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Introduction to Population Stratification

Introduction to Population Stratification. Standard definition of confounding. A confounder is Associated with the exposure in the study base Associated with disease in the unexposed Not in the causal pathway. Criteria for confounding in genetic association studies. Confounder must be:

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Introduction to Population Stratification

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  1. Introduction to Population Stratification

  2. Standard definition of confounding A confounder is • Associated with the exposure in the study base • Associated with disease in the unexposed • Not in the causal pathway

  3. Criteria for confounding in genetic association studies Confounder must be: • Correlated with a genetic/molecular variant • Associated with risk of the health outcome

  4. Confounding Bias in Genetic Studies ? Exposure Genetic Variant Disease Confounder Smoking Ethnicity Population Stratification = Confounding by ethnicity

  5. 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

  6. Criteria 1: Gene-ethnicity association • 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

  7. 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

  8. 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

  9. Adjusting for X unnecessary or insufficient; can even reduce power G D X no confounding G D X Population structure,potential confounding G D X no confounding

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