1 Genetics in Psychiatry

2 Overview General Genetics Depression Bipolar Disorder SchizophreniaOthers

3 General Genetics Autosomal dominant Autosomal recessive X-linkedComplex familial Sporadic

4 Pedigree Symbols 4

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 affectedMale 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

13

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

15 Chromosomal AbnormalitiesDown’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: 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 Endophenotypes Syndrome vs. biomarkerHeritable, state-independent, associated, segregates Physiological (P300) Behavioural (CRT) Imaging (SPECT, fMRI) Neurochemical (DAT)

18 Endophenotypes - EEG Neuroticism – gamma (36-44Hz) in anterior cingulate Cognition – gamma in dlPFC, theta (6.8-8Hz) and alpha2 ( Hz) 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 studiesMTHFR – FKBP5 5HTT-LTTR(SLC6A4)-short allele associates with MDD, COMT (val/met) Etc.

21 Unipolar Depression MDD1Pedigree based study (1800) 168 ms markers Prior studies of MDD, BPD, SCZ Male bias Gene?

22 Unipolar Depression MDD2Pedigree 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

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

29 Bipolar Disorder-MAFD1Complex segregation analysis of pedigrees 18p but no gene Multiple MAFD loci

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

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

32 Bipolar Disorder – ANK3 GWAS 4387 cases Replication studiesBrain expressed biological plausibility

33 Bipolar Disorder Tiered analysis GWAS 680, 1700, 2400, 6400 patientsNeurocan (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 familiesRett syndrome (X-linked dominant, male lethal) Aspergers (NLGN3, NLGN4)

38 Autism Sib Pair and multiplex approach5, 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 sequencing12% missense mutations 43% potential mutations 400+ genes

40 Autism

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

42 Clinical Practice FamiliesMolecular 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, GALBPD - DISC1, disordered neuronal connectivity SCZ –MHC, CNV, Autism -CNV Multiple small effect genes Endophenotype

44 Further Information http://www.ncbi.nlm.nih.gov/omim 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): Molecular Risk Factors for Schizophrenia. Modai S, Shomron N. Trends Mol Med Mar;22(3): Advances in understanding - genetic basis of intellectual disability. Chiurazzi P, Pirozzi F. F1000Res Apr 7;5.