| 1. |
- Justice, A. E., et al.
(författare)
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Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
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| 2. |
- Graff, M., et al.
(författare)
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Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
- 2017
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Ingår i: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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| 3. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 4. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 5. |
- Langenberg, C., et al.
(författare)
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Design and cohort description of the InterAct Project : an examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC Study
- 2011
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 54:9, s. 2272-2282
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Tidskriftsartikel (refereegranskat)abstract
- Studying gene-lifestyle interaction may help to identify lifestyle factors that modify genetic susceptibility and uncover genetic loci exerting important subgroup effects. Adequately powered studies with prospective, unbiased, standardised assessment of key behavioural factors for gene-lifestyle studies are lacking. This case-cohort study aims to investigate how genetic and potentially modifiable lifestyle and behavioural factors, particularly diet and physical activity, interact in their influence on the risk of developing type 2 diabetes. Incident cases of type 2 diabetes occurring in European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts between 1991 and 2007 from eight of the ten EPIC countries were ascertained and verified. Prentice-weighted Cox regression and random-effects meta-analyses were used to investigate differences in diabetes incidence by age and sex. A total of 12,403 verified incident cases of type 2 diabetes occurred during 3.99 million person-years of follow-up of 340,234 EPIC participants eligible for InterAct. We defined a centre-stratified subcohort of 16,154 individuals for comparative analyses. Individuals with incident diabetes who were randomly selected into the subcohort (n = 778) were included as cases in the analyses. All prevalent diabetes cases were excluded from the study. InterAct cases were followed-up for an average of 6.9 years; 49.7% were men. Mean baseline age and age at diagnosis were 55.6 and 62.5 years, mean BMI and waist circumference values were 29.4 kg/m(2) and 102.7 cm in men, and 30.1 kg/m(2) and 92.8 cm in women, respectively. Risk of type 2 diabetes increased linearly with age, with an overall HR of 1.56 (95% CI 1.48-1.64) for a 10 year age difference, adjusted for sex. A male excess in the risk of incident diabetes was consistently observed across all countries, with a pooled HR of 1.51 (95% CI 1.39-1.64), adjusted for age. InterAct is a large, well-powered, prospective study that will inform our understanding of the interplay between genes and lifestyle factors on the risk of type 2 diabetes development.
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| 6. |
- Wessel, Jennifer, et al.
(författare)
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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| 7. |
- Bendinelli, B., et al.
(författare)
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Association between dietary meat consumption and incident type 2 diabetes : the EPIC-InterAct study
- 2013
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 56:1, s. 47-59
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: A diet rich in meat has been reported to contribute to the risk of type 2 diabetes. The present study aims to investigate the association between meat consumption and incident type 2 diabetes in the EPIC-InterAct study, a large prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study.Methods: During 11.7 years of follow-up, 12,403 incident cases of type 2 diabetes were identified among 340,234 adults from eight European countries. A centre-stratified random subsample of 16,835 individuals was selected in order to perform a case-cohort design. Prentice-weighted Cox regression analyses were used to estimate HR and 95% CI for incident diabetes according to meat consumption.Results: Overall, multivariate analyses showed significant positive associations with incident type 2 diabetes for increasing consumption of total meat (50 g increments: HR 1.08; 95% CI 1.05, 1.12), red meat (HR 1.08; 95% CI 1.03, 1.13) and processed meat (HR 1.12; 95% CI 1.05, 1.19), and a borderline positive association with meat iron intake. Effect modifications by sex and class of BMI were observed. In men, the results of the overall analyses were confirmed. In women, the association with total and red meat persisted, although attenuated, while an association with poultry consumption also emerged (HR 1.20; 95% CI 1.07, 1.34). These associations were not evident among obese participants.Conclusions/interpretation: This prospective study confirms a positive association between high consumption of total and red meat and incident type 2 diabetes in a large cohort of European adults.
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| 8. |
- Beulens, J. W. J., et al.
(författare)
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Alcohol consumption and risk of type 2 diabetes in European men and women : influence of beverage type and body size The EPIC-InterAct study
- 2012
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Ingår i: Journal of Internal Medicine. - : Wiley-Blackwell. - 0954-6820 .- 1365-2796. ; 272:4, s. 358-370
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the association between alcohol consumption and type 2 diabetes, and determine whether this is modified by sex, body mass index (BMI) and beverage type. Design: Multicentre prospective casecohort study. Setting: Eight countries from the European Prospective Investigation into Cancer and Nutrition cohort. Subjects: A representative baseline sample of 16 154 participants and 12 403 incident cases of type 2 diabetes. Interventions: Alcohol consumption assessed using validated dietary questionnaires. Main outcome measures: Occurrence of type 2 diabetes based on multiple sources (mainly self-reports), verified against medical information. Results: Amongst men, moderate alcohol consumption was nonsignificantly associated with a lower incidence of diabetes with a hazard ratio (HR) of 0.90 (95% CI: 0.781.05) for 6.112.0 versus 0.16.0 g day-1, adjusted for dietary and diabetes risk factors. However, the lowest risk was observed at higher intakes of 24.196.0 g day-1 with an HR of 0.86 (95% CI: 0.750.98). Amongst women, moderate alcohol consumption was associated with a lower incidence of diabetes with a hazard ratio of 0.82 (95% CI: 0.720.92) for 6.112.0 g day-1 (P interaction gender <0.01). The inverse association between alcohol consumption and diabetes was more pronounced amongst overweight (BMI = 25 kg m-2) than normal-weight men and women (P interaction < 0.05). Adjusting for waist and hip circumference did not alter the results for men, but attenuated the association for women (HR=0.90, 95% CI: 0.791.03 for 6.112.0 g day-1). Wine consumption for men and fortified wine consumption for women were most strongly associated with a reduced risk of diabetes. Conclusions: The results of this study show that moderate alcohol consumption is associated with a lower risk of type 2 diabetes amongst women only. However, this risk reduction is in part explained by fat distribution. The relation between alcohol consumption and type 2 diabetes was stronger for overweight than normal-weight women and men.
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| 9. |
- Di Angelantonio, E., et al.
(författare)
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Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease
- 2014
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Ingår i: Jama-Journal of the American Medical Association. - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 311:12, s. 1225-1233
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The value of measuring levels of glycated hemoglobin (HbA(1c)) for the prediction of first cardiovascular events is uncertain. OBJECTIVE To determine whether adding information on HbA(1c) values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS Analysis of individual-participant data available from 73 prospective studies involving 294 998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (>= 7.5%) risk. RESULTS During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20 840 incident fatal and nonfatal CVD outcomes (13 237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA(1c) values and CVD risk. The association between HbA(1c) values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA(1c) was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA(1c) assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. CONCLUSIONS AND RELEVANCE In a study of individuals without known CVD or diabetes, additional assessment of HbA(1c) values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.
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