Admixture Mapping Identifies Ancestry-Associated Loci Linked to Hyperandrogenism and Insulin Resistance in HAIR-AN

Introduction: HAIR-AN syndrome, defined by hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN), represents a severe metabolic–reproductive phenotype with marked ethnic disparities in prevalence. Although overlaps with polycystic ovary syndrome are recognized, the genetic architecture underlying ancestry-related susceptibility in admixed populations remains largely unresolved, limiting translational insights and precision approaches. Objective: To identify ancestry-associated genomic loci contributing to HA and IR in HAIR-AN syndrome using an admixture mapping framework in admixed women. Methods: We performed an integrative ancestry-informed genomic analysis using publicly available multi-ethnic datasets comprising genome-wide SNP data and detailed endocrine–metabolic phenotypes. After rigorous quality control and imputation, global and local ancestry were inferred, followed by admixture mapping to test associations between local ancestry and HA- or IR–related traits. Significant loci were fine-mapped using SNP-level association analyses, functionally annotated through eQTL and regulatory datasets, and evaluated with pathway enrichment and sensitivity analyses. Results: Among 1,847 admixed women, three genome-wide significant ancestry-associated loci were identified. African ancestry at chromosome 19p13.2 was strongly associated with elevated testosterone and HOMA-IR, implicating the INSR locus and insulin signaling pathways. Native American ancestry at 11p15.5 influenced androgen indices near the IGF2 locus, while African ancestry at 10q26.3 was associated with fasting insulin levels. Fine-mapping highlighted ancestry-differentiated regulatory variants with functional effects in metabolic tissues. Associations were robust across sensitivity and stratified analyses. Conclusion: Admixture mapping reveals ancestry-specific genetic mechanisms underlying HA and IR in HAIR-AN syndrome, underscoring the importance of ancestry-aware genomic approaches to elucidate pathophysiology and inform precision endocrinology.