Dataset Information

Identification of novel SNPs associated with coronary artery disease and birth weight using a pleiotropic cFDR method.

ABSTRACT:

Objectives

Clinical and epidemiological findings indicate an association between coronary artery disease (CAD) and low birth weight (BW). However, the mechanisms underlying this relationship are largely unknown. Here, we aimed to identify novel single-nucleotide polymorphisms (SNPs) associated with CAD, BW, and their shared pleiotropic loci, and to detect the potential causal relationship between CAD and BW.

Methods

We first applied a genetic pleiotropic conditional false discovery rate (cFDR) method to two independent genome-wide association studies (GWAS) summary statistics of CAD and BW to estimate the pleiotropic enrichment between them. Then, bi-directional Mendelian randomization (MR) analyses were performed to clarify the causal association between these two traits.

Results

By incorporating related traits into a conditional analysis framework, we observed the significant pleiotropic enrichment between CAD and BW. By applying the cFDR level of 0.05, 109 variants were detected for CAD, 203 for BW, and 26 pleiotropic variants for both traits. We identified 11 CAD- and/or BW-associated SNPs that showed more than three of the metabolic quantitative trait loci (metaQTL), protein QTL (pQTL), methylation QTL (meQTL), or expression QTL (eQTL) effects. The pleiotropic SNP rs10774625, located at ATXN2, showed metaQTL, pQTL, meQTL, and eQTL effects simultaneously. Using the bi-directional MR approach, we found a negative association from BW to CAD (odds ratio [OR] = 0.68, 95% confidence interval [CI]: 0.59 to 0.80, p = 1.57× 10^-6).

Conclusion

We identified several pleiotropic loci between CAD and BW by leveraging GWAS results of related phenotypes and identified a potential causal relationship from BW to CAD. Our findings provide novel insights into the shared biological mechanisms and overlapping genetic heritability between CAD and BW.

SUBMITTER: Wu X

PROVIDER: S-EPMC7906162 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Identification of novel SNPs associated with coronary artery disease and birth weight using a pleiotropic cFDR method.

Wu Xinrui X Lin Xu X Li Qi Q Wang Zun Z Zhang Na N Tian Mengyuan M Wang Xiaolei X Deng Hongwen H Tan Hongzhuan H

Aging 20201219 3

<h4>Objectives</h4>Clinical and epidemiological findings indicate an association between coronary artery disease (CAD) and low birth weight (BW). However, the mechanisms underlying this relationship are largely unknown. Here, we aimed to identify novel single-nucleotide polymorphisms (SNPs) associated with CAD, BW, and their shared pleiotropic loci, and to detect the potential causal relationship between CAD and BW.<h4>Methods</h4>We first applied a genetic pleiotropic conditional false discover ...[more]

PMID: 33411684

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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.

Dataset Information

Identification of novel SNPs associated with coronary artery disease and birth weight using a pleiotropic cFDR method.

Objectives

Methods

Results

Conclusion

Publications

Identification of novel SNPs associated with coronary artery disease and birth weight using a pleiotropic cFDR method.

Similar Datasets

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