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Osteoporosis and obesity are two severe complex diseases threatening public health worldwide. Both diseases are under strong genetic determinants as well as genetically correlated. Aiming to identify pleiotropic genes underlying obesity and osteoporosis, we performed a bivariate genome-wide association (GWA) meta-analysis of hip bone mineral density (BMD) and total body fat mass (TBFM) in 12,981 participants from seven samples, and followed by in silico replication in the UK biobank (UKB) cohort sample (N = 217,822). Combining the results from discovery meta-analysis and replication sample, we identified one novel locus, 17q21.31 (lead SNP rs12150327, NC_000017.11:g.44956910G > A, discovery bivariate P = 4.83 × 10 -9 , replication P = 5.75 × 10 -5 ) at the genome-wide significance level (ɑ = 5.0 × 10 -8 ), which may have pleiotropic effects to both hip BMD and TBFM. Functional annotations highlighted several candidate genes, including KIF18B, C1QL1, and PRPF19 that may exert pleiotropic effects to the development of both body mass and bone mass. Our findings can improve our understanding of the etiology of osteoporosis and obesity, as well as shed light on potential new therapies.

Aiming to identify pleiotropic genomic loci for bone mineral density and bone size, we performed a bivariate GWAS in five discovery samples and replicated in two large-scale samples. We identified 2 novel loci at 2q37.1 and 6q26. Our findings provide insight into common genetic architecture underlying both traits., Introduction: Bone mineral density (BMD) and bone size (BS) are two important factors that contribute to the development of osteoporosis and osteoporotic fracture. Both BMD and BS are highly heritable and they are genetically correlated. In this study, we aim to identify pleiotropic loci associated with BMD and BS., Methods: We conducted a bivariate genome-wide association (GWA) analysis of hip BMD and hip BS in 6180 participants from 5 samples, followed by in silico replication in the UK Biobank study of BMD (N = 426,824) and the deCODE study of BS (N = 28,954), respectively., Results: SNPs from 2 genomic loci were significant at the genome-wide significance (GWS) level (p lt; 5 × 10 -8 ) in the discovery samples and were successfully replicated in the replication samples (2q37.1, lead SNP rs7575512, discovery p = 1.49 × 10 -10 , replication p = 0.05; 6q26, lead SNP rs1040724, discovery p = 1.95 × 10 -8 , replication p = 0.03). Functional annotations suggested functional relevance of the identified variants to bone development., Conclusion: Our findings provide insight into the common genetic architecture underlying BMD and BS, and enhance our understanding of the potential mechanism of osteoporosis fracture.

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.