Aiming 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 (TFM_adj) 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 SNP rs73134637, p = 3.45 × 10^–7) and 10p14 (lead SNP rs2892347, p = 2.63 × 10^–7) that were suggestively associated and that were replicated in the analyses of related traits in the UKB sample (osteoporosis p = 0.06 and 0.02, BMI p = 0.03 and 4.61 × 10^–3, N up to 499,520). Cis-eQTL analysis demonstrated that allele C at rs73134637 was positively associated with IFNG expression in whole blood (N = 369, p = 0.04), and allele A at rs11254759 (10p14, p = 9.49 × 10^–7) was negatively associated with PRKCQ 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 of rs11254759, which is 235 kb 5′-upstream from PRKCQ gene, was investigated by the dual-luciferase reporter assay, which clearly showed that the haplotype carrying rs11254759 regulated PRKCQ expression by upregulating PRKCQ promoter activity (p = 4.60 × 10^–7) in an allelic specific manner. Mouse model analysis showed that heterozygous PRKCQ deficient mice presented decreased fat mass compared to wild-type control mice (p = 3.30 × 10^–3). Mendelian randomization analysis demonstrated that both FNK-BMD and TFM_adj were causally associated with fracture risk (p = 1.26 × 10^–23 and 1.18 × 10^–11). Our findings may provide useful insights into the genetic association between osteoporosis and abdominal obesity.

为了揭示腹部肥胖和骨质疏松症的共同遗传基础，我们对来自 6 个样本的 11,496 名受试者的股骨颈 BMD (FNK-BMD) 和躯干脂肪量 (TFM _adj )进行了双变量 GWAS 荟萃分析，随后在大规模英国生物银行 (UKB) 队列中进行计算机复制。对鉴定的变体进行了一系列功能研究。双变量 GWAS 荟萃分析确定了两个新的多效性位点 12q15（先导 SNP rs73134637，p  = 3.45 × 10 ^–7）和 10p14（先导 SNP rs2892347，p  = 2.63 × 10 ^–7) 的相关性，并在 UKB 样本中的相关性状分析中得到复制（骨质疏松症p  = 0.06 和 0.02，BMI p  = 0.03 和 4.61 × 10 ^–3，N 高达 499,520）。顺-eQTL分析表明，C等位基因在rs73134637呈正相关联IFNG在全血中的表达（Ñ  = 369，p  = 0.04），并且在等位基因A rs11254759（10p14，p  = 9.49×10 ^-7）与呈负相关PRKCQ在内脏脂肪组织中的表达 ( N  = 313, p = 0.04) 和淋巴细胞 ( N  = 117, p  = 0.03)。作为原理验证实验，通过双荧光素酶报告基因检测研究了PRKCQ基因5' 上游 235 kb rs11254759的功能，这清楚地表明携带rs11254759的单倍型通过上调PRKCQ来调节PRKCQ表达等位基因特异性方式的启动子活性（p  = 4.60 × 10 ^–7）。小鼠模型分析表明，与野生型对照小鼠相比，杂合PRKCQ缺陷小鼠的脂肪量减少（p  = 3.30 × 10 ^–3）。孟德尔随机化分析表明 FNK-BMD 和 TFM _adj都与骨折风险有因果关系（p  = 1.26 × 10 ^–23和 1.18 × 10 ^–11）。我们的发现可能为骨质疏松症和腹部肥胖之间的遗传关联提供有用的见解。