuroligins involved in synapse formation and use-dependent validation of neural circuits  Partial overlapping observed in mentally retarded and autistic patients GENETICS IN SCHIZOPHRENIA 6/1/2012 63
  64. 64.  Disrupted In Schizophrenia(DISC1): › Balanced chromosomal translocation in(1,11) (q42;q14.3) › Disrupt two genes in chromosome1 : DISC1 & DISC2 › Strong evidence of linkage to- SCZ, BPAD and recurrent depression GENETICS IN SCHIZOPHRENIA 6/1/2012 64
  65. 65.  DISC1…: › May contribute to SCZ by affecting neuronal functions dependent on intact cytoskeletal regulation such as  Neuronal migration  Neurite architecture  Intracellular transport GENETICS IN SCHIZOPHRENIA 6/1/2012 65
  66. 66.  CNV: › 15q13.1 duplication  Duplicated interval in the proband contains 3 genes of which APBA2 appears most likely  APBA2 interacts with NRXN1 › 1q21.1 deletion › 15q13.2 deletion › 15q13.3 deletion  Also found in pts. With mental retardation and seizures › 16p11.2 duplication GENETICS IN SCHIZOPHRENIA 6/1/2012 66
  67. 67.  Many of the genes positive for SCZ also positive for BPAD and vice versa With BPAD › DISC1 › NRG1 › RELN › ANK3 With autism › Neurexin 1 Could have implication for diagnostis of SCZ and also lead to newer etiological and pathophysiological explanations of the psychiatric disorders GENETICS IN SCHIZOPHRENIA 6/1/2012 67
  68. 68. (Stahl SM, 208)GENETICS IN SCHIZOPHRENIA 6/1/2012 68
  69. 69.  Standardization of the phenotypes: › Syndromal diagnosis › Broad variations The effect size associated with common variant is very low and the number of total susceptibility variants may be in the order of thousands requiring upto 100,000 cases and controls for replicating the findings › To achieve such sample sizes with detailed and consistent phenotype measurement is a challenge Combining all diseases of a spectrum e.g. psychosis, broadly large sample size and also detect genes that overlap GENETICS IN SCHIZOPHRENIA 6/1/2012 69
  70. 70.  Narrow the phenotype more homogenous sub-group smaller number of genes of greater effect sizes Use of endophenotypes(Gould 2006): › Disease associated phenotypes that are heritable, state independent, cosegregate with families and also found in unaffected family members › E.g.  Abnormal eye movement while tracking a moving object in screen  Neurocognitive deficits- COMT & RELN  Structural imaging phenotypes › Creates phenotypically more homogenous group GENETICS IN SCHIZOPHRENIA 6/1/2012 70
  71. 71.  Consideration of the effect of environmental factors such as maternal infections, and drug use Consideration of epigenetic mechanisms Use of high-throughput whole-genome sequencing: › Has potential to detect virtually all SNPs, CNVs and epigenetic modifications* › Will provide comprehensive information of an individual at the DNA level › Cost concern GENETICS IN SCHIZOPHRENIA 71 6/1/2012
  72. 72.  More accurate study of the target organ in SCZ research(brain) can lead to more objective and reliable associations with the genetic variants GENETICS IN SCHIZOPHRENIA 6/1/2012 72
  73. 73. 73GENETICS IN SCHIZOPHRENIA 6/1/2012
  74. 74.  Though Psychiatric diseases, including SCZ are quite common and the burden of illness quite high still little is known for certain about the disease etiology Genetic study of SCZ can provide us with the etiological basis and also guide us into newer and better treatment With the clustering of SCZ in families, family studies showed › the average morbidity risk of 10% in the siblings of probands, › confirmed the higher risk of SCZ in the relatives of the probands but did not delineate the role of shared genetic or environmental factors in this difference
  75. 75.  Twin studies: › Compare the concordance rates in Monozygotic(MZ) and Dizygotic(DZ) twins › Probandwise concordance in Monozygotic twins in the range of 25-78%; same sex dizygotic twins 0=28%; and heritability 81- 88% › Higher concordance in the MZ twins than that in dizygotic  genetic basis but <100% concordance in MZ  possible role of environmental factors
  76. 76.  Adoption studies: › Allow dissection of genetic from environmental contributions › Overall at least 10% risk of developing SCZ and other narrow-spectrum SCZ disorders in adopted away children of SCZ parents
  77. 77.  Linkage studies: › 8p, 13q and 22q, 2q, 1q, 3p, 5p, 6p, 11q, 14q, 20q › problem with non-replication across studies s/o SCZ is caused by the effect of many genes of small effect, so studies had no power to detect the common loci
  78. 78.  Common disease/common variant hypothesis: › Common diseases caused by joint action of several common variants each having a small effect on disease susceptibility Multiple rare variants in different genes with large effect, which have low population frequencies, operate in different individuals to cause SCZ
  79. 79.  Association studies: › Compares the frequency of marker genotypes in cases with an appropriate control group › Dystrobrevin-binding protein1(DTNBP1)/ dysbindin, On 6p22.3 › Neuregulin 1(NRG1) on 8p21-22 › COMT, PRODH, RGS4, DAO, DAOA, G72/G30, CAPON, AKT1
  80. 80.  GWAS: › Thousands of common polygenic variants with very small individual effects explain about 1/3rd of the total variation in genetic liability to SCZ (Purcell et al, 2009) › The remaining heritability is still missing even after the well powered GWAS studies › RELN gene, 12q24.23, 8p23.1, 3q23, Zinc finger protein 804A(ZNF804A) on 2q32.1, Major histocompatibility complex(MHC) on chromosome 6, Transcription factor 4 (TCF4) on chromosome 18
  81. 81.  CHROMOSOMAL ABERRATIONS/COPY NUMBER VARIANTS: › Likely to have larger phenotypic effects than SNPs › Chromosome 22q11.21 deletion syndrome, 2p16.3 Neurexin1(NRXN1) deletion, Disrupted In Schizophrenia(DISC1), 15q13.1 duplication,1q21.1 deletion, 15q13.2 deletion, 15q13.3 deletion, 16p11.2 duplication Overlapping genes with BPAD: DISC1, NRG1, RELN, ANK3 lead to newer etiological and pathophysiological explanations of the psychiatric disorders
  82. 82.  Strong genetic basis of SCZ proven from age-old family studies to the ultra modern GWAS Specific genes and loci still not definitely established though showing high degrees of association Problem arising out of multiple factors:  the lack of operationalized phenotypes  The presence of large number of common variants of small effects leading to problems of replication across studies  Cost, manpower and expertise inadequacy GENETICS IN SCHIZOPHRENIA 6/1/2012 82
  83. 83. GENETICS IN SCHIZOPHRENIA 6/1/2012 83
  84. 84.  Sullivan PF. The psychiatric GWAS consortium: Big science comes to psychiatry. Neuron 2010;68(2): 182-186 Psychiatric GWAS Consortium Coordinating Committee. Genomewide association studies: history, rationale, and prospects for psychiatric disorders. Am J Psychiatry 2009;166:540-556 Kirov G, Owen MJ: Genetics of schizophrenia. In: Sadock BJ, Sadock VA, Ruiz P, editors.Kaplan and Saddock’s Comprehensive Textbook of Psychiatry.9th edition. Lippincot Williams and Wilkins; Philadelphia;2009.p 1462-1475. Sullivan PF, Kendler KS, Neale MC: Schizophrenia as a complex trait. Evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2007;60:1187. Cited in: Kirov G, Owen MJ: Genetics of schizophrenia. In: Sadock BJ, Sadock VA, Ruiz P, editors.Kaplan and Saddock’s Comprehensive Textbook of Psychiatry.9th edition. Lippincot Williams and Wilkins; Philadelphia;2009.p 1462-1475. Cardno AG, Gottesman II: Twin studies of schizophrenia: from bow- and-arrow concordances to star war MMx and functional genomics. Am J Med Genet. 2000;97:12. Cited in: Kirov G, Owen MJ: Genetics of schizophrenia. In: Sadock BJ, Sadock VA, Ruiz P, editors.Kaplan and Saddock’s Comprehensive Textbook of Psychiatry.9th edition. Lippincot Williams and Wilkins; Philadelphia;2009.p 1462-1475.
  85. 85.  Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet. 2000;26:93-96. Cited in: Tiwari AK, Zai CC, Muller DJ, Kennedy JL. Genetics in schizophrenia: where are we and what next? Dialogues in clinical neuroscience 2010;3(12):289-303. Herz J, Chen Y. Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci. 2006;7:850-859. Cited in: Tiwari AK, Zai CC, Muller DJ, Kennedy JL. Genetics in schizophrenia: where are we and what next? Dialogues in clinical neuroscience 2010;3(12):289-303 Wedenoja J, Loukola A, Tuulio-Henriksson A, et al. Replication of link-age on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families. Mol Psychiatry. 2008;13:673-684. Cited in: Tiwari AK, Zai CC, Muller DJ, Kennedy JL. Genetics in schizophrenia: where are we and what next? Dialogues in clinical neuroscience 2010;3(12):289-303 Keshavan MS, Kennedy JL, Murray R, eds. Neurodevelopment and Schizophrenia. Cambridge, UK: Cambridge University Press; 2004. Cited in: Tiwari AK, Zai CC, Muller DJ, Kennedy JL. Genetics in schizophrenia: where are we and what next? Dialogues in clinical neuroscience 2010;3(12):289-303
  86. 86.  Esslinger C, Walter H, Kirsch P, et al. Neural mechanisms of a genome-wide supported psychosis variant. Science. 2009;324:605 Cited in : Tiwari AK, Zai CC, Muller DJ, Kennedy JL. Genetics in schizophrenia: where are we and what next? Dialogues in clinical neuroscience 2010;3(12):289-303 Gejman VP, Sanders AR, Duan J. the role of genetics in the etiology of Schizophrenia. Psychiatr Clin North Am. 2010; 33(1): 35–66 Eaton WW, Byrne M, Ewald H, et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 2006;163:521. Cited in: Gejman VP, Sanders AR, Duan J. the role of genetics in the etiology of Schizophrenia. Psychiatr Clin North Am. 2010; 33(1): 35–66 Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460:748 Gould TD, Gottesman, II. Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav. 2006;5:113- 119 cited in : Tiwari AK, Zai CC, Muller DJ, Kennedy JL. Genetics in schizophrenia: where we are and what next. Dialogues in clinical neuroscience 2010;3(12): 289-303. Stahl SM, editor. Stahl’s Essential Psychopharmacology. 3rd edition. Cambridge University Press; New Delhi;2008. p. 318.
  87. 87. GENETICS IN SCHIZOPHRENIA 6/1/2012 87

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