Genetic and multi-omic insights into inflammation and metabolism in a French Polynesian cohort

Abstract

Inflammatory and metabolic diseases are a major global health burden, and their genetic mechanisms differ between populations. The stepwise settlement of the Pacific has left Polynesian communities with variants that are locally common and globally rare. Yet these communities remain underrepresented in genomic research. Here we combine whole-genome sequencing with blood metabolite and gene-activity profiling in a gout-focused cohort of 1,043 French Polynesian participants, and show that such variants shape molecular traits and disease risk. Hundreds alter metabolite levels, gene expression or splicing but are absent or rare in global reference datasets. Findings include a gene-disrupting variant in ANGPTL8 that lowers lipids and inflammatory markers; an LRMDA variant linked to type 2 diabetes; and a signal at the alpha-globin locus suggestive of thalassemia trait. Integrating molecular and phenotypic data further implicates WDR1 as an additional causal gout gene at the SLC2A9 locus. Genomic research in underrepresented populations thus reveals broadly relevant disease mechanisms.