Influence of Genetic Ancestry on Gene-Environment Interactions of Polygenic Risk and Sociocultural Factors: Results from the Hispanic Community Health Study/Study of Latinos

Abstract

Background: Many present analyses of Hispanic/Latino populations in epidemiologic research aggregate all members of this ethnic group, despite immense diversity in genetic backgrounds, environment, and culture between and across Hispanic/Latino background groups. Using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we examined the role of self-identified background group and genetic ancestry proportions in gene-environment interactions influencing the relationship between body mass index (BMI) and a polygenic score for BMI (PGS_BMI).

Methods: Weighted univariate and multivariable generalized linear models were executed to compare the effects of environmental variables identified a priori by McArdle et al. 2021. Both Amerindigenous (AME) ancestry proportion and background group identity were statistically modeled as confounders both through stratified and joint analyses to understand their influence on the relationship between BMI and PGS_BMI, while incorporating gene-environment interactions of PGS x diet and PGS x age-at-immigration.

Results: After complex survey weighting, 7,075 participants remained in the analytic sample, representing individuals of six background groups: Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American. The distributions of key environmental and sociocultural variables were heterogeneous between Hispanic/Latino background groups. Associations of these variables with AME ancestry were similarly heterogeneous upon stratification, indicating confounding by background group. In a predictive model for BMI incorporating health, immigration, and environmental variables, PGS_BMI performance decreased with increasing AME ancestry proportion. In this model, most statistically significant GxE interactions lost significance after ancestry and background stratification, except for PGS x age-at-immigration interactions in some strata: Mexican background individuals born in the US compared to those >=21 years old at migration (β=1.33, p<0.01), Dominican background individuals 6-12 years old at migration compared to those >=21 years old at migration (β=4.38, p<0.001), and Cuban background individuals 0-5 years old at migration compared to those >=21 years old at migration (β=2.20, p=0.015), where US-born includes individuals born in the US 50 states/DC.

Conclusions: Controlling for self-identified background group identity and genetic ancestry did not eliminate statistically significant differences in interactions between AME ancestry and environmental variables in certain strata of AME ancestry among some Hispanic/Latino background groups in HCHS/SOL.

Figure 1.

Conceptual Framework of Full Analytic Model

Figure 2.

Distributions of Selected Variables by AME Ancestry Proportion Aggregated and by Background Graphical depictions of relationships between AME ancestry proportion and A) BMI, B) PGS_BMI, C) immigrant generation, D) diet score (1=under 60th sex-specific percentile of JAMA Healthy Diet score, 2= top 40th sex-specific percentile of JAMA Healthy Diet score), and E) prevalent cardiovascular disease in the complete sample (left panels; 1=yes, 0=no) and stratified by self-identified background group identity (right panels). * indicates statistically significant differences (p<0.05) between categories.