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Introduction to Population Stratification
Standard definition of confounding
A confounder is 1. Associated with the exposure in the study base
2. Associated with disease in the unexposed
3. Not in the causal pathway
Criteria for confounding in genetic association studies
Confounder must be:
1. Correlated with a genetic/molecular variant
2. Associated with risk of the health outcome
Confounding Bias in Genetic Studies
Population Stratification = Confounding by ethnicity
Exposure Disease
Confounder
?
Genetic Variant
EthnicitySmoking
Criteria 1: Gene-ethnicity association
Basic cause of population stratification is non-random mating between groups
Often due to their physical separation Ex: populations of African and European descent
Followed by genetic drift of allele frequencies in each group
In some contemporary populations there has been recent admixture between individuals from different populations
Leads to populations in which ancestry is variable (as in African-Americans)
Over tens of generations, random mating can eliminate this type of stratification
Criteria 1: Gene-ethnicity association
Criteria 2: ethnicity-disease association
Numerous examples of disease risk gradients by ethnic groups
Particularly pronounced with infectious disease susceptibility – potent selection force
Well described for many cancers Example: stomach cancer is 10-20x more
common in Japanese vs. non-Hispanic whites in US
Eric Lander’s example
Would-be geneticist set out to study the "trait" of ability to eat with chopsticks
Sample: San Francisco population Genetic variant of interest: HLA-A1 allele Strong positive association would be seen
But we know that immunological determinants do not play a role in manual dexterity
The allele HLA-Al is more common among Asians than Caucasians
Asian ethnicity associated with the phenotype of interest
G
X
D
no confounding
G
X
D
no confounding
G
X
D
Population structure,potential
confounding
Adjusting for X unnecessary or
insufficient; can even reduce
power
