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Identification of novel genetic variants for type 2 diabetes, childhood obesity, and their pleiotropic loci.

ABSTRACT: Obesity has result in increased prevalence of type 2 diabetes (T2D) in children. The genetic mechanisms underlying their relationship, however, are not fully understood. Here, we aim to identify novel SNPs associated with T2D and childhood obesity (CO), especially their pleiotropic loci. We integrated the summary statistics for two independent GWASs of T2D (n = 149,821) and childhood body mass index (CBMI) (n = 35,668) using the pleiotropy-informed conditional false discovery rate (cFDR) method. By leveraging the information of different levels of association for CBMI, we observed a strong enrichment of genetic variants associated with T2D. We identified 139 T2D-associated SNPs with 125 novel ones (cFDR < 0.05). Conditioned on T2D, we identified 37 significant SNPs for CBMI (cFDR < 0.05), including 25 novel ones. The conjunctional cFDR (ccFDR) analysis showed ten novel pleiotropic loci for T2D and CBMI (ccFDR < 0.05). Interestingly, the novel SNP rs1996023 is located at protein coding gene GNPDA2 (ccFDR = 1.28E-02), which has been reported to influence the risk of T2D and CO through central nervous system. Our findings may help to explain a greater proportion of the heritability for human traits and advance the understanding of the common pathophysiology between T2D and CO.

SUBMITTER: Zeng CP

PROVIDER: S-EPMC6712986 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Identification of novel genetic variants for type 2 diabetes, childhood obesity, and their pleiotropic loci.

Zeng Chun-Ping CP Lin Xu X Peng Cheng C Zhou Lin L You Hui-Min HM Shen Jie J Deng Hong-Wen HW

Journal of human genetics 20190228 5

Obesity has result in increased prevalence of type 2 diabetes (T2D) in children. The genetic mechanisms underlying their relationship, however, are not fully understood. Here, we aim to identify novel SNPs associated with T2D and childhood obesity (CO), especially their pleiotropic loci. We integrated the summary statistics for two independent GWASs of T2D (n = 149,821) and childhood body mass index (CBMI) (n = 35,668) using the pleiotropy-informed conditional false discovery rate (cFDR) method. ...[more]

PMID: 30816286

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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: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.

Dataset Information

Identification of novel genetic variants for type 2 diabetes, childhood obesity, and their pleiotropic loci.

Publications

Identification of novel genetic variants for type 2 diabetes, childhood obesity, and their pleiotropic loci.

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