Opioid

1. Genetics in
Psychiatry

2. Overview
General Genetics
Depression
Bipolar Disorder
Schizophrenia
Others

3. General Genetics
Autosomal dominant
Autosomal recessive
X-linked
Complex familial
Sporadic

4. Pedigree Symbols

5. Autosomal Dominant
Affects either sex equally (50:50 male:female)
Individuals affected in each generation
50:50 ratio of affected and unaffected in family
Large pedigrees?
Emery-Dreifuss MD (LMNA), AD Deafness, polycystic
kidney disease (PKD1, PKD2)

6. Autosomal Dominant

7. Typical Pedigree

8. Autosomal Recessive
Roughly 1:4 offspring affected
Male to female ratio identical
Consanguinity/related
Gaucher’s disease (GBA), Cystic fibrosis (CFTR)

9. Autosomal Recessive

10. Typical Pedigree

11. X-linked
Males predominantly affected (>90%)
Recessive with gene on X-chromosome
Haemophilia A (Factor VIII, ), Duchenne Muscular Dystrophy
(dystrophin, DMD)

12. X-linked

14. Other
Mitochondrial- maternal line, males affected but no inheritance
X-linked dominant (Charcot Marie Tooth (GJB1), Hypophosphataemic
Rickets (PHEX)
Chromosomal abnormalities
Complex pedigrees/families

15. Chromosomal Abnormalities
Down’s syndrome, 47,21+
Edward’s syndrome, 47, 18+
Patau syndrome, 47, 13+
Klinefelter’s, 47, XXY
Turner’s 45, XO
XYY Males
XXX Females
Deletion (CdC), duplication (FXMR), inversion,
translocation

16. Chromosomal Abnormalities
XXX, XXY, XYY
~1:500-1000 l.b.
XXX, IQ within normal range but low, reduced language
and auditory development, poor self esteem and
increased psychiatric referral.
XXY, language delay, motor impairment, gender
problems.
XYY, pervasive language impairment, attentional
deficits, no evidence of aggressive behaviour.

17. Syndrome vs. biomarker
Heritable, state-independent, associated, segregates
Physiological (P300)
Behavioural (CRT)
Imaging (SPECT, fMRI)
Neurochemical (DAT)
Endophenotypes

18. Endophenotypes - EEG
Neuroticism – gamma (36-44Hz) in anterior cingulate
Cognition – gamma in dlPFC, theta (6.8-8Hz) and alpha2 (10.5-12Hz) in dACC
Reward lower OFC and dlPFC gamma

19. Unipolar Depression
Twin studies (h2 0.3-0.7)
Family studies 1o 2-4x,
Strong environmental component
Very rare families (e.g. StClair et al, 1990)
Sib-Pair, family based and population based genetics

20. Unipolar Depression –
Association studies
MTHFR –
FKBP5
5HTT-LTTR(SLC6A4)-short allele associates with MDD,
COMT (val/met)
Etc.

21. Unipolar Depression MDD1
Pedigree based study (1800)
168 ms markers
Prior studies of MDD, BPD, SCZ
Male bias
Gene?

22. Unipolar Depression MDD2
Pedigree based (sib pairs, trios…)
389 ms markers
No sex effect
No prior linkage

23. Unipolar Depression
No major or moderate effect gene (>5000cases)
ADCY3, GAL
CACNA1C

24. Endophenotype Approaches

28. Bipolar Disorder
Twin studies 20% DZ, 60% MZ
Anticipation (suggested)
Maternal origin?
Small and extended pedigrees

29. Bipolar Disorder-MAFD1
Complex segregation analysis of pedigrees
18p but no gene
Multiple MAFD loci

30. DISC1
Register based study in Edinburgh
Extended pedigree
Two genes in region of bkp
Association and linkage to SCZ

31. DISC1
Mice develop SCZ-like symptoms
Different mutant mice have similar phenotype
Reduced neurone density
Abnormal cell communication

32. Bipolar Disorder – ANK3
GWAS 4387 cases
Replication studies
Brain expressed biological plausibility

33. Bipolar Disorder
Tiered analysis GWAS
680, 1700, 2400, 6400 patients
Neurocan (NCAN)

34. Schizophrenia
Genetic basis from twin studies
MZ ~40-50%, DZ~15%
Higher rates if spectrum disorder included
Polygenic inheritance
Gene Locus 1p36.2, 15q15, 14q32.3, 13q34, 13q32, 13q14-q21, 12q24, 11q14-q21, 11p14-
p13, 10q22.3, 8p21, 6q13-q26, 1p36.3, 6p22.3, 6p23, 5q23-q35, 3q13.3, 3p25, 1q42.1,
1q42.1, 22q12.3, 22q12.3, 22q11.2, 22q11, 1q32.1, 11p36.2, 15q15, 14q32.3, 13q34, 13q32,
13q14-q21, 12q24, 11q14-q21, 11p14-p13, 10q22.3, 8p21, 6q13-q26, 1p36.3, 6p22.3, 6p23,
5q23-q35, 3q13.3, 3p25, 1q42.1, 1q42.1, 22q12.3, 22q12.3, 22q11.2, 22q11, 1q32.1,

35. Schizophrenia GWAS
3300 cases
Chr. 22 (MYO18B)
Major effect in MHC (NOTCH4)
Effects of multiple (>100) very rare alleles

36. Schizophrenia
Copy number variation – duplication or deletion of a small
chromosomal region
Limited to single patients/families
Multiple sites across genome

37. Autism
MZ 20-80%, DZ 2-10%,
Sibs, small multiplex families
Rett syndrome (X-linked dominant, male lethal)
Aspergers (NLGN3, NLGN4)

38. Autism
Sib Pair and multiplex approach
5, 8, 16, 19, 17, 5, 11, 4, and X
GWAS 5p14-15
CNV ~8%
Genes involved in cell cell signalling (SHANK2, NRXN1)

39. Autism
Simplex families (>2000)
Whole exome sequencing
12% missense mutations
43% potential mutations
400+ genes

40. Autism

41. Tourette Syndrome
4 genes ~12%
De-novo mutation
De-novo CNV

42. Clinical Practice
•Families
Molecular investigations for CNV, chromosomal abnormalities
•Sporadic
No specific testing
Whole exome/genome sequencing of families
https://www.genomicsengland.co.uk/
The 100,000 Genomes Project

43. Summary
MDD – 12q, 15q, ADCY3, GAL
BPD - DISC1, disordered neuronal connectivity
SCZ –MHC, CNV,
Autism -CNV
Multiple small effect genes
Endophenotype

44. Further Information
http://www.ncbi.nlm.nih.gov/omim
http://www.ncbi.nlm.nih.gov/Omim/getmorbid.cgi
After GWAS: searching for genetic risk for schizophrenia and bipolar disorder. Gershon
ES, Am J Psychiatry. 2011;168(3):253-6.
The genetics of child psychiatric disorders: focus on autism and Tourette syndrome. State
MW. Neuron. 2010;68(2):254-69.
Molecular Risk Factors for Schizophrenia. Modai S, Shomron N.
Trends Mol Med. 2016 Mar;22(3):242-53.
Advances in understanding - genetic basis of intellectual disability. Chiurazzi P, Pirozzi F.
F1000Res. 2016 Apr 7;5.