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

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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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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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 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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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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Novel susceptibility loci and genetic regulation mechanisms for type 2 diabetes

10.1101/284570 ◽

2018 ◽

Author(s):

Angli Xue ◽

Yang Wu ◽

Zhihong Zhu ◽

Futao Zhang ◽

Kathryn E Kemper ◽

...

Keyword(s):

Gene Expression ◽

Type 2 Diabetes ◽

Rare Variants ◽

Association Studies ◽

Meta Analysis ◽

Genetic Regulation ◽

Regulation Of Gene Expression ◽

European Ancestry ◽

Genome Wide Association Studies

AbstractWe conducted a meta-analysis of genome-wide association studies (GWAS) with ∼16 million genotyped/imputed genetic variants in 62,892 type 2 diabetes (T2D) cases and 596,424 controls of European ancestry. We identified 139 common and 4 rare (minor allele frequency < 0.01) variants associated with T2D, 42 of which (39 common and 3 rare variants) were independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2,765) and other T2D-relevant tissues (n = up to 385) with the GWAS results identified 33 putative functional genes for T2D, three of which were targeted by approved drugs. A further integration of DNA methylation (n = 1,980) and epigenomic annotations data highlighted three putative T2D genes (CAMK1D, TP53INP1 and ATP5G1) with plausible regulatory mechanisms whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. We further found evidence that the T2D-associated loci have been under purifying selection.

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Polygenic Prediction of Type 2 Diabetes in Africa

10.2337/figshare.17076419.v1 ◽

2022 ◽

Author(s):

Tinashe Chikowore ◽

Kenneth Ekoru ◽

Marijana Vujkovic ◽

Dipender Gill ◽

Fraser Pirie ◽

...

Keyword(s):

Type 2 Diabetes ◽

African American ◽

Association Studies ◽

Meta Analysis ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Data Set ◽

Genome Wide ◽

Design And Methods

Objective. Polygenic prediction of type 2 diabetes in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of type 2 diabetes from Africa and the poor transferability of European derived polygenic risk scores (PRS) in diverse ethnicities. We set out to evaluate if African American, European or multi-ethnic derived PRSs would improve polygenic prediction in continental Africans. Research Design and Methods. Using the PRSice software, ethnic-specific PRSs were computed with weights from the type 2 diabetes GWAS multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls. The South African Zulu study (1602 cases and 981 controls) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis was done in the Africa America Diabetes Mellitus (AADM) study (2148 cases and 2161 controls). Results. The discriminatory ability of the African American and Multi-ethnic PRS were similar. However, the African American derived PRS was more transferable in all the countries represented in the AADM cohort, and predictive of type 2 diabetes in the country combined analysis compared to the European and multi-ethnic derived scores. Notably, participants in the 10th decile of this PRS had a 3.63-fold greater risk (OR 3.63; 95%CI (2.19 - 4.03), p = 2.79 x 10-17) per risk allele of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile. Conclusions African American derived PRS enhances polygenic prediction of type 2 diabetes in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in type 2 diabetes.

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