Two novel pleiotropic loci associated with osteoporosis and abdominal obesity

AbstractAiming to uncover a shared genetic basis of abdominal obesity and osteoporosis, we performed a bivariate GWAS meta-analysis of femoral neck BMD (FNK-BMD) and trunk fat mass adjusted by trunk lean mass (TFMadj) in 11,496 subjects from 6 samples, followed by in silico replication in the large-scale UK Biobank (UKB) cohort. A series of functional investigations were conducted on the identified variants. Bivariate GWAS meta-analysis identified two novel pleiotropic loci 12q15 (lead SNPrs73134637,p = 3.45 × 10–7) and 10p14 (lead SNPrs2892347,p = 2.63 × 10–7) that were suggestively associated and that were replicated in the analyses of related traits in the UKB sample (osteoporosisp = 0.06 and 0.02, BMIp = 0.03 and 4.61 × 10–3, N up to 499,520).Cis-eQTL analysis demonstrated that allele C atrs73134637 was positively associated withIFNG expression in whole blood (N = 369,p = 0.04), and allele A atrs11254759 (10p14,p = 9.49 × 10–7) was negatively associated withPRKCQ expression in visceral adipose tissue (N = 313,p = 0.04) and in lymphocytes (N = 117,p = 0.03). As a proof-of-principle experiment, the function ofrs11254759, which is 235  kb 5′-upstream fromPRKCQ gene, was investigated by the dual-luciferase reporter assay, which clearly showed that the haplotype carryingrs11254759 regulatedPRKCQ expression by upregulatingPRKCQ promoter activity (p = 4.60 × 10–7) in an allelic specific manner....
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research