Publications
403 results found
Iotchkova V, Huang J, Morris JA, et al., 2016, Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps, Nature Genetics, Vol: 48, Pages: 1303-1312, ISSN: 1061-4036
Large-scale whole genome sequence datasets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole genome sequence data from the UK10K and the 1000 Genomes Projects into 35,981 study participants of European ancestry, followed by association analysis with twenty quantitative cardiometabolic and hematologic traits. We describe 17 novel associations, including six rare (minor allele frequency [MAF]<1%) or low frequency variants (1%<MAF<5%) with platelet count (PLT), red cell indices (MCH, MCV) and high-density lipoprotein (HDL) cholesterol. Applying fine-mapping analysis to 233 known and novel loci associated with the twenty traits, we resolve associations of 59 loci to credible sets of 20 or less variants, and describe trait enrichments within regions of predicted regulatory function. These findings augment understanding of the allelic architecture of risk factors for cardiometabolic and hematologic diseases, and provide additional functional insights with the identification of potentially novel biological targets.
Karaman I, Ferreira DL, Boulange CL, et al., 2016, A workflow for integrated processing of multi-cohort untargeted 1H NMR metabolomics data in large scale metabolic epidemiology, Journal of Proteome Research, Vol: 15, Pages: 4188-4194, ISSN: 1535-3907
Large-scale metabolomics studies involving thousands of samples present multiple challenges in data analysis, particularly when an untargeted platform is used. Studies with multiple cohorts and analysis platforms exacerbate existing problems such as peak alignment and normalization. Therefore, there is a need for robust processing pipelines which can ensure reliable data for statistical analysis. The COMBI-BIO project incorporates serum from approximately 8000 individuals, in 3 cohorts, profiled by 6 assays in 2 phases using both 1H-NMR and UPLC-MS. Here we present the COMBI-BIO NMR analysis pipeline and demonstrate its fitness for purpose using representative quality control (QC) samples. NMR spectra were first aligned and normalized. After eliminating interfering signals, outliers identified using Hotelling’s T2 were removed and a cohort/phase adjustment was applied, resulting in two NMR datasets (CPMG and NOESY). Alignment of the NMR data was shown to increase the correlation-based alignment quality measure from 0.319 to 0.391 for CPMG and from 0.536 to 0.586 for NOESY, showing that the improvement was present across both large and small peaks. End-to-end quality assessment of the pipeline was achieved using Hotelling’s T2 distributions. For CPMG spectra, the interquartile range decreased from 1.425 in raw QC data to 0.679 in processed spectra, while the corresponding change for NOESY spectra was from 0.795 to 0.636 indicating an improvement in precision following processing. PCA indicated that gross phase and cohort differences were no longer present. These results illustrate that the pipeline produces robust and reproducible data, successfully addressing the methodological challenges of this large multi-faceted study.
Chaker L, van den Berg ME, Niemeijer MN, et al., 2016, Thyroid Function and Sudden Cardiac Death: A Prospective Population-Based Cohort Study, CIRCULATION, Vol: 134, Pages: 713-722, ISSN: 0009-7322
Willeit P, Kaptoge S, Welsh P, et al., 2016, Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis, Lancet Diabetes and Endocrinology, Vol: 4, Pages: 840-849, ISSN: 2213-8595
BackgroundGuidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment.MethodsIn this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure.FindingsWe recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56–1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77–2·26) for the combination of coronary heart disease, stroke, and
Chaker L, Korevaar TIM, Medici M, et al., 2016, Thyroid Function Characteristics and Determinants: The Rotterdam Study, THYROID, Vol: 26, Pages: 1195-1204, ISSN: 1050-7256
Polfus LM, Khajuria RK, Schick UM, et al., 2016, Erratum: Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis (American Journal of Human Genetics (2016) 99(2) (481–488)(S0002929716302208)(10.1016/j.ajhg.2016.06.016)), American Journal of Human Genetics, Vol: 99, Pages: 785-785, ISSN: 0002-9297
© 2016 American Society of Human Genetics (The American Journal of Human Genetics 99, 481–488; August 4, 2016) In the originally published version of this paper, Nora Franceschini's surname was misspelled. It has now been corrected online. The authors apologize for the error.
van der Laan SW, Fall T, Soumare A, et al., 2016, Cystatin C and Cardiovascular Disease A Mendelian Randomization Study, Journal of the American College of Cardiology, Vol: 68, Pages: 934-945, ISSN: 0735-1097
BackgroundEpidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation.ObjectivesThe aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population.MethodsWe incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure.ResultsCystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10−14). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10−211), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10−5). A causal effect of cystatin C was not detected for any individual component of CVD.ConclusionsMendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.
Dehghan A, 2016, Mass spectrometry in epidemiological studies: What are the key considerations?, EUROPEAN JOURNAL OF EPIDEMIOLOGY, Vol: 31, Pages: 715-716, ISSN: 0393-2990
Amin N, Jovanova O, Adams HHH, et al., 2016, Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms (vol 22, pg 537, 2017), MOLECULAR PSYCHIATRY, Vol: 22, Pages: 634-634, ISSN: 1359-4184
Polfus LM, Khajuria RK, Schick UM, et al., 2016, Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative <i>GFI1B</i> Splice Variants in Human Hematopoiesis, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 99, Pages: 481-488, ISSN: 0002-9297
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- Citations: 30
Sedaghat S, Cremers LGM, de Groot M, et al., 2016, Lower microstructural integrity of brain white matter is related to higher mortality, NEUROLOGY, Vol: 87, Pages: 927-934, ISSN: 0028-3878
Bano A, Chaker L, Plompen EPC, et al., 2016, Thyroid Function and the Risk of Nonalcoholic Fatty Liver Disease: The Rotterdam Study, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 101, Pages: 3204-3211, ISSN: 0021-972X
Bentham J, Di Cesare M, Stevens GA, et al., 2016, A century of trends in adult human height, eLife, Vol: 5, ISSN: 2050-084X
Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
Dhana K, Nano J, Ligthart S, et al., 2016, Obesity and Life Expectancy with and without Diabetes in Adults Aged 55 Years and Older in the Netherlands: A Prospective Cohort Study, PLoS Medicine, Vol: 13, ISSN: 1549-1277
BackgroundOverweight and obesity are associated with increased risk of type 2 diabetes. Limited evidenceexists regarding the effect of excess weight on years lived with and without diabetes.We aimed to determine the association of overweight and obesity with the number of yearslived with and without diabetes in a middle-aged and elderly population.Methods and FindingsThe study included 6,499 individuals (3,656 women) aged 55 y and older from the population-basedRotterdam Study. We developed a multistate life table to calculate life expectancyfor individuals who were normal weight, overweight, and obese and the difference inyears lived with and without diabetes. For life table calculations, we used prevalence, incidencerate, and hazard ratios (HRs) for three transitions (healthy to diabetes, healthy todeath, and diabetes to death), stratifying by body mass index (BMI) at baseline and adjustingfor confounders. During a median follow-up of 11.1 y, we observed 697 incident diabetesevents and 2,192 overall deaths. Obesity was associated with an increased risk of developingdiabetes (HR: 2.13 [p < 0.001] for men and 3.54 [p < 0.001] for women). Overweightand obesity were not associated with mortality in men and women with or without diabetes.Total life expectancy remained unaffected by overweight and obesity. Nevertheless, menwith obesity aged 55 y and older lived 2.8 (95% CI −6.1 to −0.1) fewer y without diabetesthan normal weight individuals, whereas, for women, the difference between obese and normalweight counterparts was 4.7 (95% CI −9.0 to −0.6) y. Men and women with obesity lived2.8 (95% CI 0.6 to 6.2) and 5.3 (95% CI 1.6 to 9.3) y longer with diabetes, respectively, comparedto their normal weight counterparts. Since the implications of these findings could be limited to middle-aged and older white European populations, our results need confirmationin other populations.ConclusionsObesity in the middle aged and elderly is associated with
Amin N, Jovanova O, Adams HHH, et al., 2016, Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms, MOLECULAR PSYCHIATRY, Vol: 22, Pages: 537-543, ISSN: 1359-4184
Pankratz N, Schick UM, Zhou Y, et al., 2016, Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits, NATURE GENETICS, Vol: 48, Pages: 867-+, ISSN: 1061-4036
Eicher JD, Chami N, Kacprowski T, et al., 2016, Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals, American Journal of Human Genetics, Vol: 99, Pages: 40-55, ISSN: 1537-6605
Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
Tajuddin SM, Schick UM, Eicher JD, et al., 2016, Large-scale exome-wide association analysis identifies loci for white blood cell traits and pleiotropy with immune-mediated diseases, American Journal of Human Genetics, Vol: 99, Pages: 22-39, ISSN: 1537-6605
White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.
Ghanbari M, Ikram MA, De Looper HWJ, et al., 2016, Genome-wide identification of microRNA-related variants associated with risk of Alzheimer's disease, Scientific Reports, Vol: 6, ISSN: 2045-2322
MicroRNAs (miRNAs) serve as key post-Transcriptional regulators of gene expression. Genetic variation in miRNAs and miRNA-binding sites may affect miRNA function and contribute to disease risk. Here, we investigated the extent to which variants within miRNA-related sequences could constitute a part of the functional variants involved in developing Alzheimer's disease (AD), using the largest available genome-wide association study of AD. First, among 237 variants in miRNAs, we found rs2291418 in the miR-1229 precursor to be significantly associated with AD (p-value = 6.8 × 10 â '5, OR = 1.2). Our in-silico analysis and in-vitro miRNA expression experiments demonstrated that the variant's mutant allele enhances the production of miR-1229-3p. Next, we found miR-1229-3p target genes that are associated with AD and might mediate the miRNA function. We demonstrated that miR-1229-3p directly controls the expression of its top AD-Associated target gene (SORL1) using luciferase reporter assays. Additionally, we showed that miR-1229-3p and SORL1 are both expressed in the human brain. Second, among 42,855 variants in miRNA-binding sites, we identified 10 variants (in the 3′ UTR of 9 genes) that are significantly associated with AD, including rs6857 that increases the miR-320e-mediated regulation of PVRL2. Collectively, this study shows that miRNA-related variants are associated with AD and suggests miRNA-dependent regulation of several AD genes.
Prins BP, Abbasi A, Wong A, et al., 2016, Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study, PLOS Medicine, Vol: 13, ISSN: 1549-1277
BACKGROUND: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS: We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with
van Loon J, Dehghan A, Tang W, et al., 2016, Genome-wide association studies identify genetic loci for low von Willebrand factor levels (vol 24, pg 1035, 2016), EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 24, Pages: 1096-1096, ISSN: 1018-4813
Ligthart S, Vaez A, Hsu YH, et al., 2016, Bivariate genome-wide association study identifies novel pleiotropic loci for lipids and inflammation, BMC Medical Genomics, Vol: 17, ISSN: 1755-8794
Background: Genome-wide association studies (GWAS) have identified multiple genetic loci for C-reactive protein (CRP) and lipids, of which some overlap. We aimed to identify genetic pleiotropy among CRP and lipids in order to better understand the shared biology of chronic inflammation and lipid metabolism. Results: In a bivariate GWAS, we combined summary statistics of published GWAS on CRP (n = 66,185) and lipids, including LDL-cholesterol, HDL-cholesterol, triglycerides, and total cholesterol (n = 100,184), using an empirical weighted linear-combined test statistic. We sought replication for novel CRP associations in an independent sample of 17,743 genotyped individuals, and performed in silico replication of novel lipid variants in 93,982 individuals. Fifty potentially pleiotropic SNPs were identified among CRP and lipids: 21 for LDL-cholesterol and CRP, 20 for HDL-cholesterol and CRP, 21 for triglycerides, and CRP and 20 for total cholesterol and CRP. We identified and significantly replicated three novel S NPs for CRP in or near CTSB/FDFT1 (rs10435719, P replication : 2.6 × 10 -5 ), STAG1/PCCB (rs7621025, P replication : 1.4 × 10 -3 ) and FTO (rs1558902, P replication : 2.7 × 10 -5 ). Seven pleiotropic lipid loci were replicated in the independent set of MetaboChip samples of the Global Lipids Genetics Consortium. Annotating the effect of replicated CRP SNPs to the expression of nearby genes, we observed an effect of rs10435719 on gene expression of FDFT1, and an effect of rs7621025 on PCCB. Conclusions: Our large scale combined GWAS analysis identified numerous pleiotropic loci for CRP and lipids providing further insight in the genetic interrelation between lipids and inflammation. In addition, we provide evidence for FDFT1, PCCB and FTO to be associated with CRP levels.
Smith JG, Felix JF, Morrison AC, et al., 2016, Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure, PLoS Genetics, Vol: 12, ISSN: 1553-7390
van Herpt TT, Dehghan A, van Hoek M, et al., 2016, The clinical value of metabolic syndrome and risks of cardiometabolic events and mortality in the elderly: the Rotterdam study., Cardiovasc Diabetol, Vol: 15, Pages: 69-69
BACKGROUND: To evaluate the clinical value of metabolic syndrome based on different definitions [American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI), International Diabetes Federation (IDF) and European Group for the Study of Insulin Resistance (EGIR)] in middle-aged and elderly populations. METHODS: We studied 8643 participants from the Rotterdam study (1990-2012; mean age 62.7; 57.6 % female), a large prospective population-based study with predominantly elderly participants. We performed cox-proportional hazards models for different definitions, triads within definitions and each separate component for the risk of incident type 2 diabetes mellitus, coronary heart disease, stroke, cardiovascular- and all-cause mortality. RESULTS: In our population of 8643 subjects, metabolic syndrome was highly prevalent (prevalence between 19.4 and 42.4 %). Metabolic syndrome in general was associated with incident type 2 diabetes mellitus (median follow-up of 6.8 years, hazard ratios 3.13-3.78). The associations with coronary heart disease (median follow-up of 7.2 years, hazard ratios 1.08-1.32), stroke (median follow-up of 7.7 years, hazard ratios 0.98-1.32), cardiovascular mortality (median follow-up of 8.2 years, ratios 0.95-1.29) and all-cause mortality (median follow-up of 8.7 years, hazard ratios 1.05-1.10) were weaker. AHA/NHLBI- and IDF-definitions showed similar associations with clinical endpoints compared to the EGIR, which was only significantly associated with incident type 2 diabetes mellitus. All significant associations disappeared after correcting metabolic syndrome for its individual components. CONCLUSIONS: Large variability exists between and within definitions of the metabolic syndrome with respect to risk of clinical events and mortality. In a relatively old population the metabolic syndrome did not show an additional predictive value on top of its individual components. So, besides as a manner of easy identification of high risk
Muka T, Nano J, Voortman T, et al., 2016, The role of global and regional DNA methylation and histone modifications in glycemic traits and type 2 diabetes: A systematic review, NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES, Vol: 26, Pages: 553-566, ISSN: 0939-4753
Zhou B, Lu Y, Hajifathalian K, et al., 2016, Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4·4 million participants, Lancet, Vol: 387, Pages: 1513-1530, ISSN: 1474-547X
BackgroundOne of the global targets for non-communicable diseases is to halt, by 2025, the rise in the age-standardised adult prevalence of diabetes at its 2010 levels. We aimed to estimate worldwide trends in diabetes, how likely it is for countries to achieve the global target, and how changes in prevalence, together with population growth and ageing, are affecting the number of adults with diabetes.MethodsWe pooled data from population-based studies that had collected data on diabetes through measurement of its biomarkers. We used a Bayesian hierarchical model to estimate trends in diabetes prevalence—defined as fasting plasma glucose of 7·0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs—in 200 countries and territories in 21 regions, by sex and from 1980 to 2014. We also calculated the posterior probability of meeting the global diabetes target if post-2000 trends continue.FindingsWe used data from 751 studies including 4 372 000 adults from 146 of the 200 countries we make estimates for. Global age-standardised diabetes prevalence increased from 4·3% (95% credible interval 2·4–7·0) in 1980 to 9·0% (7·2–11·1) in 2014 in men, and from 5·0% (2·9–7·9) to 7·9% (6·4–9·7) in women. The number of adults with diabetes in the world increased from 108 million in 1980 to 422 million in 2014 (28·5% due to the rise in prevalence, 39·7% due to population growth and ageing, and 31·8% due to interaction of these two factors). Age-standardised adult diabetes prevalence in 2014 was lowest in northwestern Europe, and highest in Polynesia and Micronesia, at nearly 25%, followed by Melanesia and the Middle East and north Africa. Between 1980 and 2014 there was little change in age-standardised diabetes prevalence in adult women in continental western Europe, although crude prevalenc
Di Cesare M, Bentham J, Stevens GA, et al., 2016, Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants, Lancet, Vol: 387, Pages: 1377-1396, ISSN: 1474-547X
BackgroundUnderweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries.MethodsWe analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m2 [underweight], 18·5 kg/m2 to <20 kg/m2, 20 kg/m2 to <25 kg/m2, 25 kg/m2 to <30 kg/m2, 30 kg/m2 to <35 kg/m2, 35 kg/m2 to <40 kg/m2, ≥40 kg/m2 [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue.FindingsWe used 1698 population-based data sources, with more than 19·2 million adult participants (9·9 million men and 9·3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21·7 kg/m2 (95% credible interval 21·3–22·1) in 1975 to 24·2 kg/m2 (24·0–24·4) in 2014 in men, and from 22·1 kg/m2 (21·7–22·5) in 1975 to 24·4 kg/m2 (24·2–24·6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21·4 kg/m2 in central Africa and south Asia to 29·2 kg/m2 (28·6–29·8) in Polynesia and Micronesia; for women the range was from 21·8 kg/m2 (21·4–22·3) in south Asia to 32·2 kg/m2 (31·5–32·8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of un
van Leeuwen EM, Sabo A, Bis JC, et al., 2016, Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels, Journal of Medical Genetics, Vol: 53, Pages: 441-449, ISSN: 1468-6244
BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage. RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.
Joubert BR, Felix JF, Yousefi P, et al., 2016, DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis., Am J Hum Genet, Vol: 98, Pages: 680-696
Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
Jovanova O, Luik AI, Leening MJG, et al., 2016, The long-term risk of recognized and unrecognized myocardial infarction for depression in older men, PSYCHOLOGICAL MEDICINE, Vol: 46, Pages: 1951-1960, ISSN: 0033-2917
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