Genetic Diversity and Association Studies in US Hispanic/Latino Populations: Applications in the Hispanic Community Health Study/Study of Latinos

Abstract

US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population-structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy-Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rican, Mexican, and Central and South American). To control for variation among groups, we developed a multi-dimensional clustering method to define a "genetic-analysis group" variable that retains many properties of self-identified background while achieving substantially greater genetic homogeneity within groups and including participants with non-specific self-identification. In GWASs of 22 biomedical traits, we used a linear mixed model (LMM) including pairwise empirical KCs to account for familial relatedness, PCs for ancestry, and genetic-analysis groups for additional group-associated effects. Including the genetic-analysis group as a covariate accounted for significant trait variation in 8 of 22 traits, even after we fit 20 PCs. Additionally, genetic-analysis groups had significant heterogeneity of residual variance for 20 of 22 traits, and modeling this heteroscedasticity within the LMM reduced genomic inflation for 19 traits. Furthermore, fitting an LMM that utilized a genetic-analysis group rather than a self-identified background group achieved higher power to detect previously reported associations. We expect that the methods applied here will be useful in other studies with multiple ethnic groups, admixture, and relatedness.

Chronic Periodontitis Genome-wide Association Study in the Hispanic Community Health Study / Study of Latinos

“…Participants were genotyped on the HCHS Custom 15041502 array (Illumina Omni2.5M + custom content). Quality control was conducted as described (Laurie et al 2010;Conomos et al 2016). In brief, samples were checked for annotated versus genetic sex discrepancies, gross chromosomal anomalies, missing call rates, contaminations, and batch effects.…”

Detecting Heterogeneity in Population Structure Across the Genome in Admixed Populations

“…Population structure studies have largely focused on populations of European descent, and ancestry differences among European populations have been well studied and characterized (Novembre et al 2008;Nelis et al 2009). Recent studies have also investigated the genetic structure of more diverse populations, including recently admixed populations, such as African-Americans (Zakharia et al 2009;Bryc et al 2010a) and Hispanics (Manichaikul et al 2012;Conomos et al 2016), who have experienced admixing within the past few hundred years from two or more ancestral populations from different continents.Both continental and fine-scale genetic structures of human populations have largely been characterized by aggregating measures of ancestry across the autosomal chromosomes. While it may be reasonable to assume that population structure patterns across the genome are similar for populations with ancestry derived from a single continent, such as populations of European descent, this may not be a reasonable assumption for admixed populations who have recent ancestry from multiple continents.…”

“…Population structure studies have largely focused on populations of European descent, and ancestry differences among European populations have been well studied and characterized (Novembre et al 2008;Nelis et al 2009). Recent studies have also investigated the genetic structure of more diverse populations, including recently admixed populations, such as African-Americans (Zakharia et al 2009;Bryc et al 2010a) and Hispanics (Manichaikul et al 2012;Conomos et al 2016), who have experienced admixing within the past few hundred years from two or more ancestral populations from different continents.…”

“…The substantial loss in power with ANOVA is due to the method not accounting for correlated ancestry among chromosomes in the simulation study that has considerable between-individual variation in proportional ancestry. In practice, we expect that the CAnD test will provide higher power than ANOVA for detecting ancestry differences among chromosomes in recently admixed populations, such as Hispanics, who have large variation in continental admixture (Conomos et al 2016). …”

Projecting Individualized Absolute Invasive Breast Cancer Risk in US Hispanic Women

“…Studies highlighting heterogeneity in breast cancer risk between Hispanic women underscore the importance of differences in country of origin, duration of residence in the United States, and acculturation in estimating the risk of breast cancer (10,(21)(22)(23). Further, there is evidence of genomic differences between Hispanic subgroups in the Unites States (24,25). These factors were not captured in the HRM and may contribute to some of the differences in HRM relative risks and absolute risk predictions in the validation studies.…”