| 11. |
- 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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| 12. |
- 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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| 13. |
- Goedecke, Julia H., et al.
(författare)
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Waist circumference thresholds predicting incident dysglycaemia and type 2 diabetes in Black African men and women
- 2022
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 24:5, s. 918-927
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To determine the waist circumference (WC) thresholds for the prediction of incident dysglycaemia and type 2 diabetes (T2D) in Black South African (SA) men and women and to compare these to the advocated International Diabetes Federation (IDF) Europid thresholds.Materials and Methods: In this prospective study, Black SA men (n = 502) and women (n = 527) from the Middle-aged Sowetan Cohort study who had normal or impaired fasting glucose at baseline (2011-2015) were followed up until 2017 to 2018. Baseline measurements included anthropometry, blood pressure and fasting glucose, HDL cholesterol and triglyceride concentrations. At follow-up, glucose tolerance was assessed using an oral glucose tolerance test. The Youden index was used to determine the optimal threshold of WC to predict incident dysglycaemia and T2D.Results: In men, the optimal WC threshold was 96.8 cm for both dysglycaemia and T2D (sensitivity: 56% and 70%; specificity: 74% and 70%, respectively), and had higher specificity (P < 0.001) than the IDF threshold of 94 cm. In women, the optimal WC threshold for incident dysglycaemia was 91.8 cm (sensitivity 86%, specificity 37%) and for T2D it was 95.8 cm (sensitivity 85%, specificity 45%), which had lower sensitivity, but higher specificity to predict incident dysglycaemia and T2D than the IDF threshold of 80 cm (sensitivity: 97% and 100%; specificity: 12% and 11%, respectively)).Conclusions: We show for the first time using prospective cohort data from Africa that the IDF Europid WC thresholds are not appropriate for an African population, and show that African-specific WC thresholds perform better than the IDF Europid thresholds to predict incident dysglycaemia and T2D.
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| 14. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 15. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 16. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 17. |
- Kraja, Aldi T., et al.
(författare)
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New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475000 Individuals
- 2017
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 1942-325X .- 1942-3268. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.Methods and Results - Here, we augment the sample with 140886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, approximate to 475000), and the other in the subset of individuals of European descent (approximate to 423000). Twenty-one SNVs were genome-wide significant (P<5x10(-8) ) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
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| 18. |
- Kufe, Clement N., et al.
(författare)
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Increased risk for type 2 diabetes in relation to adiposity in middle-aged Black South African men compared to women
- 2022
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Ingår i: European Journal of Endocrinology. - : Bioscientifica. - 0804-4643 .- 1479-683X. ; 186:5, s. 523-533
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Despite a higher prevalence of overweight/obesity in Black South African women compared to men, the prevalence of type 2 diabetes (T2D) does not differ. We explored if this could be due to sex differences in insulin sensitivity, clearance and/or beta-cell function and also sex-specific associations with total and regional adiposity.Methods: This cross-sectional study included 804 Black South African men (n = 388) and women (n = 416). Dual-energy X-ray absorptiometry was used to measure total and regional adiposity. Insulin sensitivity (Matsuda index), secretion (C-peptide index) and clearance (C-peptide/insulin ratio) were estimated from an oral glucose tolerance test.Results: After adjusting for sex differences in the fat mass index, men were less insulin sensitive and had lower beta-cell function than women (P < 0.001), with the strength of the associations with measures of total and central adiposity being greater in men than women (P < 0.001 for interactions). Further, the association between total adiposity and T2D risk was also greater in men than women (relative risk ratio (95% CI): 2.05 (1.42-2.96), P < 0.001 vs 1.38 (1.03-1.85), P = 0.031).Conclusion: With increasing adiposity, particularly increased centralisation of body fat linked to decreased insulin sensitivity and beta-cell function, Black African men are at greater risk for T2D than their female counterparts.
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| 19. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 20. |
- Lemne, Carola, et al.
(författare)
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Dyslipoproteinemic changes in borderline hypertension
- 1994
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Ingår i: Hypertension. - 1524-4563. ; 24:5, s. 605-610
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Tidskriftsartikel (refereegranskat)abstract
- The present study examined plasma lipoprotein, lipoprotein lipase, hepatic lipase, and insulin levels in men with borderline hypertension (diastolic blood pressure 85 to 94 mm Hg) compared with age-matched normotensive control subjects (diastolic blood pressure less than or equal to 80 mm Hg, n = 75 + 75). High-density lipoprotein (HDL) subclasses were determined in a subset (n = 45 + 45). While total and low-density lipoprotein cholesterol levels were similar, levels of very-low-density lipoprotein (VLDL) cholesterol and triglycerides (0.46 versus 0.41 mmol/L, P = .027, and 1.0 versus 0.85 mmol/L, P = .031) and total triglycerides (1.53 versus 1.33 mmol/L, P = .009) were elevated and HDL cholesterol was reduced in the borderline group compared with the normotensive group (1.17 versus 1.26 mmol/L, P = .043). The HDL subclass HDL2b concentration was lower (0.16 versus 0.24 mmol/L, P = .006), while HDL3b and HDL3c concentrations were higher in the borderline group (0.38 versus 0.32 mmol/L, P = .016, and 0.19 versus 0.16 mmol/L, P = .042). Significantly higher activities of hepatic lipase in the borderline group (282 versus 232 mU/mL, P = .024) and significant correlations between lipoprotein lipase activity and VLDL and HDL concentrations suggest an involvement of these enzymes in the development of these differences. When adjusted for body mass index or insulin level, all differences disappeared, except for HDL3b and HDL3c concentrations, which remained significantly elevated. These results indicate that dyslipoproteinemic changes are present in early hypertension. Although most of these changes are related to obesity, alterations in HDL profile were not explained by influences of body mass index and insulin.
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