methods in genetic epidemiology lindon eaves vipbg march 2006
TRANSCRIPT
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Methods in Genetic Epidemiology
Lindon Eaves
VIPBG
March 2006
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Link to basic genetics
http://psych-www.colorado.edu/hgss/hgssfigures/hgssfigures.htm#Chapter10
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“Epidemiology”
Identification of “causes from clusters”
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Clusters and Causes
• Sources of water (cholera)
• Insect vectors (malaria)
• Working in mines (silicosis)
• Toxic waste (some cancers)
• Hypertension (ethnicity)
• Etc.
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THE “FAMILY”
A primary cluster
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Large pedigree from the isolate with a founder couple born in approximately 1650. Circles represent females; squares represent males. Blackened circles and squares represent individuals with at least two children affected with schizophrenia.Am J Hum Genet. October 1999; 65(4): 1114–1124. Published online September 3, 1999. Copyright © 1999 by The American Society of Human Genetics. All rights reserved.
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Insert Kuru pedigree here!
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Draw your own pedigree
http://www.genesoc.com/nutrition/pedigree.htm
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Familial disorders
• Familial hypercholesterolemia• Bovine spongiform encephalopathy• Schizohphrenia• Kuru• Colon cancer• Mental retardation• Breast cancer• Etc. etc. etc.
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Family clustering may be genetic or environmental
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“Genetic Epidemiology”
Systematic use of familial clustering to resolve and identify genetic and environmental causes of disease
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Questions in GE
• Is “it” familial?• Is it “genetic” (G), “environmental” (E) or both
(G+E)?• What are relative contributions of G and E?• What kinds of genetic effects are there (one,
few, many, additive/epistatic)?• Effects of population structure, ethnicity,
stratification, mate selection?• What is role of E? Which? GxE interaction?• Which specific genes are involved?
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P
G4G1 G2 G3 E1 E4E2 E3
GE
P1 P4P2 P3
G’4
E’4E’1G’2 E’3
G’1
Measured Genotypes Measured Environments
Outcome Phenotype
Endophenotypes
TIME?
P5
G’5
E’
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= Pathway blocked by mutant gene
A
B
BC
A
aa
bb
aa bb
Sequential (“complementary”) genesParallel (“duplicate”) genes
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Answering the questions:some approaches
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Is it familial?
• Risk to relatives (schizophrenia, colorectal cancer, mental retardation, hypertension)
• Correlation between relatives (IQ, diastolic blood pressure)
• Same trait may be category or dimension (hypertension = DBP>90mmHg)
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Causes of Family Resemblance
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Path diagram for the effects of genes and environment on phenotype
P
G E
Measured variable
Latent variables
Genotype Environment
Phenotype
h e
r
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M
C
F
Em Gm Gf Ef
Ec Gc
Mother Father
Offspring
h e
e h h e
r r
f f
½ ½
m
Family Resemblance
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-14 -10 -6 -2 2 6 10 14
IHT
0.00
0.04
0.08
0.12
0.16
Distribution of stature corrected for age and sex(Inches from mean)
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Probability ofOutcome
0
1
0 t
0.5
Liability
-
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Polygenic Inheritance (Fisher, 1918)
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0 1 2 3 4 5
Y1
0.0
0.1
0.2
0.3
0.4
Distribution of scores produced by two genes(N=1000 subjects)
-2.5 -1.5 -0.5 0.5 1.5 2.5 3.5 4.5 5.5 6.5
S1
0.0
0.1
0.2
0.3
0.4
The "smoothing" effect of the environment(N=1000 subjects, 2 gene model)
75 79 83 87 91 95 99 103 107 111 115 119 123
Y1
0.00
0.02
0.04
0.06
Continuous distribution of polygenic trait (100 genes with small cumulative effects)
b.
c.
a.
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Estimating G and E (1)
Twin Studies (Galton 1865)
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Figure 9. The correlation between twins for stature (data from the Virginia Twin Study of Adolescent Behavioral Development).
-10 -5 0 5 10
HTDEV1
-12
-7
-2
3
8
13
HT
DE
V2
Scatterplot for corrected MZ stature
r=0.924
-16 -11 -6 -1 4 9 14
HTDEV1
-20
-10
0
10
20
HT
DE
V2
Scatterplot for age and sex corrected stature in DZ twins
r=0.535
Stature in Twins
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Path diagram for twin resemblance
P1 P2
E1
A2A1
C1 C2
E2
1
g
c c
e e
a a
Twin 1 Twin 2
Phenotypes
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Four scenarios
00.10.20.30.40.50.60.70.80.9
No G No C G and C G and I
MZDZ
Twin Correlation
Causes of Variation
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Estimating G and E (2)
Adoption studies
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GAC EAC GBC EBC
GAF EAF GAM EAFEBFGBF GBM EBM
BF
BCAC
BM
AF
AM
p p
p
p1/2
1/2f
m
Biological Parents Adopting parents
Adopted Child Biological Child of Adopting Parents
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Other approaches
• Separated Twins (e.g. Shields, 1966)
• Twins and parents
• Children of Twins
• Extended twin kinships
• Combinations of Methods
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Identifying environments
Measure environment in family, twin or adoption study
(e.g. twins discordant for exposure, characteristics of
foster parents etc.)
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Finding the genes
• Linkage studies – extended pedigrees, sib pairs
• Association studies (case-control, family-based – e.g. TDT, sib-pair)
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“Linkage”
Genes that start together stay together – the closer they are, the more they stay together
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Linkage
Are relatives who are more alike for a “marker” more alike in their
phenotypes?
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Q1 Q2
G1 G2
E2E1
T1 T2
½
h h
q q
e e
QTLGENES
ENVIRONMENT
PHENOTYPE
Linkage: Sibling Resemblance
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Sib-pair similarity and linkage
0 10.5
SiblingCorrelation
0
Q
R
r
r=R+Q
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Linkage – plusses and minuses
• PLUSES• Depends only on
marker location, not effect of marker on phenotype
• Doesn’t require many markers to cover genome (100s)
• Hard to “invent” linkage - robust
• MINUSES• Works best for simple
(few-gene) traits• Gene effects need to
be big• Specific localization
poor (i.e. many genes under linkage “peak”)
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Association
Do different forms of gene (“alleles”) have different
phenotypes?
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Association: Pluses and Minuses
• PLUSES• Statistical power• “Tight” localization• Can use “candidate
genes”
• MINUSES• Association may not be
causal (e.g. “linkage disequilibrium”, population stratification) – but can control/eliminate
• Needs large number of markers for genome-wide study (?500,000+)
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P
M3
M1
M2
M4
Genome
Genome
Phenotype
Marker-Phenotype Association
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Controlling for stratification
• Analyze within strata (ethnicity, SES etc)
• Use random genes to test, characterize and eliminate
• Family-based association – TDT, sib-pairs etc.
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Complications – can’t always do genetics without environment
• GxE Interaction
• G-E correlation
• G x Age interaction
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GxE Interaction
• Genes control sensitivity to the environment (some environments only affect particular genotypes)
• Environments modulate expression of genes (some genes only expressed in particular environments)
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b. “Scalar” GxE
Environment (E)
PhenotypeGenotypes
c. “Non-scalar” GxE
Environment (E)
PhenotypeGenotypes
a. No GxE
Environment (E)
PhenotypeGenotypes
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Analyzing GxE
• Family resemblance depends on environmental exposure
• Effect of gene contingent on environment (or vice-versa)
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Genetic Variance and Shared Life Events in Adolescent Females (Silberg et al.,
1999)
00.5
11.5
22.5
33.5
44.5
0 1 2+
Number of life events
Gen
etic
Var
ian
ce
DepressionAnxiety
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0
5
10
15
20
25
30
35
40
No Probable Definite
Low MAOA
High MAOA
Figure: Prevalence of Conduct Disorder as a function of MAOA activity and exposure to environmental adversity
(Foley et al, 2004)
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G-E Correlation: Environmental exposure
caused/influenced by genes
• “Active/Evocative” - environment depends directly on genes of individual (e.g. own smoking”)
• “Passive” – environment depends on genes of relatives (e.g. parental smoking)
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Analyzing rGE
• Include environmental measures in twin, adoption and family studies – build and test path models.
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G x Age Interaction
• Genetic control of age of onset
• Different genes expressed at different ages
• Rates of growth/change depend on genes
- A bit like GxE in some ways.