Recessive Genome-wide Meta-analysis Illuminates Genetic Architecture of Type 2 Diabetes

ObjectiveWe aimed to estimate genetic correlation, identify shared loci and test causality between leptin levels and type 2 diabetes (T2D).Research design and methodsOur study consists of three parts. First, we calculated the genetic correlation of leptin levels and T2D or glycemic traits by using linkage disequilibrium score regression analysis. Second, we conducted a large-scale genome-wide cross-trait meta-analysis using cross-phenotype association to identify shared loci between trait pairs that showed significant genetic correlations in the first part. In the end, we carried out a bidirectional MR analysis to find out whether there is a causal relationship between leptin levels and T2D or glycemic traits.ResultsWe found positive genetic correlations between leptin levels and T2D (Rg=0.3165, p=0.0227), fasting insulin (FI) (Rg=0.517, p=0.0076), homeostasis model assessment-insulin resistance (HOMA-IR) (Rg=0.4785, p=0.0196), as well as surrogate estimates of β-cell function (HOMA-β) (Rg=0.4456, p=0.0214). We identified 12 shared loci between leptin levels and T2D, 1 locus between leptin levels and FI, 1 locus between leptin levels and HOMA-IR, and 1 locus between leptin levels and HOMA-β. We newly identified eight loci that did not achieve genome-wide significance in trait-specific genome-wide association studies. These shared genes were enriched in pancreas, thyroid gland, skeletal muscle, placenta, liver and cerebral cortex. In addition, we found that 1-SD increase in HOMA-IR was causally associated with a 0.329 ng/mL increase in leptin levels (β=0.329, p=0.001).ConclusionsOur results have shown the shared genetic architecture between leptin levels and T2D and found causality of HOMA-IR on leptin levels, shedding light on the molecular mechanisms underlying the association between leptin levels and T2D.

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Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

PLoS Genetics ◽

10.1371/journal.pgen.1004517 ◽

2014 ◽

Vol 10 (8) ◽

pp. e1004517 ◽

Cited By ~ 128

Author(s):

Maggie C. Y. Ng ◽

Daniel Shriner ◽

Brian H. Chen ◽

Jiang Li ◽

Wei-Min Chen ◽

...

Keyword(s):

Type 2 Diabetes ◽

African Americans ◽

Genetic Architecture ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

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Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Nature Genetics ◽

10.1038/ng.2897 ◽

2014 ◽

Vol 46 (3) ◽

pp. 234-244 ◽

Cited By ~ 663

Author(s):

Anubha Mahajan ◽

◽

Min Jin Go ◽

Weihua Zhang ◽

Jennifer E Below ◽

...

Keyword(s):

Type 2 Diabetes ◽

Genetic Architecture ◽

Meta Analysis ◽

Diabetes Susceptibility ◽

Genome Wide ◽

Insight Into

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Genome-Wide Association Studies Identify Two Novel Loci Conferring Susceptibility to Diabetic Retinopathy in Japanese Patients with Type 2 Diabetes

Human Molecular Genetics ◽

10.1093/hmg/ddab044 ◽

2021 ◽

Author(s):

Minako Imamura ◽

Atsushi Takahashi ◽

Masatoshi Matsunami ◽

Momoko Horikoshi ◽

Minoru Iwata ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Association Studies ◽

Meta Analysis ◽

Japanese Patients ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Stage 1

Abstract Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases, and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (p < 1.0 × 10−4) in an independent case–control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stage-1 and -2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, p = 1.62 × 10−9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11–1.23, and rs140508424 within PALM2 on chromosome 9, p = 4.19 × 10−8, OR = 1.61, 95% CI 1.36–1.91. However, the association of these two loci were not replicated in Korean, European, or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (p = 2.17 × 10−6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.

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Identification of shared genetic susceptibility locus for coronary artery disease, type 2 diabetes and obesity: a meta-analysis of genome-wide studies

Cardiovascular Diabetology ◽

10.1186/1475-2840-11-68 ◽

2012 ◽

Vol 11 (1) ◽

pp. 68 ◽

Cited By ~ 15

Author(s):

Chaoneng Wu ◽

Yunguo Gong ◽

Jie Yuan ◽

Hui Gong ◽

Yunzeng Zou ◽

...

Keyword(s):

Type 2 Diabetes ◽

Coronary Artery Disease ◽

Meta Analysis ◽

Disease Type ◽

Genome Wide ◽

Artery Disease ◽

Diabetes And Obesity ◽

Genetic Susceptibility Locus ◽

Shared Genetic

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Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Yearbook of Endocrinology ◽

10.1016/s0084-3741(08)79224-2 ◽

2008 ◽

Vol 2008 ◽

pp. 38-39 ◽

Cited By ~ 7

Author(s):

J.L. Leahy

Keyword(s):

Type 2 Diabetes ◽

Large Scale ◽

Meta Analysis ◽

Genome Wide Association ◽

Susceptibility Loci ◽

Genome Wide ◽

Association Data

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Identification of type 2 diabetes loci in 433,540 East Asian individuals

10.1101/685172 ◽

2019 ◽

Cited By ~ 3

Author(s):

Cassandra N Spracklen ◽

Momoko Horikoshi ◽

Young Jin Kim ◽

Kuang Lin ◽

Fiona Bragg ◽

...

Keyword(s):

Type 2 Diabetes ◽

Association Studies ◽

Meta Analysis ◽

East Asian ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

European Populations

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

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East Asian Genome-wide association study derived loci in relation to type 2 diabetes in the Han Chinese population

Acta Biochimica Polonica ◽

10.18388/abp.2018_2632 ◽

2019 ◽

Cited By ~ 1

Author(s):

Sijia Zhang ◽

Esma Jamaspishvili ◽

Huixin Tong ◽

Yongjie Chen ◽

Zhongyu Zhou ◽

...

Keyword(s):

Type 2 Diabetes ◽

Chinese Population ◽

Genome Wide Association Study ◽

Meta Analysis ◽

East Asian ◽

Repetitive Sequences ◽

Han Chinese ◽

Han Chinese Population ◽

Genome Wide

Meta-analysis of GWAS in East Asian populations had established 10 loci that were associated with type 2 diabetes. Eight of them were with genome-wide significance and two with a border line association. Since these data have not been studied in an independent Han Chinese population, we aimed to investigate the association of these susceptibility loci with type 2 diabetes in an independent Han Chinese population. We executed a case-control study in 2 000 Chinese by the SNPscan method. Firstly, the repetitive sequences of 10 loci were assessed. Next, we investigated the association of 8 SNPs out of 10 with type 2 diabetes and constructed the GRS of those 8 SNPs. Finally, the relationship of the 8 loci and diabetes-related traits was analyzed. Based on the fact, that highly repetitive sequences were detected in 2 SNPs, we investigated the remaining 8 SNPs. With the exception of four SNPs (CMIP rs16955379, PEPD rs3786897, PSMD6 rs831571, ZFAND3 rs9470794), the other SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports, especially GLIS3 rs7041847 and KCNK16 rs1535500 were significantly associated with type 2 diabetes (rs1535500: p=0.005, OR=1.224, 95% CI 1.062–1.409; rs7041847: p=0.035, OR=1.118, 95% CI 1.070–1.388). The GRS constructed from the 8 SNPs was significantly associated with type 2 diabetes in the Chinese population (p=0.004, OR=1.065, 95% CI: 1.021–1.111). Among the participants with 24≤BMI<28 kg/m2 the 8 SNPs were significantly associated with type 2 diabetes (p=0.040, OR=1.079, 95% CI: 1.003–1.160). In quantitative trait analyses, WWOX rs17797882 was associated with decreased HOMA-β and increased level of TG and HDL-Ch, while PEPD rs3786897 and MAEA rs6815464 were associated with decreased fasting plasma glucose, and KCNK16 rs1535500 has shown a significant association with increased T-Ch and PSMD6 rs831571 had a significant association with decreased HDL-Ch. In Conclusion, with high probability the 8 loci identified in the East Asian GWAS meta-analysis are associated with type 2 diabetes in the Han Chinese population.

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