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

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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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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Plasma vitamin C and type 2 diabetes: genome-wide association study and Mendelian randomization analysis in European populations

10.2337/figshare.13105559.v1 ◽

2020 ◽

Author(s):

Ju-Sheng Zheng ◽

Jian’an Luan ◽

Eleni Sofianopoulou ◽

Fumiaki Imamura ◽

Isobel D Stewart ◽

...

Keyword(s):

Type 2 Diabetes ◽

Vitamin C ◽

Mendelian Randomization ◽

Genome Wide Association ◽

European Ancestry ◽

Plasma Vitamin ◽

Genome Wide Association Studies ◽

Genome Wide ◽

European Populations

Objective Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. Research Design and Methods We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted difference in plasma vitamin C with type 2 diabetes in up-to 80,983 cases and 842,909 non-cases. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 cases and 11,073 non-cases. Results We identified 11 genomic regions associated with plasma vitamin C (p<5×10-8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1 and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per standard deviation, 0.88, 95%CI: 0.82, 0.94), <a>but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03, 95%CI: 0.96, 1.10)</a>. Conclusions <a>These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of</a> vitamin C supplementation for type 2 diabetes prevention.

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Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

Nature Genetics ◽

10.1038/ng.1019 ◽

2011 ◽

Vol 44 (1) ◽

pp. 67-72 ◽

Cited By ~ 397

Author(s):

Yoon Shin Cho ◽

◽

Chien-Hsiun Chen ◽

Cheng Hu ◽

Jirong Long ◽

...

Keyword(s):

Type 2 Diabetes ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

East Asians ◽

Genome Wide

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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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Validation of Type 2 Diabetes Risk Variants Identified by Genome-Wide Association Studies in Han Chinese Population: A Replication Study and Meta-Analysis

PLoS ONE ◽

10.1371/journal.pone.0095045 ◽

2014 ◽

Vol 9 (4) ◽

pp. e95045 ◽

Cited By ~ 19

Author(s):

Yi-Cheng Chang ◽

Pi-Hua Liu ◽

Yu-Hsiang Yu ◽

Shan-Shan Kuo ◽

Tien-Jyun Chang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Chinese Population ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Han Chinese Population ◽

Risk Variants ◽

Genome Wide

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Genome-Wide Association Meta-Analysis Using a Recessive Model Illuminates Genetic Architecture of Type 2 Diabetes

10.1101/2021.07.08.21258700 ◽

2021 ◽

Author(s):

Mark J O'Connor ◽

Alicia Huerta-Chagoya ◽

Paula Cortés-Sánchez ◽

Silvía Bonàs-Guarch ◽

Joanne B Cole ◽

...

Keyword(s):

Type 2 Diabetes ◽

Meta Analysis ◽

Recessive Model ◽

Additive Models ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Recessive Effects

Objective: Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. Research Design and Methods: We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 cases and 279,507 controls from seven European-ancestry cohorts including the UK Biobank. We then used two additional cohorts, FinnGen and a Danish cohort, for replication. For the most significant recessive signal, we conducted a phenome-wide association study across hundreds of traits to make inferences about the pathophysiology underlying the increased risk seen in homozygous carriers. Results: We identified 51 loci associated with type 2 diabetes, including five variants with recessive effects undetected by prior additive analyses. Two of the five had minor allele frequency less than 5% and were each associated with more than doubled risk. We replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19, P=1×10-16) and a stronger effect in men than in women (interaction P=7×10-7). Colocalization analysis linked this signal to reduced expression of the nearby PELO gene, and the signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL and a 20% increase in triglycerides. Conclusions: Our results demonstrate that recessive models, when compared to GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.

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Genome-Wide Association Scan of Serum Urea in European Populations Identifies Two Novel Loci

American Journal of Nephrology ◽

10.1159/000496930 ◽

2019 ◽

Vol 49 (3) ◽

pp. 193-202

Author(s):

Chris H.L. Thio ◽

Anna Reznichenko ◽

Peter J. van der Most ◽

Zoha Kamali ◽

Ahmad Vaez ◽

...

Keyword(s):

Kidney Function ◽

Association Studies ◽

Serum Magnesium ◽

East Asian ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Serum Urea ◽

Genome Wide ◽

European Populations

Background: Serum urea level is a heritable trait, commonly used as a diagnostic marker for kidney function. Genome-wide association studies (GWAS) in East-Asian populations identified a number of genetic loci related to serum urea, however there is a paucity of data for European populations. Methods: We performed a two-stage meta-analysis of GWASs on serum urea in 13,312 participants, with independent replication in 7,379 participants of European ancestry. Results: We identified 6 genome-wide significant single nucleotide polymorphisms (SNPs) in or near 6 loci, of which 2 were novel (POU2AF1 and ADAMTS9-AS2). Replication of East-Asian and Scottish data provided evidence for an additional 8 loci. SNPs tag regions previously associated with anthropometric traits, serum magnesium, and urinary albumin-to-creatinine ratio, as well as expression quantitative trait loci for genes preferentially expressed in kidney and gastro-intestinal tissues. Conclusions: Our findings provide insights into the genetic underpinnings of urea metabolism, with potential relevance to kidney function.

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

10.2337/figshare.17099780 ◽

2021 ◽

Author(s):

Mark J. O’Connor ◽

Philip Schroeder ◽

Alicia Huerta-Chagoya ◽

Paula Cortés-Sánchez ◽

Silvía Bonàs-Guarch ◽

...

Keyword(s):

Type 2 Diabetes ◽

Complex Traits ◽

Association Studies ◽

Meta Analysis ◽

Low Frequency ◽

Additive Models ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide

Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 cases and 279,507 controls from seven European-ancestry cohorts including the UK Biobank. We identified 51 loci associated with type 2 diabetes, including five variants undetected by prior additive analyses. Two of the five had minor allele frequency less than 5% and were each associated with more than doubled risk in homozygous carriers. Using two additional cohorts, FinnGen and a Danish cohort, we replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19, P=1´10-16) and a stronger effect in men than in women (interaction P=7´10-7). The signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL and a 20% increase in triglycerides, and colocalization analysis linked this signal to reduced expression of the nearby PELO gene. These results demonstrate that recessive models, when compared to GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.

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