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 G X D Population structure, potential confounding Adjusting for X unnecessary or insufficient; can even reduce power