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Identification of Novel Pleiotropic SNPs Associated with Osteoporosis and Rheumatoid Arthritis.

ABSTRACT: Genome-wide association studies (GWASs) have identified hundreds of genetic loci for osteoporosis (OP) and rheumatoid arthritis (RA), individually, however, a large proportion of the total trait heritability remains unexplained. Previous studies demonstrated that these two diseases may share some common genetic determination and risk factors, but they were generally focused on individual trait and failed to identify the common variants that play key functional roles in the etiology of these two diseases. Here, we performed a conditional false discovery rate (cFDR) analysis to identify novel pleiotropic variants shared between them by integrating two independent GWASs with summary statistics for total body bone mineral density (TB-BMD, a major risk factor for osteoporosis) (n = 66,628) and RA (n = 58,284). A fine-mapping approach was also applied to identify the most probable causal variants with biological effects on both TB-BMD and RA. As a result, we found 47 independent pleiotropic SNPs shared between TB-BMD and RA, and 40 of them were validated in heel ultrasound estimated BMD (eBMD), femoral neck BMD (FN-BMD) or lumbar spine (LS-BMD). We detected one SNP (rs13299616) was novel and not identified by previous BMD or RA-related studies. Combined with fine-mapping and GWAS-eQTL colocalization analyses, our results suggested that locus 1p13.2 (including PTPN22, MAGI3, PHTF1, and RSBN1) was an important region to regulate TB-BMD and RA simultaneously. These findings provide new insights into the shared biological mechanisms and functional genetic determinants between OP and RA, and novel potential targets for treatment development.

SUBMITTER: Liu YQ

PROVIDER: S-EPMC8238865 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Identification of Novel Pleiotropic SNPs Associated with Osteoporosis and Rheumatoid Arthritis.

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