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Genetic Epidemiology of Cancer and its Risk Factors

Genetic Epidemiology of Cancer and its Risk Factors

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Genetic Epidemiology of Cancer and its Risk Factors

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

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

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

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

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

  6. Correlations Mammography densityBoyd et al. 2002 NEJM 347:886-894

  7. Heritability Mammography densityBoyd et al. 2002 NEJM 347:886-894

  8. Familial Risk for CancerSwedish Family-Cancer Database

  9. Standardized incidence ratioHemminki et al. 2001 Br J Cancer 84:388-391

  10. Population Attributable FractionHemminki & Czene 2002 CEBP 11:1638-1644

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

  12. Obesity

  13. Cancer Mortality due to BMI -menCalle et al. 2003 NEJM 348:1625-1638

  14. Cancer Mortality due to BMI -womenCalle et al. 2003 NEJM 348:1625-1638

  15. Population Attributable FractionCalle et al. 2003 NEJM 348:1625-1638

  16. Cancer-attributable deaths EUBanegas et al. 2003 Eur J Clin Nutr 57:201-208

  17. All-cause deaths to excess weightBanegas et al. 2003 Eur J Clin Nutr 57:201-208

  18. 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: h2 • twin (.50-.90) > • family (.20-.80) > • adoption (.20-.60) studies • measure: body mass index (BMI) weight (kg)/height2 (m)

  19. Twin correlations for BMI

  20. Sibling & PO correlations for BMI

  21. Non-biological correlations BMI

  22. Correlations between RelativesMaes 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

  23. Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

  24. Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

  25. Longitudinal Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

  26. Family & Adoption Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

  27. 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

  28. 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

  29. 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

  30. 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

  31. GenomeEUtwin ProjectSchousbou et al. 2003 Twin Res 6:409-421

  32. Genetic Epidemiology of BMISchousbou et al. 2003 Twin Res 6:409-421

  33. Human Obesity Gene MapPerusse et al. 2004 Obes Res 13:381-490

  34. Heritability of change in weight/fatBouchard & Tremblay 1997 J Nutr 127:943S-947S

  35. Heritability of fat mass and BMIFaith et al. 1999 Pediatrics 104:61-67

  36. Heritability of eating patternsvan den Bree et al. 1999, Am J Clin Nutr 70:456-465

  37. Heritability of food intakeHeitmann et al. 1999 Am J Clin Nutr 69:597-602