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Psychiatric Disorder: Is It All In The Genes? Peter McGuffin MRC SGDP Centre Institute of Psychiatry, King’s College London Sir Francis Galton (1822-1911) ‘…Nature prevails enormously over nurture’(1883) The history of twins as a criterion of the relative powers of nature and nurture (1876) ‘..a devil,on who’s nature, nurture cannot stick.’ (Michael Horton as Caliban) Psychiatrists’ opening gambits 1 Have you suffered vexation, grief or reverse of fortune? Phillipe Pinel (quoted by Sir Michael Rutter) Psychiatrists’ opening gambits 2 Are you a twin? Eliot Slater (quoted by Sir Denis Hill) Excerpt from a Bethlem Royal Hospital front sheet 1823 Cardiff Study of Depression in Siblings (Farmer et al 2000) % reported current past % CATEGO cases D-siblings 7.4 17.6 18.5 C-siblings 0 4.8 1.9 Behaviours that run in families Huntington’s disease Alzheimer’s disease Depression Schizophrenia Personality Intelligence Religious involvement Attending medical school Why might a disorder run in families? Shared genes Shared environment A combination of the two behaviour Natural experiments teasing apart genes and environment Twin studies : is there more similarity monozygotic ( one egg) than dizygotic ( two egg) pairs? Adoption studies: do individuals resemble their biological relatives more than adopting relatives? The Cholmondeley Ladies c.1600-10 MZ TWINS MZ (monozygotic) twins have 100% of their genes in common (they’re ‘natural clones’) Shared environment also makes them similar DZ TWINS DZ (dizygotic) twins have 50% shared genes They also share environment to roughly the same extent as MZ twins MZ and DZ Twin Similarity Expressed as Correlations childhood fatigue ADHD DZ MZ bulimic symptoms depression (unipolar) manic depression (bipolar) autism schizophrenia 0 0.2 0.4 0.6 0.8 1 Structural Equation Modelling: a Simple Univariate Model b G1 G2 h c h CE P1 c P2 r12 = bh2 + c2 Univariate models of genes, environment and depression Data from McGuffin et al 1996 genes 68% shared E 2% residual E 30% Types of Gene Environment Interplay Coaction Additive Interaction Multiplicative Covariation G & E correlated Coaction Phenotype= Genes (G) + Environment (E) Shared Non-shared GE Correlation Vs Interaction Correlation: genetic influence on exposure to different environments Interaction: genetic control of sensitivity to different environments G-E interaction: antisocial behaviour and adversity (Cadoret et al 1995) antisocial behaviour % 30 25 20 parent ASP no ASP parent 15 10 5 0 low high Life events in Camberwell (McGuffin et al 1988) 40 35 30 25 20 proband related 15 not proband related 10 5 0 relatives controls The Causes of Depression Onsets of depression have a more than chance association with adversity (‘life events’) Depression is familial Life events are also familial Life events in Camberwell (McGuffin et al 1988) 40 35 30 25 20 proband related 15 not proband related 10 5 0 relatives controls Life events are familial Family studies: McGuffin et al 1988,Farmer et al 2000 Twin studies: Plomin et al 1993, Kendler et al 1994, Thapar et al 1998,Silberg et al 1999 Why are life events familial? Some events affect multiple members Hazard prone behaviour (risk taking or bad planning) Threat perception (neuroticism or ‘dysfunctional attitudes’) Life Events,Genes and Depression: both GxE and rGE? Self reported events heritable, parent reported not ( Thapar and McGuffin 1996) Genetic overlap between self reports of life events and depressive symptoms ( Thapar et al 1998) Genetic influence on sensitivity to events in twins (Kendler et al 1995) Personality affects response to events in sib pairs ( Farmer et al 2003) Karyotype@ensembl Chromosome 12 Finding genes One of the major benefits of the Human Genome Project is a dense map of markers (“signposts”for genome searching) Linkage studies use genetic markers track genes in families Association studies can pinpoint genes in populations Positional cloning Linkage(or LD) location prediction gene identification diagnosis structure and sequence gene product treatment Allelic association Cases Controls Sib pairs Both affected by a disease Extremely alike or unalike on a continuum eg neuroticism Chromosome 12 UP & BP Depression Findings 100 D12S1300/ D12S393 Chromosome 12 PAH 110 Abkevich23 (UP) lod = 4.6 Zubenko22 (UP) : lod = 1.9 Ekholm20 (BP): lod = 2 D12S78 Maziade21 D12S84 ATP2A2 McGuffin et al 2005 (BP) : lod >1.5 D12S1613 LOD = 1.57 Morisette11 (BP) lod = 2.5 Pedigrees 324 & 550: 1od = 4.7 120 130 D12S76 PLA2 Dawson16 (BP) : lod = 1.65 D12S342 Curtis18 (BP): lod = 2.9 D12S1639 Ewald17 (BP): lod = 3.4 140 150 D12S1609 LOD = 1.18 Serotonin genes Mitochondria MAOA 5-HTT/ SERT MAOA = Monoamine oxidase A 5-HTT/SERT = Serotonin transporter The serotonin transporter gene 14 repeats = “Short” 16 repeats = “Long” From Lesch and MÖssner Biol. Psychiatry, 1998 Self reports of depression symptoms, age 26 The association between SLEs and self-reports of depression symptoms at age 26, as a function of 5-HTTLPR genotype 12.50 10.00 7.50 5.00 5-HTT gene SS, n = 146 SL, n = 435 LL, n = 264 2.50 0.00 0 1 2 3 4+ Five groups of individuals having different numbers of life events, ages 21-26 Caspi et al , Science 2003 G-E interaction and SERT promoter polymorphism • Maternal separation stress effects ( ACTH) in macaque monkeys ( Barr et al 2004) • Amygdala activation and fearful stimuli ( Hariri et al 2002) • Short allele and adversity => depressive symptoms (Caspi et al 2003, Eley et al 2004) • Response to antidepressants (SSRIs) (eg Uher et al 2009) Specific genes that interact with environments serotonin transporter, social adversity (and medication) => depression Monoamine oxidase A,childhood maltreatment => antisocial behaviour COMT, cannabis => schizophrenia Wellcome Trust Case Control Consortium. Bipolar disorder Coronary artery disease Crohn’s Rheumatoid T1D and T2D Hypertension Wellcome Trust Case Control Consortium Design 2,000 well defined ( OPCRIT) cases ( Cardiff, IoP, Aberdeen, Newcastle) 3,000 ethnically matched controls ( blood donors and 1958 birth cohort) Affymetrix 500k chip Bipolar Disorder Genetic Consortium (Sklar, Craddock et al) 4,387 cases and 6,209 controls US, UK, Ireland (white Europeans) Identified 2 novel genes: Ankyrin-G (ANK) and CACNA1C Why do pharmacogenetics and genomics? General response to therapeutic drugs Efficacious Little or no efficacy Toxic and not efficacious Efficacious but toxic The impact of genetics: Post genomic psychiatry targeted & tailored treatments refined diagnosis understanding of neurobiology risk prediction and gene-environment effects public perception and stigma Psychiatrists’ opening gambits 3 I understand that life has not been kind to you. Tell me…. Anonymous wise old psychiatrist (quoted by Prof Kenneth Rawnsely) Psychiatrists’ opening gambits 3 … is there any other insanity in the family? Anonymous wise old psychiatrist (quoted by Prof Kenneth Rawnsely)