Genome-wide Significance Thresholds for Admixture Mapping Studies

Abstract

Admixture mapping studies have become more common in recent years, due in part to technological advances and growing international efforts to increase the diversity of genetic studies. However, many open questions remain about appropriate implementation of admixture mapping studies, including how best to control for multiple testing, particularly in the presence of population structure. In this study, we develop a theoretical framework to characterize the correlation of local ancestry and admixture mapping test statistics in admixed populations with contributions from any number of ancestral populations and arbitrary population structure. Based on this framework, we develop an analytical approach for obtaining genome-wide significance thresholds for admixture mapping studies. We validate our approach via analysis of simulated traits with real genotype data for 8,064 unrelated African American and 3,425 Hispanic/Latina women from the Women's Health Initiative SNP Health Association Resource (WHI SHARe). In an application to these WHI SHARe data, our approach yields genome-wide significant p value thresholds of 2.1 × 10^-5 and 4.5 × 10^-6 for admixture mapping studies in the African American and Hispanic/Latina cohorts, respectively. Compared to other commonly used multiple testing correction procedures, our method is fast, easy to implement (using our publicly available R package), and controls the family-wise error rate even in structured populations. Importantly, we note that the appropriate admixture mapping significance threshold depends on the number of ancestral populations, generations since admixture, and population structure of the sample; as a result, significance thresholds are not, in general, transferable across studies.

Keywords: family-wise error rate; genetic admixture; genome-wide association; multiple testing; population structure.

Figure 1

Inheritance of Genetic Material in an Admixed Population with Two Ancestral Populations Colors indicate the ancestral origin of genetic material across a single chromosome, with two ancestral populations (orange, blue). In each generation, genetic material is passed from parents to offspring, with crossover events leading to chromosomes with a mixture of genetic material from the parent’s maternal and paternal chromosomes. Over time, blocks of ancestry are broken up by additional crossover events, resulting in a mosaic of segments of different ancestral origins. We refer to the locus-specific ancestral origin of genetic material as local ancestry, while admixture proportion or global ancestry refers to the overall (genome-wide) proportion of genetic material inherited from each ancestral population.

Figure 2

Estimated Admixture Proportions in WHI SHARe (A) Estimated proportions of genetic material inherited from European (EUR) and African (AFR) ancestral populations for the African American samples. (B) Proportions of European (EUR), African (AFR), and Native American (NAM) ancestry for the Hispanic/Latina samples.

Figure 3

Correlation of Local Ancestry and Test Statistics in WHI SHARe (A) Comparison of the observed and expected (theoretical) correlation of the European component of local ancestry vectors in the Hispanic/Latina cohort, averaging across pairs of markers falling into bins defined by their distance apart. The expected correlation comes from Lemma 1, with $g=9.6$. (B) Comparison of the observed and expected (theoretical) correlation of admixture mapping test statistics in the African American cohort, with expected correlation corresponding to Theorem 1, using $g=5.9$.