ArticleBone2018
Identification of novel variants associated with osteoporosis, type 2 diabetes and potentially pleiotropic loci using pleiotropic cFDR method.
Article in Bone, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 25 citations in OpenAlex.
- Exploring causal associations between the plasma proteome and bone mineral density: a Mendelian randomization study.Endocrine connections · 2026Article
- Synergistic effects of denosumab and BMP-2 on bone regeneration in critical-sized femoral defects in ovariectomized rats.Journal of materials science. Materials in medicine · 2026Article
- Exploration of shared gene signatures and molecular mechanisms between type 2 diabetes and osteoporosis.Journal of cellular and molecular medicine · 2024Article
- Epigenome-wide analysis identifies methylome profiles linked to obsessive-compulsive disorder, disease severity, and treatment response.Molecular psychiatry · 2023Article
- Type 2 diabetes mellitus and the risk of male infertility: a Mendelian randomization study.Frontiers in endocrinology · 2023Article
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- Multiomics Integrated Analysis IdentifiesJournal of diabetes research · 2022Article
- Identification of a Potential MiRNA-mRNA Regulatory Network for Osteoporosis by Using Bioinformatics Methods: A Retrospective Study Based on the Gene Expression Omnibus Database.Frontiers in endocrinology · 2022Article
- Identification of Novel Pleiotropic SNPs Associated with Osteoporosis and Rheumatoid Arthritis.Calcified tissue international · 2021Article
- Identification of novel functional CpG-SNPs associated with Type 2 diabetes and birth weight.Aging · 2021Article
- Article
- A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data.Frontiers in genetics · 2021Article
- Detection of Genetic Overlap Between Rheumatoid Arthritis and Systemic Lupus Erythematosus Using GWAS Summary Statistics.Frontiers in genetics · 2021Article
- Helicobacter pylori Related Diseases and Osteoporotic Fractures (Narrative Review).Journal of clinical medicine · 2020Review
- Genetic Pleiotropy of Bone-Related Phenotypes: Insights from Osteoporosis.Current osteoporosis reports · 2020Review
- Observational
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5 authors at 3 institutions in 2 countries.
Funding
Abstract
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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