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  • 3
  • 7
  • There is evidence for the quantitative suicidality index: lod score of 1.5 was found on chromosome 1.
  • Grey solid line alcohol dep, black solid line md, black dashed line composite of ad and md, grey black is either or. LOD score of 2.3 between D7S1799 and D7S1817 with major depressive syndrome . The composite phenotype, alcohol dependence and major depressive syndrome resulted in a peak of the same magnitude and at the same location. The highest LOD score (3.4) was observed when the combined phenotype ‘alcohol dependence or major depressive syndrome’ was used at D7S1799.
  • P < 0.05: rs1824024 (0.003), rs2061174 (0.002), rs2350786 (0.034) and rs324650 (0.047) [SUM] : rs1824024 (0.004) and rs2061174 (0.017) [AVE] Global test : χ 2 = 29.69, p = 0.0001 [SUM]; χ 2 = 24.52, p = 0.0009 [AVE] GCA relatively common haplotype GCT rare haplotype TCA rare haplotype TTT most common haplotype No sex effects Unusual gene in that…. 5’UTR – splicing etc tissue-specific
  • There is evidence for the quantitative suicidality index: lod score of 1.5 was found on chromosome 1.

Transcript

  • 1. The Genetics of Mood Disorders Peter McGuffin, MRC SGDP Centre, Institute of Psychiatry, Kings College London
  • 2. Genetics and Genomics of Mood Disorders
    • How much do genes contribute?
    • How specific are the effects?
    • Can we locate and identify genes?
    • If so what do we do next?
    • What will be the impact on clinical practice
  • 3. Genetics and Genomics of Mood Disorders
    • How much do genes contribute ?
  • 4. Affective disorder in first degree relatives of bipolar and unipolar probands (McGuffin and Katz 1986) Proband No. of studies BZ Morbid risk Bipolar Unipolar Bipolar Unipolar 12 7 3710 3648 2319 7.8 0.6 11.4 9.1 BZ=bezugsziffer (corrected denominator)
  • 5. 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
  • 6. Results: depression in siblings
    • Relative risk of being affected for D-siblings compared to C-siblings:
    • reported  s = 5.42* (95% CI: 2.18, 13.57 )
    • CATEGO  s = 9.70* (95% CI: 2.34, 40.01)
    • * p<0.0001
  • 7. psychiatric disorder
  • 8. Teasing apart genes and environment
    • Twin studies
    • Adoption studies
  • 9. Affective illness in the parents of adoptees Biological parents (%) Adoptive parents (%) Bipolar adoptees (n = 29) Bipolar non-adoptees (n = 31) Normal adoptees 28 26 5 12 - 9 Mendlewicz and Rainer, 1977
  • 10. Twin Concordance for DSM IV Major Depression (McGuffin et al 1996)
  • 11. Twin concordance (%) for unipolar and bipolar affective disorder Data from McGuffin et al 2003
  • 12. Genetic Causes of Affective Disorders
    • Several, perhaps many, genes confer a liability to develop the disorder
  • 13. affected liability population relatives
  • 14. Structural Equation Modelling: a Simple Univariate Model G1 G2 CE P1 P2  h h c c r 12 =  h 2 + c 2
  • 15. Variances explained
  • 16.
    • Phenotype= Genes (G) + Environment (E)
    • Shared Non-shared
    ‘ real’ error
  • 17. Caseness Stability and Heritability (Kendler et al 1993)
    • Index based on N of Sx, Rx, N of episodes and impairment
    • Stability associated with higher index
    • Heritability around 70% when 2 occasions of measurement used
  • 18. Genetics and Genomics of Mood Disorders
    • Q.How much do genes contribute ?
    • A. About 80% of the variance in liability to BP Disorder
    • A. Over 70% of the variance in liability to UP Disorder in clinically ascertained adult sample (30-40% in population based samples)
  • 19. Genetics and Genomics of Mood Disorders
    • How specific are the genetic effects?
  • 20. Relatives affected +
  • 21. Relatives affected + Relatives affected ++
  • 22. Correlations in liability UP and BP disorder McGuffin,et al (2003) Archives of General Psychiatry 60 : 497-502. 0.426 0.304 BP 0.133 0.314 UP BP UP Cotwin Proband
  • 23. Bipolar Disorder :Bivariate Studies
    • genetic overlap with unipolar disorder?
    • genetic overlap with schizophrenia?
  • 24. UP BP A C E e d A C E h b c b e b r g r c r e h d c d Components of phenotypic correlation
  • 25. Depression Mania A E e d A E h a e a h d Components of phenotypic correlation r g=0.65 r e=0.59 E A
  • 26. The relationship between schizophrenic and bipolar symptoms SA Sc BP A E E A E A .82 .9 .7 .4 .57 .4 .38 .4
  • 27. Nature, Nurture and Mood Disorder
    • High heritabilities
    • Environment 20-30%, but all non shared
    • Partial overlap with between UP and BP disorder
    • Partial overlap between BP disorder and schizophrenia
  • 28. Genetics and Genomics of Mood Disorders
    • Can we locate and identify genes ?
  • 29.  
  • 30.  
  • 31. [email_address]
  • 32. Chromosome 12
  • 33. Positional cloning
    • Linkage(or LD)
    • location
    • gene identification
    • structure and sequence
    • gene product
    prediction diagnosis treatment
  • 34. Linkage v Association
    • families
    • detectable over large distances >10 cM
    • large effects OR >3, variance>10%
    • case-control or families
    • detectable over small distances <1 cM
    • small effects OR<2, variance<1%
  • 35. Regions of recent interest in BP affective disorder
    • 12q : linkage studies and Darier’s disease
    • 13q and 22q supported by meta-analysis
    • 18 centromeric or 2 regions on 18q?
    • 4p : one large and another moderately large family
    • 21q one large and many small/moderate size families
  • 36. Regions of recent interest in UP affective disorder
    • 12q 2/3 studies
    • 15q 2/3 studies
    • 13q ?
    • 1p?
  • 37. Genome-wide linkage scan of recurrent depressive disorder McGuffin et al., Hum Mol Genetics , 2005 1p36 MTHFR
  • 38. Approaches to association
    • Functional Candidates
    • Searching regions of interest (LD) for positional candidates
    • Whole genome association
  • 39. Examples of functional candidates
    • Serotonin pathways
    • NA pathways
    • DA pathways?
    • Others, eg BDNF
  • 40.  
  • 41. Wang et al. (2004) ChRM2 and UPD . 3-SNP haplotype significant [rs1824024-rs2061174-rs324650] ( χ 2 = 29.69, p = 0.0001 [SUM]; χ 2 = 24.52, p = 0.0009 [AVE] ) haplotype
  • 42. Genome-wide linkage scan of recurrent depressive disorder McGuffin et al., Hum Mol Genetics , 2005 1p36 MTHFR
  • 43. S tudies of the MTHFR C677T in depression ( T / T v s. C / C ) Lewis et al., Mol Psychiatry , 2006
  • 44. MTHFR genotype frequency in depression patients and controls Men: chi2 = 1.47, p = 0.48 Total: chi2 = 2.35, p = 0.31 Women: chi2 = 0.83, p = 0.67
  • 45. Chromosome 12q Depression & BD findings & DeNt 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`
  • 46. G72 (DAOA) and D amino acid oxidase (DAO)
    • G72 implicated by LD search across 13q22-34 linkage region
    • Primate specific gene
    • Interaction with DAO found by yeast 2 hybrid study
    • Evidence of G72-DAO epistasis
    • Multiple replications of G72 association in both schizophrenia and bipolar disorder
  • 47. Genetics and Genomics of Mood Disorders
    • Can we locate and identify genes?
    • What do we do next?
  • 48. Genetics and Genomics of Mood Disorders
    • What do we do next?
    • Functional genomics
    • Proteomics
    • Behavioural Genomics
  • 49. Toward behavioral genomics
    • ‘Top down’
    • Whole organism
    • Animal models of component traits
    • Gene environment interplay
  • 50. The serotonin transporter gene From Lesch and M Ö ssner Biol. Psychiatry, 1998 14 repeats = “Short” 16 repeats = “Long”
  • 51. 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 2003
  • 52. G-E interaction and SERT promoter polymorphism
    • Tryptophan depletion effect ( Neumeister et al 2002)
    • Amygdala activation and fearful stimuli ( Hariri et al 2002)
    • Maternal separation stress effects ( ACTH) in macaque monkeys ( Barr et al 2004)
    • Short allele and adversity => depressive symptoms (Caspi et al 2003, Eley et al 2004 –and review by Zammit and Owen 2006)
  • 53. The impact on psychiatry
    • refined diagnosis
    • understanding of neurobiology
    • risk prediction and gene-environment effects
    • influence on treatments
    • public perception and stigma
  • 54.  
  • 55. The impact on psychiatry
    • refined diagnosis +
    • understanding of neurobiology+
    • risk prediction and gene-environment effects+
    • targeted & tailored treatments+
    • improved public perception and no stigma
    • = the end of psychiatry!