scholarly journals Polygenic Prediction of Type 2 Diabetes in Africa

Diabetes Care ◽  
2022 ◽  
Author(s):  
Tinashe Chikowore ◽  
Kenneth Ekoru ◽  
Marijana Vujkovi ◽  
Dipender Gill ◽  
Fraser Pirie ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
African American ◽  
Association Studies ◽  
Meta Analysis ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Data Set ◽  
Control Subjects ◽  
Design And Methods

OBJECTIVE Polygenic prediction of type 2 diabetes (T2D) in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of T2D from Africa and the poor transferability of European-derived polygenic risk scores (PRSs) in diverse ethnicities. We set out to evaluate if African American–, European-, or multiethnic-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 T2D GWAS multiancestry meta-analysis of 228,499 case and 1,178,783 control subjects. The South African Zulu study (n = 1,602 case and 981 control subjects) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis were conducted in the Africa America Diabetes Mellitus (AADM) study (n = 2,148 case and 2,161 control subjects). RESULTS The discriminatory ability of the African American and multiethnic PRSs was similar. However, the African American–derived PRS was more transferable in all the countries represented in the AADM cohort and predictive of T2D in the country combined analysis compared with the European- and multiethnic-derived scores. Notably, participants in the 10th decile of this PRS had a 3.63-fold greater risk (odds ratio 3.63; 95% CI 2.19–4.03; P = 2.79 × 10−17) per risk allele of developing diabetes and were diagnosed 2.6 years earlier than those in the first decile. CONCLUSIONS African American–derived PRS enhances polygenic prediction of T2D in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in T2D.

scholarly journals Polygenic Prediction of Type 2 Diabetes in Africa

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

<b>Objective. </b>Polygenic prediction of type 2 diabetes in<b> </b>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. <p><b>Research Design and Methods</b>. 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).</p> <p> <b>Results. </b>The discriminatory ability of the African American and Multi-ethnic PRS were similar. However<b>, </b>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 10<sup>th</sup> 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<sup>-17</sup>) per risk allele of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile. </p> <p><b>Conclusions </b>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.</p>

scholarly journals Polygenic Prediction of Type 2 Diabetes in Africa

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

<b>Objective. </b>Polygenic prediction of type 2 diabetes in<b> </b>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. <p><b>Research Design and Methods</b>. 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).</p> <p> <b>Results. </b>The discriminatory ability of the African American and Multi-ethnic PRS were similar. However<b>, </b>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 10<sup>th</sup> 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<sup>-17</sup>) per risk allele of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile. </p> <p><b>Conclusions </b>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.</p>

scholarly journals Polygenic prediction of type 2 diabetes in continental Africa

2021 ◽  
Author(s):  
Tinashe Chikowore ◽  
Kenneth Ekoru ◽  
Marijana Vujkovic ◽  
Dipender Gill ◽  
Fraser Pirie ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
African American ◽  
South African ◽  
Association Studies ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Data Set ◽  
Genome Wide ◽  
Design And Methods

AbstractObjectivePolygenic 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 or multi-ethnic derived PRSs would improve polygenic prediction in continental Africans.Research Design and MethodsUsing the PRSice software, ethnic-specific PRSs were computed with weights from the type 2 diabetes GWAS of the Million Veteran Program (MVP) study. The South African Zulu study (1602 cases and 976 controls) was used as the target data set. Replication and assessment of the best predictive PRS association with age at diagnosis was done in the Africa America Diabetes Mellitus (AADM) study (1031 cases and 738 controls).ResultsThe African American derived PRS was more predictive of type 2 diabetes compared to the European and multi-ethnic derived scores. Notably, participants in the 10th decile of this PRS had a 3.19-fold greater risk (OR 3.19; 95%CI (1.94-5.29), p = 5.33 x10-6) of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile.ConclusionsAfrican American derived PRS enhances polygenic prediction of type 2 diabetes in continental Africans. Improved representation of non-Europeans populations (including Africans) in GWAS, promises to provide better tools for precision medicine interventions in type 2 diabetes.

scholarly journals Validation of a Trans-Ancestry Polygenic Risk Score for Type 2 Diabetes in Diverse Populations

2021 ◽  
Author(s):  
Tian Ge ◽  
Amit Patki ◽  
Vinodh Srinivasasainagendra ◽  
Yen-Feng Lin ◽  
Marguerite Ryan Irvin ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
African American ◽  
Large Scale ◽  
Association Studies ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk

ABSTRACTType 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for an equitable deployment of PRS to clinical practice that benefits global populations. Here we integrate T2D GWAS in European, African American and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and evaluate the PRS in the multi-ethnic eMERGE study, four African American cohorts, and the Taiwan Biobank. The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined, and the top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5 fold of increase in T2D risk, suggesting the potential of using the trans-ancestry PRS as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.

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

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 &lt; 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.

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

2019 ◽  
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.

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

2011 ◽  
Vol 44 (1) ◽  
pp. 67-72 ◽  
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

scholarly journals Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

2020 ◽  
Author(s):  
Anubha Mahajan ◽  
Cassandra N Spracklen ◽  
Weihua Zhang ◽  
Maggie CY Ng ◽  
Lauren E Petty ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fine Mapping ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Population Diversity ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Diverse Populations ◽  
Genome Wide

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p<5x10-8), including 237 attaining a more stringent trans-ancestry threshold (p<5x10-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

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