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Two novel pleiotropic loci associated with osteoporosis and abdominal obesity.

ABSTRACT: 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.

SUBMITTER: Liu L

PROVIDER: S-EPMC7883472 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Two novel pleiotropic loci associated with osteoporosis and abdominal obesity.

Liu Lu L Yang Xiao-Lin XL Zhang Hong H Zhang Zi-Jia ZJ Wei Xin-Tong XT Feng Gui-Juan GJ Liu Ju J Peng Hui-Ping HP Hai Rong R Shen Hui H Tian Qing Q Deng Hong-Wen HW Pei Yu-Fang YF Zhang Lei L

Human genetics 20200401 8

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<sub>adj</sub>) 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 rs ...[more]

PMID: 32239398

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Project description:AimsClinical and epidemiological findings point to an association between type 2 diabetes (T2D) and osteoporosis. Genome-wide association studies (GWASs) have been fruitful in identifying some loci potentially associated with osteoporosis and T2D respectively. However, the total genetic variance for each of these two diseases and the shared genetic determination between them are largely unknown. The aim of this study was to identify novel genetic variants for osteoporosis and/or T2D.MethodsFirst, using a pleiotropic conditional false discovery rate (cFDR) method, we analyzed two GWAS summary data of femoral neck bone mineral density (FN_BMD, n = 53,236) and T2D (n = 159,208) to identify novel shared genetic loci. FN_BMD is an important risk factor for osteoporosis. Next, to explore the potential functions of the identified potential pleiotropic genes, differential expression analysis was performed for them in monocytes and peripheral blood mononuclear cells (PBMCs) as these cells are relevant to the etiology of osteoporosis and/or T2D. Further, weighted gene co-expression analysis (WGCNA) was conducted to identify functional connections between novel pleiotropic genes and known osteoporosis/T2D susceptibility genes by using transcriptomic expression datasets in bone biopsies (E-MEXP-1618) and pancreatic islets (GSE50397). Finally, multi-trait fine mapping for the detected pleiotropic risk loci were conducted to identify the SNPs that have the highest probability of being causal for both FN_BMD and T2D.ResultsWe identified 27 significant SNPs with cFDR<0.05 for FN_BMD and 61 SNPs for T2D respectively. Four loci, rs7068487 (PLEKHA1), rs10885421 (TCF7L2), rs944082 (GNG12-AS1 (WLS)) and rs2065929 (PIFO||PGCP1), were found to be potentially pleiotropic and shared between FN_BMD and T2D (ccFDR<0.05). PLEKHA1 was found differentially expressed in circulating monocytes between high and low BMD subjects, and PBMCs between diabetic and non-diabetic conditions. WGCNA showed that PLEKHA1 and TCF7L2 were interconnected with multiple osteoporosis and T2D associated genes in bone biopsy and pancreatic islets, such as JAG, EN1 and CPE. Fine mapping showed that rs11200594 was a potentially causal variant in the locus of PLEKHA1. rs11200594 is also an eQTL of PLEKHA1 in multiple tissue (e.g. peripheral blood cells, adipose and ovary) and is in strong LD with a number of functional variants.ConclusionsFour potential pleiotropic loci were identified for shared genetic determination of osteoporosis and T2D. Our study highlights PLEKHA1 as an important potentially pleiotropic gene. The findings may help us gain a better understanding of the shared genetic determination between these two important disorders.

Project description:Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with cancer risk, several of which have shown pleiotropic effects across cancers. Therefore, we performed a systematic cross-cancer pleiotropic analysis to detect the effects of GWAS-identified variants from non-lung cancers on lung cancer risk in 12,843 cases and 12,639 controls from four lung cancer GWASs. The overall association between variants in each cancer and risk of lung cancer was explored using sequential kernel association test (SKAT) analysis. For single variant analysis, we combined the result of specific study using fixed-effect meta-analysis. We performed functional exploration of significant associations based on features from public databases. To further detect the biological mechanism underlying identified observations, pathway enrichment analysis were conducted with R package "clusterProfiler." SNP-set analysis revealed the overall associations between variants of 8 cancer types and lung cancer risk. Single variant analysis identified 6 novel SNPs related to lung cancer risk after multiple correction (P fdr < 0.10), including rs1707302 (1p34.1, OR = 0.93, 95% CI: 0.90-0.97, P = 7.60 × 10-4), rs2516448 (6p21.33, OR = 1.07, 95% CI: 1.03-1.11, P = 1.00 × 10-3), rs3869062 (6p22.1, OR = 0.91, 95% CI: 0.86-0.96, P = 7.10 × 10-4), rs174549 (11q12.2, OR = 0.90, 95% CI: 0.87-0.94, P = 1.00 × 10-7), rs7193541 (16q23.1, OR = 0.93, 95% CI: 0.90-0.96, P = 1.20 × 10-4), and rs8064454 (17q12, OR = 1.07, 95% CI: 1.03-1.11, P = 4.30 × 10-4). The eQTL analysis and functional annotation suggested that these variants might modify lung cancer susceptibility through regulating the expression of related genes. Pathway enrichment analysis showed that genes modulated by these variants play important roles in cancer carcinogenesis. Our findings demonstrate the pleiotropic associations between non-lung cancer susceptibility loci and lung cancer risk, providing important insights into the shared mechanisms of carcinogenesis across cancers.

Project description:Childhood obesity remains one of the most important issues in global health, which is implicated in many chronic diseases. Converging evidence suggests that a higher body mass index during childhood (CBMI) is significantly associated with increased coronary artery disease (CAD) susceptibility in adulthood, which may partly arise from the shared genetic determination. Despite genome-wide association studies (GWASs) have successfully identified some loci associated with CBMI and CAD individually, the genetic overlap and common biological mechanism between them remains largely unexplored. Here, relying on the results from the two large-scale GWASs (n = 35,668 for CBMI and n = 547,261 for CAD), linkage disequilibrium score regression (LDSC) was used to estimate the genetic correlation of CBMI and CAD in the first step. Then, we applied different pleiotropy-informed methods including conditional false discovery rate ([Formula: see text]) and genetic analysis incorporating pleiotropy and annotation (GPA) to detect potentially common loci for childhood obesity and CAD. By integrating the genetic information from the existing GWASs summary statistics, we found a significant positive genetic correlation ([Formula: see text] = 0.127, p = 2E-4) and strong pleiotropic enrichment between CBMI and CAD (LRT = 79.352, p = 5.2E-19). Importantly, 28 loci were simultaneously discovered to be associated with CBMI, and 13 of them were identified as potentially pleiotropic loci by [Formula: see text] and GPA. Those corresponding pleiotropic genes were enriched in trait-associated gene ontology (GO) terms "amino sugar catabolic process", "regulation of fat cell differentiation" and "synaptic transmission". Overall, the findings of the pleiotropic loci will help to further elucidate the common molecular mechanisms underlying the association of childhood obesity and CAD, and provide a theoretical direction for early disease prevention and potential therapeutic targets.

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Two novel pleiotropic loci associated with osteoporosis and abdominal obesity.

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Two novel pleiotropic loci associated with osteoporosis and abdominal obesity.

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