| 1. |
- Flannick, Jason, et al.
(författare)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 2. |
- Fuchsberger, Christian, et al.
(författare)
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The genetic architecture of type 2 diabetes
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 3. |
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| 4. |
- Manning, Alisa, et al.
(författare)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 5. |
- Tan, Kristin H. X., et al.
(författare)
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Diabetes mellitus prevalence is increasing in South Asians but is stable in Chinese living in Singapore and Mauritius
- 2017
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Ingår i: Journal of Diabetes. - : John Wiley & Sons. - 1753-0393 .- 1753-0407. ; 9:9, s. 855-864
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Asia is experiencing a type 2 diabetes epidemic but prevalence differs by ethnicity and level of socio-economic development. Singapore and Mauritius have implemented comprehensive campaigns to address this public health problem. We compared diabetes and obesity prevalence trends among Chinese and South Asians living in Singapore and Mauritius to determine the contribution of ethnicity and economic development to diabetes.METHODS: Age-specific data from serial national population-based surveys in Singapore and Mauritius between 1987 and 2010 were used to estimate age-standardised diabetes and obesity prevalence. Modified Breslow-Cox Proportional hazard models were used to obtain rate ratios for diabetes risk factors.RESULTS: In Singapore, the age-standardised prevalence of diabetes remained stable for Chinese (men 14% in 1992 and 13% in 2010; women 12% in 1992 and 10% in 2010); however, increases were observed for South Asians (men 20% in 1992 and 26% in 2010; women 18% in 1992 and 20% in 2010). There were similar patterns in Mauritius. In both countries, obesity prevalence trends were stable for Chinese women, but increased for Chinese men and South Asians. Associations between obesity and diabetes were stronger in Chinese than South Asians irrespective of country.CONCLUSIONS: Despite different socio-economic settings in Singapore and Mauritius, we observed rising diabetes prevalence among South Asians but stable prevalence in Chinese in both countries. This provides further evidence that ethnicity contributes to the development of diabetes, and that there should be an increased emphasis on future prevention strategies targeting South Asian populations in these countries.
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