The PAGE Study: How Genetic Diversity Improves Our Understanding of the Architecture of Complex Traits

Abstract

Summary/AbstractGenome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development, and clinical guidelines. However, the dominance of European-ancestry populations in GWAS creates a biased view of the role of human variation in disease, and hinders the equitable translation of genetic associations into clinical and public health applications. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioral phenotypes in 49,839 non-European individuals. Using strategies designed for analysis of multi-ethnic and admixed populations, we confirm 574 GWAS catalog variants across these traits, and find 38 secondary signals in known loci and 27 novel loci. Our data shows strong evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts, and insights into clinical implications. We strongly advocate for continued, large genome-wide efforts in diverse populations to reduce health disparities.

Generalization and fine mapping of red blood cell trait genetic associations to multi‐ethnic populations: The PAGE study

“…By examining visualizations of generalized association signals, we further identified several cases in which the lead SNP in LD with the European index SNP was not the most significant SNP in the region, indicating differences. These findings are consistent with recent work in large trans-ethnic populations, which demonstrated considerable effect heterogeneity by genetic ancestry in GWAS index SNPs reported in studies of predominantly European populations; considerably less evidence of heterogeneity was detected when examining index SNPs identified in multi-ethnic populations 54 . Of particular relevance are recent demonstrations of inappropriate designation of variants which are rare in European populations as pathogenic when they are in fact common in other ancestral groups 55 .…”

Father Absence and Accelerated Reproductive Development in Non-Hispanic White Women in the United States

“…Data include measures of family structure, reproductive development, and genome-wide molecular genetic data (Harris 2010; Harris et al 2013). Given the complications inherent in working with genetic data in diverse samples (Martin et al 2017; Wojcik et al 2017), we restrict our primary analytic sample to 2,681 unrelated non-Hispanic white women, and supplementary analyses of sisters to 411 genetically confirmed non-Hispanic white sisters. Add Health genetic data are available on roughly 800 non-Hispanic black and 700 Hispanic females for future research.…”

“…However, because patterns of linkage disequilibrium reflect genetic inheritance, they vary across populations of different ancestry. A result of ancestry-associated differences in patterns of linkage disequilibrium is that a given genotype may contain different information about the genome when measured in one population versus another (Carlson et al 2013; Shifman et al 2003; Wojcik et al 2017). In the context of polygenic scoring, applying GWAS results derived in one population to compute a polygenic score in a different population introduces measurement error, which is one reason why polygenic scores derived from GWAS of European ancestry populations have reduced effect sizes in African ancestry populations (Belsky et al 2013; Domingue et al 2014, 2015).…”

Rapid detection of identity-by-descent tracts for mega-scale datasets

“…To explore the utility of IBD haplotypes inferred by iLASH in a large genomic dataset we constructed an IBD-based network of distant relatedness among the PAGE dataset 27 . In this network individuals are represented by nodes (N=38,919 across 3 PAGE Studies: WHI, MEC and HCHS/SOL) that are connected by edges (e= 55,069,482) if they share any haplotypes IBD.…”