Fine-scale structure of a whole regional population through genetics and genealogies

Abstract

Population stratification can confound genetic association studies and often persists despite adjustment using principal components of common variants. Demographic history and rare variants can also contribute to this confounding. But to what extent does demographic history impact fine structure and can be detected in human populations? To address this question, we analysed the Saguenay–Lac-Saint-Jean region of Quebec, a recent founder population long assumed to be homogeneous. Integrating genotype data with genealogical records, we show a strong concordance between realised (genetic) and expected (genealogical) kinship. Using a time-efficient algorithm capable of computing billions of pairwise kinship coefficients for all individuals married in the region between 1931 and 1960, we reveal fine structure at the municipal level, including an east–west genetic gradient shaped by differential founders’ contribution, migration patterns and socioeconomic factors. These findings challenge the assumption of regional homogeneity and suggest that similar recent structure likely exists in other populations worldwide. These signals may be obscured by coarse, ancient structure under standard stratification corrections used in genome-wide association studies and polygenic risk score analyses which can lead to biases and false associations when realised allele frequencies correlate with phenotypic variation.