2. Psychiatric Disorder: Is It All In The Genes?

3. Sir Francis Galton (1822-1911) The history of twins as a criterion of the relative powers of nature and nurture (1876) ‘…Nature prevails enormously over nurture’(1883)

4. ‘..a devil,on who’s nature, nurture cannot stick.’ (Michael Horton as Caliban)

6. Psychiatrists’ opening gambits 1 Have you suffered vexation, grief or reverse of fortune? Phillipe Pinel (quoted by Sir Michael Rutter)

8. Psychiatrists’ opening gambits 2 Are you a twin? Eliot Slater (quoted by Sir Denis Hill)

9. Excerpt from a Bethlem Royal Hospital front sheet 1823

10. Cardiff Study of Depression in Siblings (Farmer et al 2000) % reported % CATEGO current past cases D-siblings 7.4 17.6 18.5 C-siblings 0 4.8 1.9

11. Behaviours that run in families §Huntington’s disease §Alzheimer’s disease §Depression §Schizophrenia §Personality §Intelligence §Religious involvement §Attending medical school

12. Why might a disorder run in families? §Shared genes §Shared environment §A combination of the two

13. behaviour

14. 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?

15. The Cholmondeley Ladies c.1600-10

16. MZ TWINS §MZ (monozygotic) twins have 100% of their genes in common (they’re ‘natural clones’) §Shared environment also makes them similar

17. DZ TWINS §DZ (dizygotic) twins have 50% shared genes §They also share environment to roughly the same extent as MZ twins

18. MZ and DZ Twin Similarity Expressed as Correlations

19. Structural Equation Modelling: a Simple Univariate Model G1G2 CE P1P2  hh c c r 12 =  h 2 + c 2

20. Univariate models of genes, environment and depression Data from McGuffin et al 1996

21. Types of Gene Environment Interplay §Coaction §Interaction §Covariation §Additive §Multiplicative §G & E correlated

22. Coaction §Phenotype= Genes (G) + Environment (E) Shared Non-shared

23. GE Correlation Vs Interaction §Correlation: genetic influence on exposure to different environments §Interaction: genetic control of sensitivity to different environments

24. G-E interaction: antisocial behaviour and adversity (Cadoret et al 1995)

25. Life events in Camberwell (McGuffin et al 1988)

26. 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

27. Life events in Camberwell (McGuffin et al 1988)

28. 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

29. Why are life events familial? §Some events affect multiple members §Hazard prone behaviour (risk taking or bad planning) §Threat perception (neuroticism or ‘dysfunctional attitudes’)

30. 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)

34. Karyotype@ensembl

35. Chromosome 12

36. 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

37. Positional cloning §Linkage(or LD) §location §gene identification §structure and sequence §gene product prediction diagnosis treatment

38. Allelic association §Cases §Controls

39. Sib pairs §Both affected by a disease §Extremely alike or unalike on a continuum eg neuroticism

40. Chromosome 12 UP & BP Depression Findings 110 120 130 140 150 PAH Ekholm 20 (BP): lod = 2 D12S78 D12S84 D12S76 PLA2 D12S342 Curtis 18 (BP): lod = 2.9 ATP2A2 Dawson 16 (BP) : lod = 1.65 Chromosome 12 Morisette 11 (BP) lod = 2.5 Pedigrees 324 & 550: 1od = 4.7 D12S1639 Ewald 17 (BP): lod = 3.4 100 D12S1300/ Abkevich 23 (UP) lod = 4.6 D12S393 Zubenko 22 (UP) : lod = 1.9 Maziade 21 (BP) : lod >1.5 D12S1613 LOD = 1.57 McGuffin et al 2005 D12S1609 LOD = 1.18

41. Serotonin genes MAOA Mitochondria MAOA = Monoamine oxidase A 5-HTT/SERT = Serotonin transporter 5-HTT/SERT

42. The serotonin transporter gene From Lesch and M Ö ssner Biol. Psychiatry, 1998 14 repeats = “Short” 16 repeats = “Long”

43. Five groups of individuals having different numbers of life events, ages 21-26 Self reports of depression symptoms, age 26 5-HTT gene The association between SLEs and self-reports of depression symptoms at age 26, as a function of 5-HTTLPR genotype Caspi et al, Science 2003

44. 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)

45. Specific genes that interact with environments § serotonin transporter, social adversity (and medication) => depression §Monoamine oxidase A,childhood maltreatment => antisocial behaviour §COMT, cannabis => schizophrenia

46. Wellcome Trust Case Control Consortium. §Bipolar disorder §Coronary artery disease §Crohn’s §Rheumatoid §T1D and T2D §Hypertension

47. 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

49. 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

50. Why do pharmacogenetics and genomics? General response to therapeutic drugs §Efficacious §Little or no efficacy §Toxic and not efficacious §Efficacious but toxic

51. 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

52. 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)

53. Psychiatrists’ opening gambits 3 … is there any other insanity in the family? Anonymous wise old psychiatrist (quoted by Prof Kenneth Rawnsely)