Lessons from single cell omics: admixed American ancestry and sex confer cardiometabolic disease risk in Mexicans

Subcutaneous adipose tissue (SAT), the key human fat depot for cardiometabolic health, exhibits high cellular heterogeneity. However, the contributions of contexts and cardiometabolic diseases (CMDs) to this heterogeneity are poorly understood, especially in admixed populations. Despite the substantially increased risk of obesity and obesity-related CMDs in Mexicans, cell-type-level mechanisms behind their elevated CMD risk have remained elusive. To investigate how cell-type and subcell-type level profiles of SAT are impacted by sex, admixed American ancestry, CMD traits, and cell-type level cis regulation in Mexicans, we generated a Mexican SAT single nucleus RNA sequencing cohort (n = 49). We performed cell-type level differential expression testing, weighted gene co-expression analysis, and cis-expression quantitative trait locus (eQTL) mappings. We then integrated genome-wide association study (GWAS) and Mexican population level data to assess partitioned polygenic risk for lipid outcomes and colocalization between SAT cell-type level cis-eQTL variants and lipid GWAS variants. First, we discovered and validated a sex-associated adipocyte subtype, overlapping an adipocyte co-expression network with 132 adipocyte function centered genes, including key triglyceride biosynthesis genes, GPAM, DGAT2, ACSL1, and LPL, that are differentially expressed (DE) by sex. The cis regional variants of these network genes DE by sex confer a significant sex-specific polygenic risk to serum triglycerides, a clinically important atherogenic lipid trait. We also found significant enrichment of progesterone receptor binding at these variant sites, contributing to the sex-specific findings. Second, we identified 34 colocalized genes for three lipid traits, of which 25 (74%) genes have not been identified in previous European colocalization studies using SAT bulk tissue. Among the discovered 25 lipid GWAS genes, 12 are regulated by Mexican enriched and seven by European enriched cis-eQTL variants, thus mechanistically elucidating the genetic dyslipidemia susceptibility at the cell-type level in both Europeans and Mexicans. The identified 12 lipid GWAS genes regulated by a Mexican enriched variant include an important adipogenesis gene, CYP26B1, and a regulator of adipocyte browning and beiging, GPR180. We identify sex- and ancestry-stratified genes and variants contributing to the risk of adverse cardiometabolic outcomes and improve understanding of the complex cell-type level biological mechanisms underlying CMDs in Mexicans.