Evaluation of Genome Wide Association Study Associated Type 2 Diabetes Susceptibility Loci in Sub Saharan Africans

Adeyemo, Adebowale; Tekola‐Ayele, Fasil; Doumatey, Ayo P.; Bentley, Amy R.; Chen, Guanjie; Huang, Hanxia; Zhou, Jie; Shriner, Daniel; Fasanmade, O.A; Okafor, Godfrey; Eghan, Benjamin; Agyenim-Boateng, Kofi; Adeleye, Jokotade; Balogun, Williams; Elkahloun, Abdel G.; Chandrasekharappa, Settara C.; Owusu, Samuel; Amoah, Albert; Acheampong, Joseph; Johnson, Thomas; Oli, Johnnie; Adebamowo, Clement; Collins, Francis S.; Dunston, Georgia M.; Rotimi, Charles N.

doi:10.3389/fgene.2015.00335

Cited by 55 publications

(61 citation statements)

References 32 publications

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“…rs11717195 and rs11708067 exhibit strong linkage disequilibrium (LD) with each other ( r 2 ≥0.938, 1000 Genomes phase 3) in individuals of European, East Asian, and South Asian ancestry (7,8). In individuals of sub-Saharan African ancestry, rs143882978 (LD r 2 = 0.005 with rs11708067, 1000 Genomes phase 3 African) was also associated ( P = 0.02) with type 2 diabetes (9). …”

Section: Introductionmentioning

confidence: 99%

A Type 2 Diabetes–Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus

Roman¹,

Cannon²,

Vadlamudi³

et al. 2017

Diabetes

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Molecular mechanisms remain unknown for most type 2 diabetes genome-wide association study identified loci. Variants associated with type 2 diabetes and fasting glucose levels reside in introns of ADCY5, a gene that encodes adenylate cyclase 5. Adenylate cyclase 5 catalyzes the production of cyclic AMP, which is a second messenger molecule involved in cell signaling and pancreatic β-cell insulin secretion. We demonstrated that type 2 diabetes risk alleles are associated with decreased ADCY5 expression in human islets and examined candidate variants for regulatory function. rs11708067 overlaps a predicted enhancer region in pancreatic islets. The type 2 diabetes risk rs11708067-A allele showed fewer H3K27ac ChIP-seq reads in human islets, lower transcriptional activity in reporter assays in rodent β-cells (rat 832/13 and mouse MIN6), and increased nuclear protein binding compared with the rs11708067-G allele. Homozygous deletion of the orthologous enhancer region in 832/13 cells resulted in a 64% reduction in expression level of Adcy5, but not adjacent gene Sec22a, and a 39% reduction in insulin secretion. Together, these data suggest that rs11708067-A risk allele contributes to type 2 diabetes by disrupting an islet enhancer, which results in reduced ADCY5 expression and impaired insulin secretion.

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Section: Introductionmentioning

confidence: 99%

A Type 2 Diabetes–Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus

Roman¹,

Cannon²,

Vadlamudi³

et al. 2017

Diabetes

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show abstract

“…Under many scenarios, the top PCs from genome-wide array data are highly correlated with underlying ancestry. Thus, such PCs provide surrogate measures of "global" ancestry-that is, a picture of an individual's average ancestral origin across the genome-and can be used as covariates in regression models for association analysis (Adeyemo et al, 2015;Armstrong et al, 2014;Beecham et al, 2014;Cruchaga et al, 2013;Melton et al, 2013;Naj et al, 2011;Nalls et al, 2014). However, global ancestry is not always representative of ancestry at individual genomic loci.…”

Section: Introductionmentioning

confidence: 99%

Properties of global‐ and local‐ancestry adjustments in genetic association tests in admixed populations

Martin

Tunc

et al. 2017

Genetic Epidemiology

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Population substructure can lead to confounding in tests for genetic association, and failure to adjust properly can result in spurious findings. Here we address this issue of confounding by considering the impact of global ancestry (average ancestry across the genome) and local ancestry (ancestry at a specific chromosomal location) on regression parameters and relative power in ancestry-adjusted and -unadjusted models. We examine theoretical expectations under different scenarios for population substructure; applying different regression models, verifying and generalizing using simulations, and exploring the findings in real-world admixed populations. We show that admixture does not lead to confounding when the trait locus is tested directly in a single admixed population. However, if there is more complex population structure or a marker locus in linkage disequilibrium (LD) with the trait locus is tested, both global and local ancestry can be confounders. Additionally, we show the genotype parameters of adjusted and unadjusted models all provide tests for LD between the marker and trait locus, but in different contexts. The local ancestry adjusted model tests for LD in the ancestral populations, while tests using the unadjusted and the global ancestry adjusted models depend on LD in the admixed population(s), which may be enriched due to different ancestral allele frequencies. Practically, this implies that global-ancestry adjustment should be used for screening, but local-ancestry adjustment may better inform fine mapping and provide better effect estimates at trait loci.

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“…Environmental and genetic factors both contribute to the development of type 2 diabetes mellitus (Mrozikiewicz-Rakowska et al, 2015;Pearson, 2015). Previous genome-wide association studies have implicated many loci in the onset, prognosis, and severity of type 2 diabetes mellitus (Adeyemo et al, 2015;Wei et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Association between transcription factor 7-like 2 genetic polymorphisms and development of type 2 diabetes in a Chinese population

Jia

2016

Genet. Mol. Res.

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ABSTRACT. We conducted a hospital-based case-control study to evaluate the relationship between the transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism and type 2 diabetes mellitus risk in a Chinese population. Genotyping of TCF7L2 rs7903146 was carried out using the polymerase chain reaction-restriction fragment length polymorphism method. A chi-square test revealed a statistically significant difference between the distributions of rs7903146 genotypes in type 2 diabetes mellitus patient and control groups (chi-square = 10.49, P = 0.005). Using unconditional logistic regression analysis, we observed that the TT genotype of this polymorphism was significantly correlated with increased risk of developing type 2 diabetes mellitus compared to the CC genotype [odds ratio (OR) = 2.31, 95% confidence interval (CI) = 1.33-4.04]. Furthermore, we found that the rs7903146 sequence variation was also significantly associated with susceptibility to this disease under dominant (OR = 1.58, 95%CI = 1.09-2.28) and recessive models (OR = 2.11, 95%CI = 1.25-3.62). We conclude that the TCF7L2 rs7903146 genetic polymorphism is independently associated with the risk of developing type 2 diabetes mellitus under co-dominant, dominant, and recessive models.

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Evaluation of Genome Wide Association Study Associated Type 2 Diabetes Susceptibility Loci in Sub Saharan Africans

Cited by 55 publications

References 32 publications

A Type 2 Diabetes–Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus

A Type 2 Diabetes–Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus

Properties of global‐ and local‐ancestry adjustments in genetic association tests in admixed populations

Association between transcription factor 7-like 2 genetic polymorphisms and development of type 2 diabetes in a Chinese population

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