Mika Kivimaki

University College London, Londinium, England, United Kingdom

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Publications (267)2301.05 Total impact

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    ABSTRACT: Metabolically healthy obesity possibly reflects a transitional stage before the onset of metabolic dysfunction, but few studies have characterised this transition. We examined the behavioural and biological characteristics of healthy obese adults that progressed to an unhealthy state over 8 years follow up. Participants were 2422 men and women (aged 63.3 ± 7.7 years, 44.2% men) from the English Longitudinal Study of Ageing. Obesity was defined as body mass index ≥ 30 kg/m2. Based on blood pressure, HDL-cholesterol, triglycerides, glycated haemoglobin, and C-reactive protein participants were classified as 'healthy' (0 or 1 metabolic abnormality) or 'unhealthy' (≥ 2 metabolic abnormalities). Over eight years follow-up, 44.5% of healthy obese had transitioned into an unhealthy state, compared to only 16.6% and 26.2% of healthy normal weight and overweight adults, respectively. Compared with healthy obese adults who remained stable, those who progressed to an unhealthy state were more likely to have high blood pressure (75.0% vs 37.0%, age- and sex-adjusted odds ratio [OR] 8.9, 95% confidence interval [CI] 4.7-17.0), high C-reactive protein (53.7% vs 17.0%, OR=8.6, 95% CI 4.1-18.0), high glycated haemoglobin (46.3% vs 5.9%, OR=13.8, 95% CI 6.1-31.2) and high triglycerides (45.4% vs 11.9%, OR=5.9, 95% CI 2.9-12.0) at follow-up, with excess risk remaining independent of lifestyle factors including self-reported physical activity. Progression to an unhealthy state was also linked with significant gains in waist circumference (B=2.7, 95% CI, 0.5 - 4.9 cm). These data show that a healthy obesity phenotype is relatively unstable. Transition to an unhealthy state is characterised by multiple biological changes which are not fully explained by lifestyle risk factors.
    European Journal of Endocrinology 08/2015; DOI:10.1530/EJE-15-0449 · 3.69 Impact Factor
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    ABSTRACT: There is growing evidence that obese adults without metabolic risk factor clustering (the so-called "healthy obese") progress to unhealthy obesity over time (1). However, the pathophysiological changes underlying the long-term transition into an unhealthy obese state have not been well characterized. To inform the clinical management of healthy obesity, we aimed to identify the metabolic risk factors responsible for this transition, as well as the timing of their onset.
    Journal of the American College of Cardiology 08/2015; 66(7):871-873. DOI:10.1016/j.jacc.2015.06.014 · 15.34 Impact Factor
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    ABSTRACT: To investigate, using a Mendelian randomisation approach, whether heavier smoking is associated with a range of regional adiposity phenotypes, in particular those related to abdominal adiposity. Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730 in the CHRNA5-CHRNA3-CHRNB4 gene region) as a proxy for smoking heaviness, of the associations of smoking heaviness with a range of adiposity phenotypes. 148 731 current, former and never-smokers of European ancestry aged ≥16 years from 29 studies in the consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Waist and hip circumferences, and waist-hip ratio. The data included up to 66 809 never-smokers, 43 009 former smokers and 38 913 current daily cigarette smokers. Among current smokers, for each extra minor allele, the geometric mean was lower for waist circumference by -0.40% (95% CI -0.57% to -0.22%), with effects on hip circumference, waist-hip ratio and body mass index (BMI) being -0.31% (95% CI -0.42% to -0.19), -0.08% (-0.19% to 0.03%) and -0.74% (-0.96% to -0.51%), respectively. In contrast, among never-smokers, these effects were higher by 0.23% (0.09% to 0.36%), 0.17% (0.08% to 0.26%), 0.07% (-0.01% to 0.15%) and 0.35% (0.18% to 0.52%), respectively. When adjusting the three central adiposity measures for BMI, the effects among current smokers changed direction and were higher by 0.14% (0.05% to 0.22%) for waist circumference, 0.02% (-0.05% to 0.08%) for hip circumference and 0.10% (0.02% to 0.19%) for waist-hip ratio, for each extra minor allele. For a given BMI, a gene variant associated with increased cigarette consumption was associated with increased waist circumference. Smoking in an effort to control weight may lead to accumulation of central adiposity. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    BMJ Open 08/2015; 5(8):e008808. DOI:10.1136/bmjopen-2015-008808 · 2.06 Impact Factor
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    ABSTRACT: Participants' non adherence to protocol affects data quality. In longitudinal studies, this leads to outliers that can be present at the level of the population or the individual. The purpose of the present study is to elaborate a method for detection of outliers in a study of cognitive ageing. In the Whitehall II study, data on a cognitive test battery have been collected in 1997-99, 2002-04, 2007-09 and 2012-13. Outliers at the 2012-13 wave were identified using a 4-step procedure: (1) identify cognitive tests with potential non-adherence to protocol, (2) choose a prediction model between a simple model with socio-demographic covariates and one that also includes health behaviours and health measures, (3) define an outlier using a studentized residual, and (4) study the impact of exclusion of outliers by estimating the effect of age and diabetes on cognitive decline. 5516 participants provided cognitive data in 2012-13. Comparisons of rates of annual decline over the first three and all four waves of data suggested outliers in three of the 5 tests. Mean residuals for the 2012-13 wave were larger for the basic compared to the more complex prediction model (all p<0.001), leading us to use the latter for the identification of outliers. Residuals greater than two standard deviation of residuals identified approximately 7% of observations as being outliers. Removal of these observations from the analyses showed that both age and diabetes had associations with cognitive decline similar to that observed with the first three waves of data; these associations were weaker or absent in non-cleaned data. Identification of outliers is important as they obscure the effects of known risk factor and introduce bias in the estimates of cognitive decline. We showed that an informed approach, using the range of data collected in a longitudinal study, may be able to identify outliers.
    PLoS ONE 07/2015; 10(7):e0132110. DOI:10.1371/journal.pone.0132110 · 3.23 Impact Factor
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    ABSTRACT: Disease risk is lower in metabolically healthy obese adults than in their unhealthy obese counterparts. Studies considering physical activity as a modifiable determinant of healthy obesity have relied on self-reported measures, which are prone to inaccuracies and do not capture all movements that contribute to health. We aimed to examine differences in total and moderate-to-vigorous physical activity between healthy and unhealthy obese groups by using both self-report and wrist-worn accelerometer assessments. Cross-sectional analyses were based on 3457 adults aged 60-82 y (77% male) participating in the British Whitehall II cohort study in 2012-2013. Normal-weight, overweight, and obese adults were considered "healthy" if they had <2 of the following risk factors: low HDL cholesterol, hypertension, high blood glucose, high triacylglycerol, and insulin resistance. Differences across groups in total physical activity, based on questionnaire and wrist-worn triaxial accelerometer assessments (GENEActiv), were examined by using linear regression. The likelihood of meeting 2010 World Health Organization recommendations for moderate-to-vigorous activity (≥2.5 h/wk) was compared by using prevalence ratios. Of 3457 adults, 616 were obese [body mass index (in kg/m(2)) ≥30]; 161 (26%) of those were healthy obese. Obese adults were less physically active than were normal-weight adults, regardless of metabolic health status or method of physical activity assessment. Healthy obese adults had higher total physical activity than did unhealthy obese adults only when assessed by accelerometer (P = 0.002). Healthy obese adults were less likely to meet recommendations for moderate-to-vigorous physical activity than were healthy normal-weight adults based on accelerometer assessment (prevalence ratio: 0.59; 95% CI: 0.43, 0.79) but were not more likely to meet these recommendations than were unhealthy obese adults (prevalence ratio: 1.26; 95% CI: 0.89, 1.80). Higher total physical activity in healthy than in unhealthy obese adults is evident only when measured objectively, which suggests that physical activity has a greater role in promoting health among obese populations than previously thought.
    American Journal of Clinical Nutrition 07/2015; DOI:10.3945/ajcn.115.110924 · 6.92 Impact Factor
  • M Hamer · G D Batty · M Kivimaki
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    ABSTRACT: We examined the role of sarcopenic obesity as a risk factor for new-onset depressive symptoms over 6 years follow up in a large sample of older adults. The sample comprised 3862 community dwelling participants (1779 men, 2083 women; mean age 64.6±8.3 yrs) without depressive symptoms at baseline, recruited from the English Longitudinal Study of Ageing (ELSA). At baseline and 4 years follow up, handgrip strength (kg) of the dominant hand was assessed using a hand-held dynamometer, as a measure of sarcopenia. The outcome was new onset depressive symptoms at 6 years follow-up, defined as a score of ≥4 on the 8-item Centre of Epidemiological Studies Depression (CES-D) scale. Sarcopenic obesity was defined as obese individuals (BMI≥30 kg/m(2)) in the lowest tertile of sex specific grip strength (<35.3 kg men;<19.6 kg women). Using a multivariable logistic regression model, the risk of depressive symptoms was greatest in obese adults in the lowest tertile of handgrip strength (Odds ratio, 1.79, 95% CI, 1.10, 2.89) compared to non-obese individuals with high handgrip strength. Participants who were obese at baseline and had a decrease of more than 1 standard deviation in grip strength over 4 years follow up were at greatest risk of depressive symptoms (OR=1.97, 95% CI, 1.22, 3.17) compared to non-obese with stable grip strength. A reduction in grip strength was associated with higher risk of depressive symptoms in obese participants only, suggesting that sarcopenic obesity is a risk factor for depressive symptoms.International Journal of Obesity accepted article preview online, 30 June 2015. doi:10.1038/ijo.2015.124.
    International journal of obesity (2005) 06/2015; DOI:10.1038/ijo.2015.124 · 5.39 Impact Factor
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    ABSTRACT: We sought to determine whether adiposity in later midlife is an independent predictor of accelerated stiffening of the aorta. Whitehall II study participants (3789 men; 1383 women) underwent carotid-femoral applanation tonometry at the mean age of 66 and again 4 years later. General adiposity by body mass index, central adiposity by waist circumference and waist:hip ratio, and fat mass percent by body impedance were assessed 5 years before and at baseline. In linear mixed models adjusted for age, sex, ethnicity, and mean arterial pressure, all adiposity measures were associated with aortic stiffening measured as increase in pulse wave velocity (PWV) between baseline and follow-up. The associations were similar in the metabolically healthy and unhealthy, according to Adult Treatment Panel-III criteria excluding waist circumference. C-reactive protein and interleukin-6 levels accounted for part of the longitudinal association between adiposity and PWV change. Adjusting for chronic disease, antihypertensive medication and risk factors, standardized effects of general and central adiposity and fat mass percent on PWV increase (m/s) were similar (0.14, 95% confidence interval: 0.05-0.24, P=0.003; 0.17, 0.08-0.27, P<0.001; 0.14, 0.05-0.22, P=0.002, respectively). Previous adiposity was associated with aortic stiffening independent of change in adiposity, glycaemia, and lipid levels across PWV assessments. We estimated that the body mass index-linked PWV increase will account for 12% of the projected increase in cardiovascular risk because of high body mass index. General and central adiposity in later midlife were strong independent predictors of aortic stiffening. Our findings suggest that adiposity is an important and potentially modifiable determinant of arterial aging. © 2015 American Heart Association, Inc.
    Hypertension 06/2015; DOI:10.1161/HYPERTENSIONAHA.115.05494 · 7.63 Impact Factor
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    ABSTRACT: The direction of the association between mental health and adiposity is poorly understood. Our objective was to empirically examine this link in a UK study. This is a prospective cohort study of 3 388 people (men) aged ≥ 18 years at study induction who participated in both the UK Health and Lifestyle Survey at baseline (HALS-1, 1984/1985) and the re-survey (HALS-2, 1991/1992). At both survey examinations, body mass index, waist circumference and self-reported common mental disorder (the 30-item General Health Questionnaire, GHQ) were measured. Logistic regression models were used to compute odds ratios (OR) and accompanying 95% confidence intervals (CI) for the associations between (1) baseline common mental disorder (QHQ score > 4) and subsequent general and abdominal obesity and (2) baseline general and abdominal obesity and re-survey common mental disorders. After controlling for a range of covariates, participants with common mental disorder at baseline experienced greater odds of subsequently becoming overweight (women, OR: 1.30, 1.03 - 1.64; men, 1.05, 0.81 - 1.38) and obese (women, 1.26, 0.82 - 1.94; men, OR: 2.10, 1.23 - 3.55) than those who were free of common mental disorder. Similarly, having baseline common mental health disorder was also related to a greater risk of developing moderate (1.57, 1.21 - 2.04) and severe (1.48, 1.09 - 2.01) abdominal obesity (women only). Baseline general or abdominal obesity was not associated with the risk of future common mental disorder. These findings of the present study suggest that the direction of association between common mental disorders and adiposity is from common mental disorder to increased future risk of adiposity as opposed to the converse.
    PLoS ONE 05/2015; 10(5):e0119970. DOI:10.1371/journal.pone.0119970 · 3.23 Impact Factor
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    ABSTRACT: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis. We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D. IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index (P < 0.001), triglycerides (P < 0.001), non high-density (non-HDL) cholesterol (P < 0.001), C-reactive protein (P = 0.042), and systolic blood pressure (P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity (P < 0.001 for both). Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
    International Journal of Epidemiology 05/2015; DOI:10.1093/ije/dyv074 · 9.20 Impact Factor
  • Médecine du Sommeil 03/2015; 12(1). DOI:10.1016/j.msom.2015.01.112
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    ABSTRACT: Physical activity is critically important for successful aging, but its effect on adiposity markers at older ages is unclear as much of the evidence comes from self-reported data on physical activity. We assessed the associations of questionnaire-assessed and accelerometer-assessed physical activity with adiposity markers in older adults. This was a cross-sectional study on 3940 participants (age range 60-83 years) of the Whitehall II study who completed a 20-item physical activity questionnaire and wore a wrist-mounted accelerometer for 9 days in 2012 and 2013. Total physical activity was estimated using metabolic equivalent hours/week for the questionnaire and mean acceleration for the accelerometer. Time spent in moderate-and-vigorous physical activity (MVPA) was also assessed by questionnaire and accelerometer. Adiposity assessment included body mass index, waist circumference, and fat mass index. Fat mass index was calculated as fat mass/height² (kg/m²), with fat mass estimated using bioimpedance. Greater total physical activity was associated with lower adiposity for all adiposity markers in a dose-response manner. In men, the strength of this association was 2.4 to 2.8 times stronger with the accelerometer than with questionnaire data. In women, it was 1.9 to 2.3 times stronger. For MVPA, questionnaire data in men suggested no further benefit for adiposity markers past 1 hour/week of activity. This was not the case for accelerometer-assessed MVPA where, for example, compared with men undertaking <1 hour/week of accelerometer-assessed MVPA, waist circumference was 3.06 (95% confidence interval 2.06-4.06) cm lower in those performing MVPA 1-2.5 hours/week, 4.69 (3.47-5.91) cm lower in those undertaking 2.5-4 hours/week, and 7.11 (5.93-8.29) cm lower in those performing ≥4 hours/week. The association of physical activity with adiposity markers in older adults was stronger when physical activity was assessed by accelerometer compared with questionnaire, suggesting that physical activity might be more important for adiposity than previously estimated. Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
    Journal of the American Medical Directors Association 03/2015; 36(5). DOI:10.1016/j.jamda.2015.01.086 · 4.78 Impact Factor
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    ABSTRACT: Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis
    Nature 02/2015; 518(7538). DOI:10.1038/nature14177 · 42.35 Impact Factor
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    ABSTRACT: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
    Nature 02/2015; 518(7538-7538):187-96. DOI:10.1038/nature14132 · 42.35 Impact Factor
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    M. Futema · M. Kumari · C. Boustred · M. Kivimaki · S.E. Humphries
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    ABSTRACT: A previous report suggested that 88% of individuals in the general population with total cholesterol (TC)>9.3mmol/L have familial hypercholesterolaemia (FH). We tested this hypothesis in a cohort of 4896 UK civil servants, mean (SD) age 44(±6) years, using next generation sequencing to achieve a comprehensive genetic diagnosis. 25(0.5%) participants (mean age 49.2 years) had baseline TC>9.3 mmol/L, and overall we found an FH-causing mutation in the LDLR gene in seven (28%) subjects. The detection rate increased to 39% by excluding eight paticipants with triglyceride levels over 2.3mmol/L, and reached 75% in those with TC>10.4mmol/L. By extrapolation, the detection rate would be ∼25% by including all participants with TC>8.6mmol/L (2.5 standard deviations from the mean). Based on the 1/500 FH frequency, 30% of all FH-cases in this cohort would be missed using the 9.3mmol/L cut-off. Given that an overall detection rate of 25% is considered economically acceptable, these data suggest that a diagnostic TC cut-off of 8.6mmol/L, rather than 9.3mmol/L would be clinically useful for FH in the general population.
    Atherosclerosis 01/2015; 97(2). DOI:10.1016/j.atherosclerosis.2015.01.028 · 3.97 Impact Factor
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    ABSTRACT: Objective: Positive psychological well-being has protective associations with cardiovascular outcomes, but no studies have considered its association with diabetes. This study investigated links between well-being and incident diabetes. Methods: At study baseline (1991-1994), 7,800 middle-aged British men and women without diabetes indicated their life satisfaction, emotional vitality, and optimism. Diabetes status was determined by self-reported physician diagnosis and oral glucose tolerance test (screen detection) at baseline and through 2002-2004. Incident diabetes was defined by physician-diagnosed and screen-detected cases combined and separately. Logistic regression estimated the odds of developing diabetes controlling for relevant covariates (e.g., demographics, depressive symptoms). Models were also stratified by gender and weight status. Results: There were 562 combined cases of incident diabetes during follow-up (up to 13 years). Well-being was not associated with incident diabetes for combined physician-diagnosed and screen-detected cases. However, when examining the 288 physician-diagnosed cases, life satisfaction and emotional vitality were associated with up to a 15% decrease in the odds of physician-diagnosed diabetes, controlling for demographics (results were similar with other covariates). Optimism was not associated with physician-diagnosed diabetes, and no well-being indicator was associated with screen-detected diabetes. Gender and weight status were not moderators. Conclusions: Life satisfaction and emotional vitality, but not optimism, were associated with reduced risk of physician-diagnosed diabetes. These findings suggest that well-being may contribute to reducing risk of a prevalent and burdensome condition, although intervention studies are needed to confirm this. It is unclear why findings differed for physician-diagnosed versus study-screened diabetes. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
    Health Psychology 01/2015; DOI:10.1037/hea0000200 · 3.95 Impact Factor
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    ABSTRACT: Intense interest surrounds the “healthy” obese phenotype, which is defined as obesity in the absence of metabolic risk factor clustering (1). Efforts to understand the cardiovascular consequences of healthy obesity are ongoing (2); however, its conceptual validity and clinical value rest on the assumption that it is a stable physiological state, rather than a transient phase of obesity-associated metabolic deterioration. Therefore, a fundamental question is whether healthy obese adults maintain this metabolically healthy profile over the long term or naturally transition into unhealthy obesity over time. Few studies have examined this; in those that have, durations of follow-up have been modest, with none exceeding 10 years (3,4). Accordingly, we aimed to describe the natural course of healthy obesity over 2 decades in a large population-based study.
    Journal of the American College of Cardiology 01/2015; 65(1):101-102. DOI:10.1016/j.jacc.2014.09.077 · 15.34 Impact Factor
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    ABSTRACT: We developed a 65-T2D variant weighted gene score to examine the impact on T2D risk assessment in a UK-based consortium of prospective studies, initially free from type 2 diabetes (T2D) (N=13,294; 37.3% women; mean age 58.5 (38-99) years). We compared the performance of the gene score with the phenotypically-derived Framingham Offspring Study T2D risk model, and then the two in combination. Over the median 10 years follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95%CI 2.12-3.43). With a 10% false positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together, 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI: 0.58-0.62), 0.75 (95% CI: 0.73 to 0.77) and 0.76 (95% CI: 0.75 to 0.78). The combined risk scores Net Reclassification Improvement (NRI) was 8.1% (5.0 to 11.2) p=3.31x10(-7). While BMI stratification into tertiles influenced the NRI (95% CI) (BMI<24.5kg/m(2) (27.6% (17.7 to 37.5) p=4.82x10(-8)); 24.5-27.5kg/m(2) (11.6% (5.8 to 17.4) p=9.88x10(-5)); >27.5kg/m(2) (2.6% (-1.4 to 6.6) p=0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 12/2014; 64(5). DOI:10.2337/db14-1504 · 8.47 Impact Factor
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    ABSTRACT: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
    Nature Genetics 12/2014; DOI:10.1038/ng.3014 · 29.65 Impact Factor

Publication Stats

7k Citations
2,301.05 Total Impact Points

Institutions

  • 2009–2015
    • University College London
      • Department of Epidemiology and Public Health
      Londinium, England, United Kingdom
    • Stockholm University
      • Stress Research Institute
      Stockholm, Stockholm, Sweden
  • 2006–2015
    • Finnish Institute of Occupational Health
      • Centre of Expertise for Work Organizations
      Helsinki, Uusimaa, Finland
  • 2010–2014
    • Research Institute of the Finnish Economy, Finland, Helsinki
      Helsinki, Uusimaa, Finland
    • French Institute of Health and Medical Research
      • Centre de Recherche en Épidémiologie et Santé des Populations CESP U1018
      Paris, Ile-de-France, France
  • 2004–2014
    • University of Helsinki
      • Department of Psychology
      Helsinki, Uusimaa, Finland
  • 2013
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2012
    • McGill University
      • Department of Epidemiology, Biostatistics and Occupational Health
      Montréal, Quebec, Canada
  • 2007–2012
    • University of Turku
      • Division of Psychology
      Turku, Varsinais-Suomi, Finland
    • University of Nottingham
      • Institute of Work, Health and Organisations
      Nottigham, England, United Kingdom
    • University of Glasgow
      • MRC/CSO Social and Public Health Sciences Unit
      Glasgow, SCT, United Kingdom
  • 2007–2011
    • London School of Hygiene and Tropical Medicine
      • Faculty of Epidemiology and Population Health
      Londinium, England, United Kingdom
  • 1999
    • University of Jyväskylä
      Jyväskylä, Province of Western Finland, Finland