Showing papers by "Henry Völzke published in 2016"
TL;DR: In this article, the results of a genome-wide association study (GWAS) for educational attainment were reported, showing that single-nucleotide polymorphisms associated with educational attainment disproportionately occur in genomic regions regulating gene expression in the fetal brain.
Abstract: Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
1,102 citations
17 Jun 2016
975 citations
Stanford University1, Illinois Institute of Technology2, University of Melbourne3, Greifswald University Hospital4, University of Münster5, University of Marburg6, VU University Medical Center7, University of Göttingen8, Humboldt University of Berlin9, Harvard University10, University Medical Center Groningen11, University of Cape Town12, Max Planck Society13, University of Southern California14
TL;DR: Three-dimensional brain magnetic resonance imaging data was meta-analyzed to identify subcortical brain volumes that robustly discriminate major depressive disorder patients from healthy controls and showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
Abstract: The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
759 citations
01 Jun 2016
TL;DR: In this paper, the authors meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 major depressive disorder (MDD) patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls.
Abstract: The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen’s d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen’s d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen’s d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen’s d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen’s d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
691 citations
TL;DR: A meta-analysis of genome-wide association studies for estimated glomerular filtration rate suggests that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
409 citations
Renal Association1, Catholic University of the Sacred Heart2, Norwegian University of Science and Technology3, Greifswald University Hospital4, Uppsala University5, National Institutes of Health6, Geneva College7, French Institute of Health and Medical Research8, German Cancer Research Center9, Medical University of Silesia10, Freeman Hospital11, University of Alberta12, University of Toulouse13, Istituto Superiore di Sanità14, University College Cork15, Ghent University Hospital16, University of Ulm17, University of London18
TL;DR: In this paper, the authors collected data from 19 general-population studies from 13 European countries and investigated international variation in CKD prevalence by age, sex, and presence of diabetes, hypertension, and obesity.
Abstract: CKD prevalence estimation is central to CKD management and prevention planning at the population level. This study estimated CKD prevalence in the European adult general population and investigated international variation in CKD prevalence by age, sex, and presence of diabetes, hypertension, and obesity. We collected data from 19 general-population studies from 13 European countries. CKD stages 1-5 was defined as eGFR 30 mg/g, and CKD stages 3-5 was defined as eGFR<60 ml/min per 1.73 m(2) CKD prevalence was age- and sex-standardized to the population of the 27 Member States of the European Union (EU27). We found considerable differences in both CKD stages 1-5 and CKD stages 3-5 prevalence across European study populations. The adjusted CKD stages 1-5 prevalence varied between 3.31% (95% confidence interval [95% CI], 3.30% to 3.33%) in Norway and 17.3% (95% CI, 16.5% to 18.1%) in northeast Germany. The adjusted CKD stages 3-5 prevalence varied between 1.0% (95% CI, 0.7% to 1.3%) in central Italy and 5.9% (95% CI, 5.2% to 6.6%) in northeast Germany. The variation in CKD prevalence stratified by diabetes, hypertension, and obesity status followed the same pattern as the overall prevalence. In conclusion, this large-scale attempt to carefully characterize CKD prevalence in Europe identified substantial variation in CKD prevalence that appears to be due to factors other than the prevalence of diabetes, hypertension, and obesity.
387 citations
TL;DR: The hypothesis that white matter hyperintensities contribute to patterns of brain atrophy found in beyond-normal brain ageing in the general population is supported.
Abstract: White matter hyperintensities are associated with increased risk of dementia and cognitive decline. The current study investigates the relationship between white matter hyperintensities burden and patterns of brain atrophy associated with brain ageing and Alzheimer's disease in a large populatison-based sample (n = 2367) encompassing a wide age range (20-90 years), from the Study of Health in Pomerania. We quantified white matter hyperintensities using automated segmentation and summarized atrophy patterns using machine learning methods resulting in two indices: the SPARE-BA index (capturing age-related brain atrophy), and the SPARE-AD index (previously developed to capture patterns of atrophy found in patients with Alzheimer's disease). A characteristic pattern of age-related accumulation of white matter hyperintensities in both periventricular and deep white matter areas was found. Individuals with high white matter hyperintensities burden showed significantly (P < 0.0001) lower SPARE-BA and higher SPARE-AD values compared to those with low white matter hyperintensities burden, indicating that the former had more patterns of atrophy in brain regions typically affected by ageing and Alzheimer's disease dementia. To investigate a possibly causal role of white matter hyperintensities, structural equation modelling was used to quantify the effect of Framingham cardiovascular disease risk score and white matter hyperintensities burden on SPARE-BA, revealing a statistically significant (P < 0.0001) causal relationship between them. Structural equation modelling showed that the age effect on SPARE-BA was mediated by white matter hyperintensities and cardiovascular risk score each explaining 10.4% and 21.6% of the variance, respectively. The direct age effect explained 70.2% of the SPARE-BA variance. Only white matter hyperintensities significantly mediated the age effect on SPARE-AD explaining 32.8% of the variance. The direct age effect explained 66.0% of the SPARE-AD variance. Multivariable regression showed significant relationship between white matter hyperintensities volume and hypertension (P = 0.001), diabetes mellitus (P = 0.023), smoking (P = 0.002) and education level (P = 0.003). The only significant association with cognitive tests was with the immediate recall of the California verbal and learning memory test. No significant association was present with the APOE genotype. These results support the hypothesis that white matter hyperintensities contribute to patterns of brain atrophy found in beyond-normal brain ageing in the general population. White matter hyperintensities also contribute to brain atrophy patterns in regions related to Alzheimer's disease dementia, in agreement with their known additive role to the likelihood of dementia. Preventive strategies reducing the odds to develop cardiovascular disease and white matter hyperintensities could decrease the incidence or delay the onset of dementia.
297 citations
TL;DR: In this article, the authors reported a large genome-wide association study of both sexes including 251,151 individuals for AB and 343,072 individuals for NEB and identified 12 independent loci that are significantly associated with AB and NEB.
Abstract: The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits
237 citations
Boston University1, Washington University in St. Louis2, University of Michigan3, University of Washington4, University of North Carolina at Chapel Hill5, University of Texas Health Science Center at Houston6, Icahn School of Medicine at Mount Sinai7, University of Greifswald8, Los Angeles Biomedical Research Institute9, Columbia University Medical Center10, George Washington University11, University of Cambridge12, University College London13, University of Bristol14, University of Leicester15, University of Liverpool16, University of Wisconsin–Milwaukee17, Brigham and Women's Hospital18, Vanderbilt University Medical Center19, Wake Forest University20, Erasmus University Rotterdam21, University of Mississippi Medical Center22, Bill & Melinda Gates Foundation23, University of Iceland24, Harvard University25, Broad Institute26, Glenfield Hospital27, Technische Universität München28, Queen Mary University of London29, King Abdulaziz University30, European Academy of Bozen31, University of Regensburg32, National Institutes of Health33, Pennington Biomedical Research Center34, Cedars-Sinai Medical Center35, Northwestern University36, Johns Hopkins University School of Medicine37, Greifswald University Hospital38, Chung Shan Medical University39, National Yang-Ming University40, Wake Forest Baptist Medical Center41, Geneva College42
TL;DR: This large collection of blood pressure–associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
Abstract: Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
218 citations
University of Greifswald1, Johns Hopkins University2, National Research Council3, University of Regensburg4, Medical College of Wisconsin5, Harvard University6, National Institutes of Health7, University of Freiburg8, University of Verona9, University of Pennsylvania10, University of Zurich11, Boston University12, Tufts University13, University of Toronto14, Loyola University Chicago15, German Cancer Research Center16, University of Maryland, Baltimore17, University of Iceland18, Innsbruck Medical University19, University of Geneva20, Heidelberg University21, University of Edinburgh22, University of Bordeaux23, Vanderbilt University24, University of Hamburg25, University of Cambridge26, University of Bern27, University of Washington28, University of Texas Health Science Center at Houston29, Greifswald University Hospital30, University of Lausanne31, University of Groningen32, Agostino Gemelli University Polyclinic33, Ludwig Maximilian University of Munich34, Technische Universität München35, Swiss Institute of Bioinformatics36, Pasteur Institute37, University of Sydney38, University of Oxford39, Wellcome Trust Sanger Institute40, University of Split41, University of Mainz42, Icahn School of Medicine at Mount Sinai43, Hannover Medical School44, University of Ulm45, Université de Montréal46
TL;DR: In this article, the authors conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies.
Abstract: Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 x 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 x 10(-7)) and 13% for RAB38/CTSC (P = 5.8 x 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.
127 citations
Max Planck Society1, Technische Universität München2, University of Marburg3, Augsburg College4, Otto-von-Guericke University Magdeburg5, Leipzig University6, University of Bern7, Ruhr University Bochum8, University of Mainz9, University Hospital Heidelberg10, University of Rostock11, Max Delbrück Center for Molecular Medicine12, University of Erlangen-Nuremberg13, University of Münster14, Hannover Medical School15, University of Ulm16, University of Düsseldorf17, Medical Park18, University of Tübingen19, University of Lübeck20, Emory University21, Imperial College London22, University of Kiel23, University of Bonn24, University of Basel25, Greifswald University Hospital26, University of Duisburg-Essen27, Ludwig Maximilian University of Munich28, University of Sassari29, Center for Advanced Studies Research and Development in Sardinia30, University of KwaZulu-Natal31, University of Liverpool32
TL;DR: A genome-wide association study on multiple sclerosis susceptibility in German cohorts with 4888 cases and 10,395 controls detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.
Abstract: We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.
TL;DR: Structural imaging patterns of advanced brain aging in the general-population suggest that ABA is likely characterized by pathophysiologic mechanisms that are distinct from, or only partially overlapping with those of AD.
Abstract: We systematically compared structural imaging patterns of advanced brain aging (ABA) in the general-population, herein defined as significant deviation from typical BA to those found in Alzheimer disease (AD). The hypothesis that ABA would show different patterns of structural change compared with those found in AD was tested via advanced pattern analysis methods. In particular, magnetic resonance images of 2705 participants from the Study of Health in Pomerania (aged 20–90 years) were analyzed using an index that captures aging atrophy patterns (Spatial Pattern of Atrophy for Recognition of BA (SPARE-BA)), and an index previously shown to capture atrophy patterns found in clinical AD (Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease (SPARE-AD)). We studied the association between these indices and risk factors, including an AD polygenic risk score. Finally, we compared the ABA-associated atrophy with typical AD-like patterns. We observed that SPARE-BA had significant association with: smoking (P<0.05), anti-hypertensive (P<0.05), anti-diabetic drug use (men P<0.05, women P=0.06) and waist circumference for the male cohort (P<0.05), after adjusting for age. Subjects with ABA had spatially extensive gray matter loss in the frontal, parietal and temporal lobes (false-discovery-rate-corrected q<0.001). ABA patterns of atrophy were partially overlapping with, but notably deviating from those typically found in AD. Subjects with ABA had higher SPARE-AD values; largely due to the partial spatial overlap of associated patterns in temporal regions. The AD polygenic risk score was significantly associated with SPARE-AD but not with SPARE-BA. Our findings suggest that ABA is likely characterized by pathophysiologic mechanisms that are distinct from, or only partially overlapping with those of AD.
Northwestern University1, University of Greifswald2, St Thomas' Hospital3, Science for Life Laboratory4, University Hospital of Lausanne5, Technische Universität München6, University of Lausanne7, Johns Hopkins University8, Geneva College9, Greifswald University Hospital10, Harvard University11, Broad Institute12, Emory University13, Uppsala University14, Karolinska Institutet15, Cornell University16, Stanford University17
TL;DR: Takeaway is that genetic factors contributing to variation in caffeine metabolism are identified and an important modulating role of systemic caffeine levels in dietary caffeine consumption behavior is confirmed.
Abstract: Caffeine is the most widely consumed psychoactive substance in the world and presents with wide interindividual variation in metabolism. This variation may modify potential adverse or beneficial effects of caffeine on health. We conducted a genome-wide association study (GWAS) of plasma caffeine, paraxanthine, theophylline, theobromine and paraxanthine/caffeine ratio among up to 9,876 individuals of European ancestry from six population-based studies. A single SNP at 6p23 (near CD83) and several SNPs at 7p21 (near AHR), 15q24 (near CYP1A2) and 19q13.2 (near CYP2A6) met GW-significance (P < 5 × 10-8) and were associated with one or more metabolites. Variants at 7p21 and 15q24 associated with higher plasma caffeine and lower plasma paraxanthine/caffeine (slow caffeine metabolism) were previously associated with lower coffee and caffeine consumption behavior in GWAS. Variants at 19q13.2 associated with higher plasma paraxanthine/caffeine (slow paraxanthine metabolism) were also associated with lower coffee consumption in the UK Biobank (n = 94 343, P < 1.0 × 10-6). Variants at 2p24 (in GCKR), 4q22 (in ABCG2) and 7q11.23 (near POR) that were previously associated with coffee consumption in GWAS were nominally associated with plasma caffeine or its metabolites. Taken together, we have identified genetic factors contributing to variation in caffeine metabolism and confirm an important modulating role of systemic caffeine levels in dietary caffeine consumption behavior. Moreover, candidate genes identified encode proteins with important clinical functions that extend beyond caffeine metabolism.
Riccardo E. Marioni1, Riccardo E. Marioni2, Stuart J. Ritchie1, Peter K. Joshi1 +305 more•Institutions (84)
TL;DR: Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity.
Abstract: Educational attainment is associated with many health outcomes, including longevity It is also known to be substantially heritable Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length We did so by using cohort members' polygenic profile score for education to predict their parents' longevity Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼27% lower mortality risk for both mothers (total ndeaths = 79,702) and ∼24% lower risk for fathers (total ndeaths = 97,630) On average, the parents of offspring in the upper third of the polygenic score distribution lived 055 y longer compared with those of offspring in the lower third Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity
TL;DR: The metabolic age score is an informative measurement of biological age with possible applications in personalized medicine and was prognostic for weight loss in a sample of individuals who underwent bariatric surgery.
Abstract: Chronological age is one of the most important risk factors for adverse clinical outcome. Still, two individuals at the same chronological age could have different biological aging states, leading to different individual risk profiles. Capturing this individual variance could constitute an even more powerful predictor enhancing prediction in age-related morbidity. Applying a nonlinear regression technique, we constructed a metabonomic measurement for biological age, the metabolic age score, based on urine data measured via 1H NMR spectroscopy. We validated the score in two large independent population-based samples by revealing its significant associations with chronological age and age-related clinical phenotypes as well as its independent predictive value for survival over approximately 13 years of follow-up. Furthermore, the metabolic age score was prognostic for weight loss in a sample of individuals who underwent bariatric surgery. We conclude that the metabolic age score is an informative measuremen...
National Institutes of Health1, Université de Montréal2, University of Greifswald3, Kanazawa University4, Harvard University5, Broad Institute6, Johns Hopkins University7, Icahn School of Medicine at Mount Sinai8, GlaxoSmithKline9, University of Minnesota10, University of Texas Health Science Center at Houston11, Vanderbilt University12, University of Washington13, University of North Carolina at Chapel Hill14, University of Virginia15, University of Edinburgh16, Erasmus University Rotterdam17, Imperial College London18, University of Ioannina19, University of Turku20, University of Vermont21, Morehouse School of Medicine22, University of Michigan23, Boston University24, Pennsylvania State University25, King Abdulaziz University26, Queen Mary University of London27, University of Leicester28, Glenfield Hospital29, Technische Universität München30, University of Lübeck31, University of Iceland32, Wake Forest University33, University of California, Los Angeles34, Baylor College of Medicine35, Stanford University36, University of Mississippi37, University of Tartu38, Stony Brook University39, Lund University40, Uppsala University41, University of Auckland42, Group Health Cooperative43, Greifswald University Hospital44, University of Wisconsin–Milwaukee45, Fred Hutchinson Cancer Research Center46
TL;DR: The authors' 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.
Abstract: 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.
University of Cambridge1, Oslo University Hospital2, University of Gothenburg3, Technische Universität München4, University of Milan5, National Taiwan University6, Paris Descartes University7, Erasmus University Rotterdam8, Paracelsus Private Medical University of Salzburg9, University of Tromsø10, Uppsala University11, Odense University Hospital12, Aristotle University of Thessaloniki13, University of Edinburgh14, University of Miami15, University of Washington16, University of Greifswald17, Tufts University18, Harvard University19, Greifswald University Hospital20, University of Eastern Finland21, EHESP22
TL;DR: Inflammation was independently associated with CCA-IMT cross-sectionally and the findings for ‘inflammatory load’ suggest important combined effects of the three inflammatory markers on early atherosclerosis.
Abstract: BackgroundLarge-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudina...
Heidelberg University1, German Cancer Research Center2, University of Bonn3, Greifswald University Hospital4, German Center for Neurodegenerative Diseases5, QIMR Berghofer Medical Research Institute6, University of Missouri7, University of Greifswald8, Paracelsus Private Medical University of Salzburg9, University of Hamburg10
TL;DR: First genome-wide association study of pathological gambling finds genetic overlap between non-substance- and substance-related addictions and pathway analysis suggests shared pathology between Huntington's disease and pathological gambling.
Erasmus University Medical Center1, University of Washington2, Boston University3, University of Iceland4, University of Texas Health Science Center at Houston5, Leiden University6, Brigham and Women's Hospital7, University of Auckland8, Greifswald University Hospital9, University College Cork10, Wake Forest University11, Harvard University12, University of Minnesota13, University of North Carolina at Chapel Hill14, Merck & Co.15, Robertson Centre for Biostatistics16, National Institutes of Health17, Erasmus University Rotterdam18, Fred Hutchinson Cancer Research Center19, Pasteur Institute of Lille20, University of Strasbourg21, Group Health Research Institute22, University of Toulouse23, United States Department of Veterans Affairs24, Novartis25, New York Academy of Medicine26, Umeå University27, University of California, Los Angeles28, Queen's University Belfast29, University of Jyväskylä30, University of Helsinki31, University of Glasgow32, Leiden University Medical Center33, University of Hamburg34, Baylor College of Medicine35
TL;DR: The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
Abstract: Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5x10(-6) in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5x10(-6); 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8x10(-3)) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2x10(-9)). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2x10(-3)). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
TL;DR: This is the first investigation to report a significant association between circulating irisin and a favourable lipid profile in the general population, and may infer that higher irisin concentrations are associated with a reduced risk for non-communicable diseases.
Abstract: Background/aims
Irisin is a myokine, which is mainly inversely associated with the risk for non-communicable diseases. Irisin improves cellular energy metabolism by uncoupling the mitochondrial respiratory chain resulting in increased energy expenditure using lipids. To date potential associations between irisin concentration and lipid profile are poorly understood. Therefore, this investigation aimed to evaluate potential associations between irisin and lipid levels in the general population.
TL;DR: MSSA and MRSA prevalences and the molecular diversity of S. aureus in Northeast Germany are consistent with those of other European countries, and possible transmission from hospitals and livestock should be closely monitored.
Abstract: Population-based studies on Staphylococcus aureus nasal colonization are scarce. We examined the prevalence, resistance, and molecular diversity of S. aureus in the general population in Northeast Germany. Nasal swabs were obtained from 3,891 adults in the large-scale population-based Study of Health in Pomerania (SHIP-TREND). Isolates were characterized using spa genotyping, as well as antibiotic resistance and virulence gene profiling. We observed an S. aureus prevalence of 27.2%. Nasal S. aureus carriage was associated with male sex and inversely correlated with age. Methicillin-resistant S. aureus (MRSA) accounted for 0.95% of the colonizing S. aureus strains. MRSA carriage was associated with frequent visits to hospitals, nursing homes, or retirement homes within the previous 24 months. All MRSA strains were resistant to multiple antibiotics. Most MRSA isolates belonged to the pandemic European hospital-acquired MRSA sequence type 22 (HA-MRSA-ST22) lineage. We also detected one livestock-associated MRSA ST398 (LA-MRSA-ST398) isolate, as well as six livestock-associated methicillin-susceptible S. aureus (LA-MSSA) isolates (clonal complex 1 [CC1], CC97, and CC398). spa typing revealed a diverse but also highly clonal S. aureus population structure. We identified a total of 357 spa types, which were grouped into 30 CCs or sequence types. The major seven CCs (CC30, CC45, CC15, CC8, CC7, CC22, and CC25) included 75% of all isolates. Virulence gene patterns were strongly linked to the clonal background. In conclusion, MSSA and MRSA prevalences and the molecular diversity of S. aureus in Northeast Germany are consistent with those of other European countries. The detection of HA-MRSA and LA-MRSA within the general population indicates possible transmission from hospitals and livestock, respectively, and should be closely monitored.
Harvard University1, National Institutes of Health2, Dresden University of Technology3, Erasmus University Rotterdam4, University of Minnesota5, Vanderbilt University6, University of Wisconsin–Milwaukee7, Fred Hutchinson Cancer Research Center8, University of Ulm9, Brigham and Women's Hospital10, University of Kiel11, University Health Network12, Herlev Hospital13, University of Copenhagen14, Massachusetts Eye and Ear Infirmary15, Greifswald University Hospital16
TL;DR: A large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.
Erasmus University Medical Center1, Erasmus University Rotterdam2, University of Bern3, Leiden University Medical Center4, University Hospital of Lausanne5, University of Cambridge6, University of Glasgow7, University of Groningen8, Robertson Centre for Biostatistics9, University of Western Australia10, University of Pittsburgh11, Faculdade de Medicina de Marília12, Federal University of São Paulo13, University of Washington14, Group Health Research Institute15, National Institutes of Health16, University of Copenhagen17, University of Parma18, Radiation Effects Research Foundation19, Harvard University20, University of Birmingham21, University of California, San Francisco22, Sir Charles Gairdner Hospital23, National Health Service24, University of Pennsylvania25
TL;DR: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within thereference range of thyroid function.
Abstract: Context: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously. Design and Setting: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T4, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L. Results: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1–13.9), including 449 908 person-years. Age- and sex-adjusted poole...
TL;DR: Evidence suggested that subjects exposed to childhood abuse and carrying the TT genotype of the FKBP5 gene single nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to stress‐related disorders.
Abstract: OBJECTIVE: The FKBP5 gene codes for a co-chaperone that regulates glucocorticoid receptor sensitivity and thereby impacts the reactivity of the hypothalamic-pituitary-adrenal (HPA)-axis. Evidence suggested that subjects exposed to childhood abuse and carrying the TT genotype of the FKBP5 gene single nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to stress-related disorders. METHOD: The hypothesis that abused TT genotype carriers show changes in gray matter (GM) volumes in affect-processing brain areas was investigated. About 1,826 Caucasian subjects (age ≤ 65 years) from the general population [Study of Health in Pomerania (SHIP)] in Germany were investigated. The interaction between rs1360780 and child abuse (Childhood Trauma Questionnaire) and its effect on GM were analyzed. RESULTS: Voxel-based whole-brain interaction analysis revealed three large clusters (FWE-corrected) of reduced GM volumes comprising the bilateral insula, the superior and middle temporal gyrus, the bilateral hippocampus, the right amygdala, and the bilateral anterior cingulate cortex in abused TT carriers. These results were not confounded by major depressive disorders. In region of interest analyses, highly significant volume reductions in the right hippocampus/parahippocampus, the bilateral anterior and middle cingulate cortex, the insula, and the amygdala were confirmed in abused TT carriers compared with abused CT/CC carriers. CONCLUSION: The results supported the hypothesis that the FKBP5 rs1360780 TT genotype predisposes subjects who have experienced childhood abuse to widespread structural brain changes in the subcortical and cortical emotion-processing brain areas. Those brain changes might contribute to an increased vulnerability of stress-related disorders in TT genotype carriers. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc. Language: en
TL;DR: The authors found stronger associations between anthropometric markers that reflect abdominal obesity (ie, WC and WHtR) and incident T2DM than for BMI and weight.
Abstract: Objective To compare the association between different anthropometric measurements and incident type 2 diabetes mellitus (T2DM) and to assess their predictive ability in different regions of Germany. Methods Data of 10 258 participants from 4 prospective population-based cohorts were pooled to assess the association of body weight, body mass index (BMI), waist circumference (WC), waist-to-hip-ratio (WHR) and waist-to-height-ratio (WHtR) with incident T2DM by calculating HRs of the crude, adjusted and standardised markers, as well as providing receiver operator characteristic (ROC) curves. Differences between HRs and ROCs for the different anthropometric markers were calculated to compare their predictive ability. In addition, data of 3105 participants from the nationwide survey were analysed separately using the same methods to provide a nationally representative comparison. Results Strong associations were found for each anthropometric marker and incidence of T2DM. Among the standardised anthropometric measures, we found the strongest effect on incident T2DM for WC and WHtR in the pooled sample (HR for 1 SD difference in WC 1.97, 95% CI 1.75 to 2.22, HR for WHtR 1.93, 95% CI 1.71 to 2.17 in women) and in female DEGS participants (HR for WC 2.24, 95% CI 1.91 to 2.63, HR for WHtR 2.10, 95% CI 1.81 to 2.44), whereas the strongest association in men was found for WHR among DEGS participants (HR 2.29, 95% CI 1.89 to 2.78). ROC analysis showed WHtR to be the strongest predictor for incident T2DM. Differences in HR and ROCs between the different markers confirmed WC and WHtR to be the best predictors of incident T2DM. Findings were consistent across study regions and age groups ( Conclusions We found stronger associations between anthropometric markers that reflect abdominal obesity (ie, WC and WHtR) and incident T2DM than for BMI and weight. The use of these measurements in risk prediction should be encouraged.
Broad Institute1, University of Michigan2, Wake Forest University3, University of North Carolina at Chapel Hill4, University of California, Los Angeles5, National Institutes of Health6, Maastricht University7, Erasmus University Rotterdam8, Leiden University9, University of Queensland10, University of Edinburgh11, Washington University in St. Louis12, Kanazawa University13, Utrecht University14, University of Iceland15, Johns Hopkins University16, University of Maryland, Baltimore17, Icahn School of Medicine at Mount Sinai18, Regeneron19, Boston University20, Cedars-Sinai Medical Center21, University of Washington22, Harvard University23, Veterans Health Administration24, University of Pittsburgh25, Merck & Co.26, University of Groningen27, University of Minnesota28, University of Turku29, Mayo Clinic30, Greifswald University Hospital31, University of Vermont32, University of Texas Health Science Center at Houston33, Group Health Cooperative34, Imperial College London35, University of Pennsylvania36, University of Mississippi37, University of Greifswald38
TL;DR: APOE &egr;2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease, and exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical Atherosclerosis.
Abstract: Background —The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.
Methods and Results —We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC ( P = 3×10 -10 ). The APOE e2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC ( P = 1×10 -12 ) and 1.4% reduced CIMT ( P = 4×10 -14 ) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the e2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of e2 was associated with reduced risk for CHD (OR 0.77; P = 1×10 -11 ). Conclusions —Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE e2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.
Johns Hopkins University School of Medicine1, National Institutes of Health2, Beth Israel Deaconess Medical Center3, Bar-Ilan University4, Albert Einstein College of Medicine5, University of Haifa6, University of Washington7, Menzies Research Institute8, Monash University, Clayton campus9, University of Edinburgh10, California Pacific Medical Center11, Greifswald University Hospital12, Wake Forest University13, Boston University14, Guy's and St Thomas' NHS Foundation Trust15, King's College London16, University of Michigan17, Rush University Medical Center18, Broad Institute19, Brigham and Women's Hospital20, University of Iceland21, Erasmus University Rotterdam22, Harvard University23, Ghent University Hospital24, Los Angeles Biomedical Research Institute25, San Francisco VA Medical Center26, Creighton University27, University of Pittsburgh28, Group Health Research Institute29, University of Mississippi Medical Center30
TL;DR: A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly.
Abstract: Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.
TL;DR: A visual overview of epidemiological data that allows for the first time an interactive regression-based analysis of large feature sets with respect to a disease and new hypotheses about relations between breast density and breast lesions with breast cancer are derived.
Abstract: Epidemiological studies comprise heterogeneous data about a subject group to define disease-specific risk factors. These data contain information ( features ) about a subject's lifestyle, medical status as well as medical image data. Statistical regression analysis is used to evaluate these features and to identify feature combinations indicating a disease (the target feature ). We propose an analysis approach of epidemiological data sets by incorporating all features in an exhaustive regression-based analysis. This approach combines all independent features w.r.t. a target feature . It provides a visualization that reveals insights into the data by highlighting relationships. The 3D Regression Heat Map , a novel 3D visual encoding, acts as an overview of the whole data set. It shows all combinations of two to three independent features with a specific target disease. Slicing through the 3D Regression Heat Map allows for the detailed analysis of the underlying relationships. Expert knowledge about disease-specific hypotheses can be included into the analysis by adjusting the regression model formulas. Furthermore, the influences of features can be assessed using a difference view comparing different calculation results. We applied our 3D Regression Heat Map method to a hepatic steatosis data set to reproduce results from a data mining-driven analysis. A qualitative analysis was conducted on a breast density data set. We were able to derive new hypotheses about relations between breast density and breast lesions with breast cancer. With the 3D Regression Heat Map , we present a visual overview of epidemiological data that allows for the first time an interactive regression-based analysis of large feature sets with respect to a disease.
TL;DR: It is indicated that moderately elevated serum liver enzymes, but not sonographic liver hyperechogenicity, were associated with increased AF prevalence in the general adult population.
TL;DR: Investigation of the association of serum vitamin B12 with the progression of periodontitis and risk of tooth loss in a prospective cohort study found inversely associated with changes in mean PD and mean CAL, and risk ratios of Tooth loss over time.
Abstract: AIM The aim of this study was to investigate the association of serum vitamin B12 with the progression of periodontitis and risk of tooth loss in a prospective cohort study. MATERIALS AND METHODS In the Study of Health in Pomerania, 1648 participants were followed from 2002-2006 to 2008-2012 (mean duration 5.9 years). Serum vitamin B12 was measured by chemiluminescent enzyme immunoassay. Probing pocket depth (PD) and clinical attachment loss (CAL) were measured to reflect periodontal status on a half-mouth basis at each survey cycle. Tooth numbers are based upon a full-mouth tooth count. RESULTS AND CONCLUSIONS In multivariate regression models, baseline vitamin B12 was inversely associated with changes in mean PD (Ptrend = 0.06) and mean CAL (Ptrend = 0.01), and risk ratios of tooth loss (TL; Ptrend = 0.006) over time. Compared to participants in the highest vitamin B12 quartile, those in the lowest quartile had 0.10 mm (95%CI: 0.03, 0.17; Pdifference = 0.007) greater increase in mean PD, 0.23 mm (95%CI: 0.09, 0.36; Pdifference = 0.001) greater increase in mean CAL and a relative risk of 1.57 (95%CI: 1.22, 2.03; Pdifference < 0.001) for TL. Stratified analyses showed stronger associations between vitamin B12 and changes in mean CAL among never smokers (Pinteraction = 0.058). Further studies are needed to understand the potential mechanisms of these findings.