1. Genetic Epidemiology of Cancer and its Risk Factors Hermine Maes Cancer Control March 2006

3. Scandinavian Twin Registries Lichtenstein et al. 2000 NEJM 343:78-85 Swedish Twin Registry  Born 1886-1925: N=10,503pNcancer=4490  Born 1926-1958: N=12,883pNcancer=1157  Swedish Mortality Registry/ Swedish Cancer Registry Danish Twin Registry  Born 1870-1930: N=8461pNcancer=3572  Central register of Deaths/ Danish Cancer Registry Finnish Twins  Born 1880-1958: N=12,941pNcancer=1584  Central Population Register/ Finnish Cancer Registry

4. Types of cancer and concordance by sex/zygosity in 44,788 pairs of twins from Sweden, Denmark and Finland Lichtenstein et al. 2000 NEJM 343:78-85

5. Genetic Epidemiology of Cancers Lichtenstein et al. 2000 NEJM 343:78-85

8. Correlations Mammography density Boyd et al. 2002 NEJM 347:886-894

9. Heritability Mammography density Boyd et al. 2002 NEJM 347:886-894

10. Familial Risk for Cancer Swedish Family-Cancer Database

12. Standardized incidence ratio Hemminki et al. 2001 Br J Cancer 84:388-391

14. Population Attributable Fraction Hemminki & Czene 2002 CEBP 11:1638-1644

15. Risk Factors for Cancer Obesity Exercise / Physical Activity Smoking Alcohol / Drug Use

16. Obesity

18. Cancer Mortality due to BMI -men Calle et al. 2003 NEJM 348:1625-1638

19. Cancer Mortality due to BMI -women Calle et al. 2003 NEJM 348:1625-1638

20. Population Attributable Fraction Calle et al. 2003 NEJM 348:1625-1638

22. Cancer-attributable deaths EU Banegas et al. 2003 Eur J Clin Nutr 57:201-208

23. All-cause deaths to excess weight Banegas et al. 2003 Eur J Clin Nutr 57:201-208

24. Reviews on Genetics of Obesity Price, 1987; Bouchard & Pérusse, 1988; Stunkard, 1991; Meyer and Stunkard, 1993; Sorensen and Stunkard, 1994; Meyer and Stunkard, 1994; Bouchard and Pérusse, 1994; Sorensen, 1995, Meyer, 1995; Maes et al. 1997; …. focus: particular type of study: adoption, twin or family main conclusion: genetic factors play a significant role in variation of body fatness debate: how much is explained by genetic factors? heritability: h 2  twin (.50-.90) >  family (.20-.80) >  adoption (.20-.60) studies measure: body mass index (BMI) weight (kg)/height2 (m)

26. Twin correlations for BMI

27. Sibling & PO correlations for BMI

28. Non-biological correlations BMI

30. Correlations between Relatives Maes et al. 1997 Behav Genet 27:325-351 Weighted mean correlation pooled across studies: .74 MZ twins.32 DZ twins .24 siblings.19 parents and offspring (PO) .12 spouses.06 adoptive relatives Expectations based on correlations:  1-rMZ: specific environmental factors  rMZ > rDZ: additive genetic factors  rDZ > 1/2rMZ: shared environmental factors  rDZ < 1/2rMZ: dominance genetic factors  rDZ > rSib: twin effects  rSib > rPO: age x gene interaction, dominance  rPO > rSib: cultural transmission  rSpouse > 0: assortment  rAdoptSib/PO > 0: shared environmental factors

31. Twin Studies of BMI Maes et al. 1997 Behav Genet 27:325-351

33. Longitudinal Twin Studies of BMI Maes et al. 1997 Behav Genet 27:325-351

34. Family & Adoption Studies of BMI Maes et al. 1997 Behav Genet 27:325-351

35. Integrated Approach all collateral two- generational relationships identified in kinships of twins (first and second degree relatives)  > estimate sex-dependent contributions of genes and environment to complex traits in presence of assortative mating  > resolve genetic and cultural transmission, and both special MZ and special DZ twin environment effects Stealth Eaves, 1999; ET-model Maes, 2006

36. Virginia 30,000 Structure of the Virginia 30,000 Sample  pedigrees: twins + parents, siblings, spouses, children  > 80 sex-specific two-generation relationships Ascertainment of the Virginia 30,000 Sample  questionnaires on 14,763 twins, ascertained from 2 sources:  N=5287 families <Virginia Twin Registry  N=9476 twins <American Association of Retired Persons BMI  log transformed, corrected for the linear and quadratic effects of age, sex, twin status, source of ascertainment (Virginia vs. AARP), and interactions between these terms

37. ET Model Results proportions of variance for most parsimonious model  additive genes: 35% males 39% females  genetic effects of assortative mating: 2%  dominance: 31% males 26% females > broad heritabilities of.66 males.65 females  special twin environment: 7-8%  unique environmental: remaining 27%  special MZ twin environment, non-scalar sex limitation, cultural transmission, non-parental shared environment not significant confidence intervals: quite narrow < large sample sizes < relative simplicity of model which accounts for covariation in 88 different familial relationships with only 10 parameters

38. Summary convergent results for wide variety of relationship  studies with smaller sample sizes: greater variability in estimates of correlation between relatives > substantial role for genetic factors in the etiology of individual differences in BMI why higher heritability estimates in twin vs family studies:  separate special twin environment for MZs &DZs  significance of dominance variance  twins controlled for age effects  maternal effect (intrauterine effects on growth of fetus with lasting differences)  special MZ twin environment  epistatic effects from interaction of genes at two or more loci

40. GenomeEUtwin Project Schousbou et al. 2003 Twin Res 6:409-421

43. Genetic Epidemiology of BMI Schousbou et al. 2003 Twin Res 6:409-421

45. Human Obesity Gene Map Perusse et al. 2004 Obes Res 13:381-490

47. Heritability of change in weight/fat Bouchard & Tremblay 1997 J Nutr 127:943S-947S

48. Heritability of fat mass and BMI Faith et al. 1999 Pediatrics 104:61-67

49. Heritability of eating patterns van den Bree et al. 1999, Am J Clin Nutr 70:456-465

50. Heritability of food intake Heitmann et al. 1999 Am J Clin Nutr 69:597-602

51. Exercise

54. Physical activity and Cancer Friedenreich & Orenstein 2002 J Nutr 132:3456S-3464S

55. Biological Mechanisms of activity Friedenreich & Orenstein 2002 J Nutr 132:3456S-3464S

56. Framework PEACE Friedenreich & Orenstein 2002 J Nutr 132:3456S-3464S

57. Twin Studies of Exercise Stubbe & de Geus, 2006 Handbook of Behavior Genetics

59. Twin Studies of Physical Activity Stubbe & de Geus, 2006 Handbook of Behavior Genetics

60. Genetics of Exercise Behavior Stubbe & de Geus, 2006 Handbook of Behavior Genetics

62. Heritability of exercise by age Stubbe et al. 2005 Med Sci Sports Exerc 37:563-570

63. Genetic Epidemiology Studies Advantages & Disadvantages

64. Classical Twin Study I MZ & DZ twins reared together ) age matching  > age-dependent influences of genes or environment ) sex limitation (male/female same + opposite sex twins)  > magnitude/source of effects of genes and environment ; twins versus singletons  not generalizable if twins not representative of population twins not significantly different from singletons birth / first years of life, but twins ‘catch up’ by age 8 ; self-report zygosity measures (difficulty being told apart)  discrepant MZ twins more likely classified as DZ twins  > increasing heritability estimates

65. Classical Twin Study II ; equal environment assumption  MZ/DZs equal proportion of salient environmental factors similarity > contact > more shared environmental experiences (Lykken et al., 1990) parents respond to, rather than create differences (Lytton, 1977)  genetic factors control degree to which ‘environmental’ factors are shared by twins ; special twin environment  twins/sibs equal proportion of salient environmental factors ; intrauterine effects on the growth of the fetus  siblings < twins (dichorionic < monochorionic twins) correlating intrapair differences in birth weight with those in adult BMI > intra-uterine period not a critical period for development of adiposity (Allison et al., 1995)

66. Classical Twin Study III ; GE correlation  genetic and environmental factors not independent particular genetic make-up limits choice of environment common source for genes & environment: parent’s phenotype > offspring’s environment > combined genetic & cultural transmission different genotypes actively select different environment  ‘eliciting’ = genetic effect - with environmental pathway ; GxE interaction  sensitivity to unique environment genotype-dependent  GxE interaction = specific environmental effect ; random mating  assortment of partners < significant marital correlation  > h 2 overestimated in AE, underestimated in ACE model spouse corr significant but low, c 2 not significant > h 2 overestimated

67. Twins Reared Apart ) prenatal environment ) post-natal environment (age of separation) ; representativeness  parents who put children up for adoption: representative?  parents who adopt: representative?  > sampling of both genotypes and environments suspect ; random placement  no correlation between biological and adoptive parents  > independence of genetic and cultural transmission ; generalizability of twin data ; GxE interaction ; random mating ; no test of common environment

68. Family Studies Nuclear Family Design: parent-offspring, sibling & spouse pairs ; no separation of genetic and environmental transmission  significant correlations < shared genes or environments (siblings: cultural transmission/ non-parental shared env)  > measured indices of the environment > construct environmental index free from any genetic background? Twin Parent Design: classical twin design with parents ) separation of genetic and environmental transmission  5 parameters: heritability, non-parental shared env., cultural transmission, assortative mating, unique env. model with sex differences applied to sum of skinfolds from LLTS (Maes et al., 1996) h2.79 males.90 females, genetic effects of assortment 2%, no shared environment

69. Extended Family Design ) separation of genetic and cultural transmission  addition of second-degree relatives (over first-degree relatives)  > estimation of additional parameters, such as dominance ) assortative mating  estimate of assortment <marital correlation assortative mating more likely explanation than cohabitation/marital interaction (Allison et al., 1996; Knuiman et al., 1996) ; age x genotype interaction  children & parents or siblings measured at different ages  > different genetic/environmental factors at different ages > parent-offspring & sibling correlations reduced > reduced h 2 higher correlations of sibs close in age than further apart (Mueller & Malina, 1980; Tambs et al.,1991) longitudinal twin studies: genetic correlations between twins measured at different ages > mostly same genetic factors, but new genetic factors switch on at various ages  > discrepancies between results from family & twin studies

70. Adoption Studies I Complete Adoption Design: adopted/natural children & adoptive/biological parents ) resolution of effects from genes and shared environment  correlation of adopted children - biological parents > estimate of genetic transmission  correlation of adopted children - adoptive parents > estimate of cultural transmission ) assortment ; age effects ; selective placement  adopted parents not selected based on any characteristic of adopted child or biological parents of adopted child  > separation of genetic and environmental pathways ; prenatal environment/ early postnatal environment  > genotype-environment covariance

71. Adoption Studies II Partial Adoption Design: adopted children & adoptive parents ) estimate of cultural transmission not confounded with genetic transmission  adoptive versus regular parent-offspring correlations  > estimate of the genetic transmission by subtracting and doubling adoptive parent-offspring correlation from biological parent-offspring correlation ) assortment ; age effects ; selective placement ; prenatal environment/ early postnatal environment