Introduction to Population
Stratification
Standard definition of
confounding
A confounder is
1.
2.
3.
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:
1.
2.
Correlated with a genetic/molecular variant
Associated with risk of the health outcome
Confounding Bias in Genetic Studies
?
Exposure
Genetic
Variant
Disease
Confounder
Smoking
Ethnicity
Population Stratification = Confounding by
ethnicity
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
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
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
D
X
no confounding
G
D
Adjusting for X
unnecessary or
insufficient;
can even reduce
power
X
no confounding
G
D
X
Population
structure,
potential
confounding