Genetic Epidemiology of Cancer and itsRisk Factors
Hermine MaesCancer ControlMarch 2006
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
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
sex sex
MZ DZ MZ DZ MZ DZ MZ DZ MZ DZ MZ DZLip M 0 0 27 57 0 0 Prostate M 40 20 299 584 0.21 0.06
F 0 0 4 8 0 0 Testis M 1 0 22 38 0.08 0Oral cavity M 0 0 10 20 0 0 Kidney M 0 0 61 108 0 0
F 0 0 6 24 0 0 F 0 0 48 99 0 0Pharynx M 0 0 11 19 0 0 Bladder M 5 2 146 253 0.06 0.02
F 0 0 7 5 0 0 F 0 0 43 76 0 0Esophagus M 0 1 16 50 0 0.04 Skin M 0 2 49 78 0 0.05
F 0 0 17 31 0 0 F 1 0 58 105 0.03 0Stomach M 6 8 131 256 0.08 0.06 Brain, ONS M 1 0 65 112 0.03 0
F 5 4 92 198 0.1 0.04 F 0 1 66 142 0 0.01Colorectum M 10 17 202 393 0.09 0.08 Thyroid M 0 0 10 19 0 0
F 20 15 214 453 0.16 0.06 F 0 0 29 44 0 0Liver M 0 1 30 44 0 0.04 Bone M 0 0 5 0
F 0 1 23 35 0 0.05 F 0 0 2 6 0 0Galbladder M 0 0 16 25 0 0 Soft Tissue M 0 0 12 27 0 0
F 1 1 51 81 0.04 0.02 F 0 0 14 23 0 0Pancreas M 2 1 64 127 0.06 0.03 Non-Hodgkin's M 0 0 36 99 0 0
F 1 0 59 127 0.03 0 lymphoma F 0 0 45 84 0 0Larynx M 2 1 22 36 0.15 0.05 Hodgkin's M 0 0 14 19 0 0
F 0 0 3 11 0 0 F 0 0 18 12 0 0Lung M 15 24 233 436 0.11 0.1 Multiple myeloma M 1 0 36 57 0.05 0
F 3 1 63 185 0.09 0.01 F 0 0 28 38 0 0Breast M 0 0 2 5 0 0 Leukemia M 2 1 51 105 0.07 0.02
F 42 52 505 1023 0.14 0.09 F 0 1 52 93 0 0.02Cervix uteri F 1 3 107 201 0.02 0.03Corpus uteri F 1 5 122 245 0.02 0.04 All sites M 262 356 1252 2459 0.29 0.22Ovary F 3 1 125 230 0.05 0.01 F 265 408 1487 3023 0.26 0.21
discordant affected
concordanceconcordant affected
discordant affected
concordance concordant affected
Genetic Epidemiology of Cancers Lichtenstein et al. 2000 NEJM 343:78-85
Genetic Epidemiology of CancersLichtenstein et al. 2000 NEJM 343:78-85
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
stomach
colorectum
pancreas
lung
breast
cervix uteri
corpus uteri
ovary
prostate
bladder
leukemia
additive genetic shared environment
Correlations Mammography densityBoyd et al. 2002 NEJM 347:886-894
Heritability Mammography densityBoyd et al. 2002 NEJM 347:886-894
Familial Risk for CancerSwedish Family-Cancer Database
Standardized incidence ratioHemminki et al. 2001 Br J Cancer 84:388-391
Population Attributable FractionHemminki & Czene 2002 CEBP 11:1638-1644
Risk Factors for Cancer
Obesity Exercise / Physical Activity
Smoking Alcohol / Drug Use
Obesity
Cancer Mortality due to BMI -menCalle et al. 2003 NEJM 348:1625-1638
Cancer Mortality due to BMI -womenCalle et al. 2003 NEJM 348:1625-1638
Population Attributable FractionCalle et al. 2003 NEJM 348:1625-1638
Cancer-attributable deaths EUBanegas et al. 2003 Eur J Clin Nutr 57:201-208
All-cause deaths to excess weightBanegas et al. 2003 Eur J Clin Nutr 57:201-208
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)
MZ twins
0
0.2
0.4
0.6
0.8
1
0 500 1000 1500 2000 2500
DZ twins
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
0 500 1000 1500 2000 2500 3000
Twin correlations for BMI
Parent-Offspring
-0.1
0
0.1
0.2
0.3
0.4
0.5
0 2000 4000 6000 8000 10000 12000 14000
Siblings
0
0.1
0.2
0.3
0.4
0.5
0.6
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000
Sibling & PO correlations for BMI
Adoptive Pairs
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0 50 100 150 200 250 300 350 400 450 500
Spouses
-0.1
0
0.1
0.2
0.3
0.4
0.5
0 5000 10000 15000 20000 25000 30000
Non-biological correlations BMI
MZ twins
0
0.2
0.4
0.6
0.8
1
0 500 1000 1500 2000 2500
Parent-Offspring
-0.1
0
0.1
0.2
0.3
0.4
0.5
0 2000 4000 6000 8000 10000 12000 14000
Siblings
0
0.1
0.2
0.3
0.4
0.5
0.6
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000
Adoptive Pairs
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0 50 100 150 200 250 300 350 400 450 500
DZ twins
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
0 500 1000 1500 2000 2500 3000
Spouses
-0.1
0
0.1
0.2
0.3
0.4
0.5
0 5000 10000 15000 20000 25000 30000
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
Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
NAS-NRC (VA)Finnish TR
Sweden SATSA mSweden SATSA f
Danish TR mDanish TR f
Norway TP mNorway TP f
TrondelagOZ NH&MRC <30yOZ NH&MRC >30y
Virginia 30k mVirginia 30k fMI MTSADA
Utah pedigreesKP TRBritain
US CAATSA
heritability adults
Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Sweden SATSA
Britain m
Britain f
Britain
Finland,Japan
heritability twins reared apart
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
MCV TS
China
US (GA,KE,IN)
Belgium
VTSABD 8-10y
VTSABD 11-13y
VTSABD 14-16y
heritability adolescents
Longitudinal Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
NAS-NRC Y-MNAS-NRC M-L
Finnish TCMCV TS mMCV TS fVTSABD
LLTS
genetic correlations
Family & Adoption Studies of BMIMaes et al. 1997 Behav Genet 27:325-351
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Quebec FSCanada Fitness SNorway Trondelag
NHLBI FHS
heritability family studies
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Danish ARLondon
TOPSMontrealQuebec
IowaColorado AP sibs
Colorado AP po
heritability adoption studies
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
CA B
T F
a f c f
CA B
T M
b m c m
i
on
CA B
P F
a f c f
CA B
P M
a m b m c m
m p
a m
K
l f
L
k m k f
lm
L
Kk f
l f
L
Kk m
lm
L
r vs
euqr v
s
euq
y
eu*q* eu*q*
1
1
1
1
1
1
1
K
1
d
Ttm t fT
w
1 1
Ttm
1t f T
1
.5 .5 .5.5.5 .5.5 .5
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
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
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
GenomeEUtwin ProjectSchousbou et al. 2003 Twin Res 6:409-421
Genetic Epidemiology of BMISchousbou et al. 2003 Twin Res 6:409-421
Human Obesity Gene MapPerusse et al. 2004 Obes Res 13:381-490
Heritability of change in weight/fatBouchard & Tremblay 1997 J Nutr 127:943S-947S
Heritability of fat mass and BMIFaith et al. 1999 Pediatrics 104:61-67
Heritability of eating patternsvan den Bree et al. 1999, Am J Clin Nutr 70:456-465
Heritability of food intakeHeitmann et al. 1999 Am J Clin Nutr 69:597-602
Exercise
Physical activity and CancerFriedenreich & Orenstein 2002 J Nutr 132:3456S-3464S
Biological Mechanisms of activity Friedenreich & Orenstein 2002 J Nutr 132:3456S-3464S
Framework PEACEFriedenreich & Orenstein 2002 J Nutr 132:3456S-3464S
Twin Studies of ExerciseStubbe & de Geus, 2006 Handbook of Behavior Genetics
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Canada
Dutch 14-20y
Dutch 13-22y
Portugal m
Portugal f
Dutch 13-22y
Belgium 15y m
Belgium 15y f
Dutch 13-14y
Dutch 15-16y
Dutch 17-18y
Dutch 19-20y
addtive genetic shared environment adolescents
Twin Studies of ExerciseStubbe & de Geus, 2006 Handbook of Behavior Genetics
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Australia
VETS
Dutch 14-20y
Dutch 13-22y
Danish
Dutch 35-62
GenomeEUtwin m
GenomeEUtwin f
addtive genetic shared environment adults
Twin Studies of Physical ActivityStubbe & de Geus, 2006 Handbook of Behavior Genetics
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Finland >18y
Canada 15y
Finland 16y m
Finland 16y f
Portugal 12-25y m
Portugal 12-25y f
Finland 24-60y va
Finland 24-60y la
US (AZ) 4-10y paee
US (AZ) 4-10y tee
addtive genetic shared environment
Genetics of Exercise BehaviorStubbe & de Geus, 2006 Handbook of Behavior Genetics
Country N twin pairs
male female male femaleAustralia 2,728 64% 56% 48% 48%Denmark 9,456 43% 33% 52% 52%Finland 8,842 37% 29% 62% 62%The Netherlands 2,681 58% 55% 67% 67%Norway 3,995 55% 51% 27% 56%Sweden 8,927 37% 23% 62% 62%United Kingdom 422 - 53% - 70%
percentage exercisers
heritability estimates
Heritability of exercise by ageStubbe et al. 2005 Med Sci Sports Exerc 37:563-570
Genetic Epidemiology Studies
Advantages & Disadvantages
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
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)
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 > h2 overestimated in AE, underestimated in ACE model
spouse corr significant but low, c2 not significant > h2 overestimated
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
Family StudiesNuclear 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
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 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 > mostly same genetic factors, but new genetic factors switch on at various ages
> discrepancies between results from family & twin studies
Adoption Studies IComplete 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
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