Genetic Epidemiology of Cancer and its Risk Factors

1
Genetic Epidemiology of Cancer and itsRisk
Factors

• Hermine Maes
• Cancer Control
• March 2006

2
(No Transcript)
3
Scandinavian Twin RegistriesLichtenstein et al.
2000 NEJM 34378-85

• Swedish Twin Registry
• Born 1886-1925 N10,503p Ncancer4490
• Born 1926-1958 N12,883p Ncancer1157
• Swedish Mortality Registry/ Swedish Cancer
  Registry
• Danish Twin Registry
• Born 1870-1930 N8461p Ncancer3572
• Central register of Deaths/ Danish Cancer
  Registry
• Finnish Twins
• Born 1880-1958 N12,941p Ncancer1584
• 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
FinlandLichtenstein et al. 2000 NEJM 34378-85
5
Genetic Epidemiology of Cancers Lichtenstein et
al. 2000 NEJM 34378-85
6
Genetic Epidemiology of CancersLichtenstein et
al. 2000 NEJM 34378-85
7
(No Transcript)
8
Correlations Mammography densityBoyd et al. 2002
NEJM 347886-894
9
Heritability Mammography densityBoyd et al. 2002
NEJM 347886-894
10
Familial Risk for CancerSwedish Family-Cancer
Database
11
(No Transcript)
12
Standardized incidence ratioHemminki et al. 2001
Br J Cancer 84388-391
13
(No Transcript)
14
Population Attributable FractionHemminki Czene
2002 CEBP 111638-1644
15
Risk Factors for Cancer

• Obesity
• Exercise / Physical Activity
• Smoking
• Alcohol / Drug Use

16
Obesity
17
(No Transcript)
18
Cancer Mortality due to BMI -menCalle et al.
2003 NEJM 3481625-1638
19
Cancer Mortality due to BMI -womenCalle et al.
2003 NEJM 3481625-1638
20
Population Attributable FractionCalle et al.
2003 NEJM 3481625-1638
21
(No Transcript)
22
Cancer-attributable deaths EUBanegas et al. 2003
Eur J Clin Nutr 57201-208
23
All-cause deaths to excess weightBanegas et al.
2003 Eur J Clin Nutr 57201-208
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 h2
• twin (.50-.90) gt
• family (.20-.80) gt
• adoption (.20-.60) studies
• measure body mass index (BMI) weight
  (kg)/height2 (m)

25
(No Transcript)
26
Twin correlations for BMI
27
Sibling PO correlations for BMI
28
Non-biological correlations BMI
29
(No Transcript)
30
Correlations between RelativesMaes et al. 1997
Behav Genet 27325-351

• 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 gt rDZ additive genetic factors
• rDZ gt 1/2rMZ shared environmental factors
• rDZ lt 1/2rMZ dominance genetic factors
• rDZ gt rSib twin effects
• rSib gt rPO age x gene interaction, dominance
• rPO gt rSib cultural transmission
• rSpouse gt 0 assortment
• rAdoptSib/PO gt 0 shared environmental factors

31
Twin Studies of BMIMaes et al. 1997 Behav Genet
27325-351
32
Twin Studies of BMIMaes et al. 1997 Behav Genet
27325-351
33
Longitudinal Twin Studies of BMIMaes et al. 1997
Behav Genet 27325-351
34
Family Adoption Studies of BMIMaes et al. 1997
Behav Genet 27325-351
35
Integrated Approach

• all collateral two-generational relationships
  identified in kinships of twins (first and second
  degree relatives)
• gt estimate sex-dependent contributions of genes
  and environment to complex traits in presence of
  assortative mating
• gt 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
• gt 80 sex-specific two-generation relationships
• Ascertainment of the Virginia 30,000 Sample
• questionnaires on 14,763 twins, ascertained from
  2 sources
• N5287 families ltVirginia Twin Registry
• N9476 twins ltAmerican 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
• gt 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 lt large sample
  sizes
• lt 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
• gt 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

39
(No Transcript)
40
GenomeEUtwin ProjectSchousbou et al. 2003 Twin
Res 6409-421
41
(No Transcript)
42
(No Transcript)
43
Genetic Epidemiology of BMISchousbou et al. 2003
Twin Res 6409-421
44
(No Transcript)
45
Human Obesity Gene MapPerusse et al. 2004 Obes
Res 13381-490
46
(No Transcript)
47
Heritability of change in weight/fatBouchard
Tremblay 1997 J Nutr 127943S-947S
48
Heritability of fat mass and BMIFaith et al.
1999 Pediatrics 10461-67
49
Heritability of eating patternsvan den Bree et
al. 1999, Am J Clin Nutr 70456-465
50
Heritability of food intakeHeitmann et al. 1999
Am J Clin Nutr 69597-602
51
Exercise
52
(No Transcript)
53
(No Transcript)
54
Physical activity and CancerFriedenreich
Orenstein 2002 J Nutr 1323456S-3464S
55
Biological Mechanisms of activity Friedenreich
Orenstein 2002 J Nutr 1323456S-3464S
56
Framework PEACEFriedenreich Orenstein 2002 J
Nutr 1323456S-3464S
57
Twin Studies of ExerciseStubbe de Geus, 2006
Handbook of Behavior Genetics
58
Twin Studies of ExerciseStubbe de Geus, 2006
Handbook of Behavior Genetics
59
Twin Studies of Physical ActivityStubbe de
Geus, 2006 Handbook of Behavior Genetics
60
Genetics of Exercise BehaviorStubbe de Geus,
2006 Handbook of Behavior Genetics
61
(No Transcript)
62
Heritability of exercise by ageStubbe et al.
2005 Med Sci Sports Exerc 37563-570
63
Genetic Epidemiology Studies

• Advantages Disadvantages

64
Classical Twin Study I

• MZ DZ twins reared together
• ) age matching
• gt age-dependent influences of genes or
  environment
• ) sex limitation (male/female same opposite sex
  twins)
• gt 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
• gt increasing heritability estimates

65
Classical Twin Study II

• equal environment assumption
• MZ/DZs equal proportion of salient environmental
  factors
• similarity gt contact gt 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 lt twins (dichorionic lt monochorionic
  twins)
• correlating intrapair differences in birth weight
  with those in adult BMI gt 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 parents
  phenotype gt offsprings environment gt 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 lt significant marital
  correlation
• gt h2 overestimated in AE, underestimated in ACE
  model
• spouse corr significant but low, c2 not
  significant gt h2 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?
• gt sampling of both genotypes and environments
  suspect
• random placement
• no correlation between biological and adoptive
  parents
• gt 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 lt shared genes or
  environments (siblings cultural transmission/
  non-parental shared env)
• gt measured indices of the environment gt 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)
• gt estimation of additional parameters, such as
  dominance
• ) assortative mating
• estimate of assortment ltmarital 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
• gt different genetic/environmental factors at
  different ages gt parent-offspring sibling
  correlations reduced gt reduced h2
• 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 gt mostly
  same genetic factors, but new genetic factors
  switch on at various ages
• gt 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 gt estimate of genetic transmission
• correlation of adopted children - adoptive
  parents gt 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
• gt separation of genetic and environmental
  pathways
• prenatal environment/ early postnatal
  environment
• gt 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
• gt 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