19 th International Workshop on Methodology of Twin and Family Studies: Introductory course

1. Mike Neale (director) Hermine Maes Nathan Gillespie Ben Neale Fruhling Rijsdijk Dorret Boomsma Danielle Posthuma Danielle Dick John Hewitt (host) Jeff Lessem Stacey Cherny Nick Martin Sarah Medland Manuel Ferreira Kate Morley 19th International Workshop on Methodology of Twin and Family Studies: Introductory course

2. History of International Methodology Workshops

3. Attendance at International Methodology Workshops

4. Causes of Human Variation Nick Martin Queensland Institute of Medical Research Boulder workshop: March 6, 2006

5. It’s all about genetic variation ...

7. Stature in adolescent twins

11. [Galton, 1889]

12. Biometricians Mendelians The height vs. pea debate(early 1900s) Do quantitative traits have the same hereditary and evolutionary properties as discrete characters?

14. RA Fisher (1918). Transactions of the Royal Society of Edinburgh 52: 399-433. var(A)=2p(1-p)a2

15. Kenneth Mather 1911-1990 John Jinks 1929-1987

19. 1 Gene  3 Genotypes  3 Phenotypes 2 Genes  9 Genotypes  5 Phenotypes 3 Genes  27 Genotypes  7 Phenotypes 4 Genes  81 Genotypes  9 Phenotypes Polygenic Traits

20. Central Limit Theorem The normal distribution is to be expected whenever variation is produced by the addition of a large number of effects.

21. Multifactorial Threshold Model of Disease Multiple thresholds Single threshold unaffected affected normal mild mod severe Diseaseliability Disease liability

22. Complex Trait Model Linkage Marker Gene1 Linkage disequilibrium Mode of inheritance Linkage Association Gene2 Disease Phenotype Individual environment Gene3 Common environment Polygenic background

23. 3 Stages of Genetic Mapping • Are there genes influencing this trait? • Genetic epidemiological studies • Where are those genes? • Linkage analysis • What are those genes? • Association analysis

24. C D E A Variance components Additive Genetic Effects Dominance Genetic Effects Unique Environment Shared Environment c a e d Phenotype P = eE + aA + cC + dD

25. Controversy: nature vs nurture

26. Designs to disentangle G + E Resemblance between relatives caused by: • shared Genes (G = A + D) • environment Common to family members (C) Differences between relatives caused by: • nonshared Genes • Unique environment (U or E)

27. http://genepi.qimr.edu.au/staff/classicpapers.html

28. Designs to disentangle G + E • Family studies – G + C confounded • MZ twins alone – G + C confounded • MZ twins reared apart – rare, atypical, selective placement ? • Adoptions – increasingly rare, atypical, selective placement ? • MZ and DZ twins reared together • Extended twin design

29. MZ twins reared apart - note the same way of supporting their cans of beer

30. Body postures of MZ twins reared apart Body postures of DZ twins reared apart

32. Designs to disentangle G + E • Family studies – G + C confounded • MZ twins alone – G + C confounded • MZ twins reared apart – rare, atypical, selective placement ? • Adoptions – increasingly rare, atypical, selective placement ? • MZ and DZ twins reared together • Extended twin design

33. Percentage of adoptees convicted of violent and property offenses by biological parents’ convictions • Denmark • 14,427 nonfamilial adoptions 1927-47 • Court convictions available for biological and adoptive parents • Mednick et al (1984) Science 224:891-4

34. Designs to disentangle G + E • Family studies – G + C confounded • MZ twins alone – G + C confounded • MZ twins reared apart – rare, atypical, selective placement ? • Adoptions – increasingly rare, atypical, selective placement ? • MZ and DZ twins reared together • Extended twin design

35. Placentation and zygosity Dichorionic Two placentas MZ 19% DZ 58% Dichorionic Fused placentas MZ 14% DZ 42% Monochorionic Diamniotic MZ 63% DZ 0% Monochorionic Monoamniotic MZ 4% DZ 0%

36. Identity at marker loci - except for rare mutation MZ and DZ twins: determining zygosity using ABI Profiler™ genotyping (9 STR markers + sex) MZ DZ DZ

37. Total mole count for MZ and DZ twins MZ twins - 153 pairs, r = 0.94 DZ twins - 199 pairs, r = 0.60 400 400 300 300 Twin 1 Twin 1 200 200 100 100 0 0 0 100 200 300 400 0 100 200 300 400 Twin 2 Twin 2

38. Twin Research 6: 399-408

40. Genetic covariance between relatives covG(yi,yj) = aijsA2 + dijsD2 a = additive coefficient of relationship = 2 * coefficient of kinship (= E(p)) d = coefficient of fraternity = Prob(2 alleles are IBD)

41. Examples Relatives a d Parent-offspring ½ 0 MZ twins 1 1 Fullsibs ½ ¼ Double first cousins ¼ 1/16 [Lynch & Walsh 1998]

42. ACE Model for twin data 1 MZ=1.0 / DZ=0.5 E C A A C E e c a a c e PT1 PT2

43. Both continuous and categorical variables Systematic approach to hypothesis testing Tests of significance Can be extended to: More complex questions Multiple variables Other relatives Structural equation modeling

44. E G VAR 1 VAR 2 VAR 3 E E G G G E

45. Sources of variation in male sexual orientation EC AC 0.30 0.70 Homosexuality 0.94 0.73 0.88 Orientation of sexual feelings Number of same-sex partners Attitude to sex with a man EP AF AP AA EA EF < 0.01 0.04 0.08 0.16 0.11 0.06

46. Direction of causation modeling with cross-sectional twin data c D c Model df AIC 2 2 Full Bivariate 145.66 107 -69.34 Reciprocal 146.00 108 .34 -70.00 Distress Parenting 161.74 109 16.08 -56.26 è Parenting Distress 146.71 109 1.05 -71.29 è No causation 376.29 110 230.63 156.29 Final 151.26 116 5.60 -80.74 A A E C E .20 .45 .25 .38 .55 DISTRESS PARENTING + .18 .56 .63 .52 .49 .16 .67 DEP ANX SOM COLD OVERP AUTON C E A E A E C E A C E C E .36 .13 .21 .11 .40 .17 .26 .21 .14 .49 .11 .37

47. Designs to disentangle G + E • Family studies – G + C confounded • MZ twins alone – G + C confounded • MZ twins reared apart – rare, atypical, selective placement ? • Adoptions – increasingly rare, atypical, selective placement ? • MZ and DZ twins reared together • Extended twin design

48. Extended Twin Design Truett, et al (1994) Behavior Genetics, 24: 35-49

49. cm cm cf mf mm cm • Extended kinship model • twins • siblings • parents • children • grandparents • aunts, uncles • cousins Male- specific Additive Genes Gender-common Additive Genes Male- specific Additive Genes Gender-common Additive Genes Female Unique Environment Male Unique Environment 0.5 0.5 0.5 ef hmm 0.5 em 0.5 0.5 Female Twin Environment Male Twin Environment 0.5 hfc hmc 0.5 tf tm sf Female Sibling Environment sm  Male Sibling Environment Female parent Male parent wfm wmf df wmm dm wff Female Dominant Genes Male Dominant Genes Male- specific Additive Genes Male- specific Additive Genes Gender-common Additive Genes Gender-common Additive Genes Female Unique Environment Male Unique Environment hmm hfc ef em hmc rt tm tf Female Twin Environment Male Twin Environment Female twin Male twin sf sm Female Sibling Environment rs Male Sibling Environment df dm Male Dominant Genes rd Female Dominant Genes