FRMD6 is associated with peripheral fat distribution in Qinghai Tibetans

Tibetan highlanders have adapted to chronic hypoxia, but the genetic basis of their body composition is poorly understood. We conducted the first genome-wide association study of body composition in a Qinghai Tibetan highland migrant population to identify genetic variants associated with regional adiposity. We analyzed 33 body composition phenotypes in 1,231 Qinghai Tibetan individuals genotyped on an Asian-Screening Array (438,823 SNPs). Outliers beyond ± 3 SD were excluded, and phenotypes were adjusted for age and sex. Genome-wide association analyses were performed using a linear mixed model implemented in GEMMA to account for relatedness and population stratification. The lead variant rs11626565, located upstream of FRMD6 , showed genome-wide significant associations with multiple fat traits. The strongest signals were for limb and gynoid fat percentages, including right leg ( P = 3.56 × 10 − 12 ), gynoid ( P = 2.37 × 10 − 11 ), left leg ( P = 3.50 × 10 − 11 ), left arm ( P = 1.68 × 10 − 10 ), and right arm ( P = 1.50 × 10 − 9 ). Effect sizes were substantially larger for these regional fat measures than for android+gynoid fat percentage ( P = 8.44 × 10 − 8 ). Suggestive associations ( P < 1.0 × 10 − 5 ) were also identified for height ( TMC2 ), BMI and weight ( SFXN1 , ADCY2 ), waist and hip circumference ( NTM , WAPL-LDB3 ), fat-free and skeletal muscle mass ( DLGAP2 ), and android and visceral fat measures ( ETS1 ). This first GWAS of body composition in a Tibetan population identifies FRMD6 as a novel locus with particularly strong and specific effects on limb and gynoid fat distribution, highlighting its potential role in regional subcutaneous adipose tissue distribution.