Multi-Ancestry Genome-Wide Association Analysis Incorporating SNP-by-Psychosocial Interactions Identify Novel Loci for Serum Lipids

Serum lipid levels are key biomarkers for cardiometabolic outcomes influenced by both genetic and environmental factors; understanding their underlying mechanisms can have important public health implications. Over 700 lipid loci have been identified by GWAS without accounting for the environmental context. Psychosocial factors, such as depression (DEPR), anxiety (ANXT), and perceived social support (SOCS), are associated with serum lipid levels, yet it is unknown if they could modify the effect of lipid loci. We conducted a genome-wide gene-by-psychosocial interactions (G×Psy) study in 133,157 individuals from multiple ancestries to evaluate if G×Psy influence serum lipid levels. 
We conducted a 2-Stage meta-analysis of G×Psy using 1000 Genomes imputed variants using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analysis on 77,413 individuals across five ancestries and evaluated variants from all suggestive associations (p<10-5) in Stage 2 (n=55,744). Main findings were defined as significant associations from the meta-analysis of the two stages (p<5×10-8). 
We identified novel associations for variants in 5 loci using the 1df test of interaction and an additional 7 loci that were associated using the 2df joint test of the main effect and interaction and were independent of known lipids loci (3 loci were associated for both 1df and 2df tests). Four of the 2df associations appeared to be driven by a main effect of the variant: rs34636484 (CD96), rs10742937 (CTD-2026G22.1), rs13339410 (KIAA0895L), and rs11702544 (RRP1B). However, most of the associations could not have been detected using a standard GWAS model without accounting for interaction. The diversity of included samples was key in identifying novel loci, and 4 of our lead associations were for variants with no data available for European ancestry studies. Functional annotation highlighted the promise of some of these loci for further follow-up, particularly rs13339140 (KIAA0895L)-DEPR-HDL, rs73597733 (MACROD2)-DEPR-HDL, rs59808825 (GRAMD1B)-ANXT-LDL, and rs11702544 (RRP1B)-DEPR-HDL. Overall, our findings suggest that consideration of interaction between genetic variants and psychosocial factors can lead to gene discovery for serum lipids.