Showing papers by "Henry Völzke published in 2017"
Leandra Abarca-Gómez1, Ziad Abdeen2, Zargar Abdul Hamid2, Niveen M E Abu-Rmeileh +1021 more•Institutions (7)
TL;DR: Trends in mean BMI have recently flattened in northwestern Europe and the high-income English-speaking and Asia-Pacific regions for both sexes, southwestern Europe for boys, and central and Andean Latin America for girls, and by contrast, the rise in BMI has accelerated in east and south Asia forboth sexes, and southeast Asia for boys.
4,317 citations
VU University Medical Center1, University of Southern California2, Max Planck Society3, McMaster University4, University of Adelaide5, University of California, Irvine6, Erasmus University Rotterdam7, Delft University of Technology8, Erasmus University Medical Center9, German Center for Neurodegenerative Diseases10, Greifswald University Hospital11, University of Münster12, University of Marburg13, QIMR Berghofer Medical Research Institute14, University of Queensland15, Queensland University of Technology16, Virginia Commonwealth University17, University of Göttingen18, University Hospital Heidelberg19, University of Sydney20, Otto-von-Guericke University Magdeburg21, Trinity College, Dublin22, University of Regensburg23, University Medical Center Groningen24, Leiden University Medical Center25, University of Melbourne26, University of Texas Health Science Center at Houston27, Charité28, University of Bonn29, University of Lübeck30, University Medical Center Freiburg31, Stanford University32, University of Calgary33, Warneford Hospital34, Royal Edinburgh Hospital35, University of Edinburgh36, University of Bern37, Cardiff University38, Leibniz Institute for Neurobiology39, University of Tübingen40, Tomsk State University41, Siberian State Medical University42, Mental Health Research Institute43
TL;DR: In this article, the authors present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD.
Abstract: The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.
728 citations
TL;DR: In this article, the authors used 1000 Genomes Project-imputed genotype data in up to ∼370,000 women to identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development.
Abstract: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
392 citations
University College London1, Imperial College London2, University of Oxford3, Clinical Trial Service Unit4, St Bartholomew's Hospital5, Wellcome Trust Centre for Human Genetics6, University of Glasgow7, Universidade Federal de Pelotas8, UCL Institute of Child Health9, University of South Australia10, European Bioinformatics Institute11, Charité12, University of Lübeck13, Max Planck Society14, Innsbruck Medical University15, Bradford Royal Infirmary16, University of Bristol17, St George's, University of London18, University of Edinburgh19, University of Lausanne20, University of Nicosia21, Cyprus University of Technology22, Utrecht University23, University of Turin24, Cancer Epidemiology Unit25, University of Cambridge26, Russian Academy27, Jagiellonian University28, Lithuanian University of Health Sciences29, University of Copenhagen30, Marshfield Clinic31, Children's Hospital of Philadelphia32, Group Health Research Institute33, Mayo Clinic34, Vanderbilt University35, George Washington University36, University of Newcastle37, Population Health Research Institute38, University Medical Center Groningen39, Leiden University Medical Center40, Uppsala University41, Stanford University42, Science for Life Laboratory43, Erasmus University Medical Center44, Greifswald University Hospital45, University of Regensburg46, University of London47, Robertson Centre for Biostatistics48, university of lille49, French Institute of Health and Medical Research50, University of Nantes51, University of Essex52, Brigham and Women's Hospital53, Fred Hutchinson Cancer Research Center54, University of Colorado Denver55, Geisinger Health System56, Pennsylvania State University57, University of Pennsylvania58
TL;DR: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes.
296 citations
Mariaelisa Graff1, Robert A. Scott2, Anne E. Justice1, Kristin L. Young1 +346 more•Institutions (101)
TL;DR: In additional genome-wide meta-analyses adjusting for PA and interaction with PA, 11 novel adiposity loci are identified, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
275 citations
TL;DR: It is shown that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=−0.155), and these findings suggest novel biological pathways through which human genetic variation influences hippocampus volume and risk for neuropsychiatric illness.
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
256 citations
01 Jan 2017
TL;DR: Using 1000 Genomes Project–imputed genotype data in up to ∼370,000 women, 389 independent signals for age at menarche, a milestone in female pubertal development are identified, highlighting the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
229 citations
TL;DR: This corrects the article DOI: 10.1038/srep45040 to indicate that the author of the paper is a doctor of medicine rather than a scientist, as previously reported.
Abstract: Scientific Reports 7: Article number: 45040; published online: 28 April 2017; updated: 26 May 2017 The original version of this Article contained a typographical error in the spelling of the author Martin H. de Borst, which was incorrectly given as Martin de Borst. This has now been corrected in both the PDF and HTML versions of the Article.
167 citations
TL;DR: The results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution, and highlight the importance of accounting for environment in genetic analyses.
Abstract: Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
159 citations
University of Bern1, University Hospital of Lausanne2, University of California, San Francisco3, University of Pennsylvania4, University of Washington5, Leiden University Medical Center6, Erasmus University Rotterdam7, Sir Charles Gairdner Hospital8, University of Western Australia9, University of Bari10, University of Copenhagen11, University of Pittsburgh12
TL;DR: In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.
Abstract: Background -Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF. Methods -We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF. Results -Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in ageand sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease. Conclusions -In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.
130 citations
M. Carola Zillikens1, Serkalem Demissie2, Yi-Hsiang Hsu3, Laura M. Yerges-Armstrong4 +224 more•Institutions (83)
TL;DR: A meta-analysis of genome-wide association studies for whole body lean body mass and five novel genetic loci to be significantly associated is performed and provides new insight into the genetics ofLean body mass.
Abstract: Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10−8) or suggestively genome wide (p < 2.3 × 10−6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.
Merck & Co.1, Harvard University2, National Institutes of Health3, Boston University4, University of Oxford5, Washington University in St. Louis6, Wright State University7, University of North Carolina at Chapel Hill8, University of Texas Health Science Center at San Antonio9, University of California, Los Angeles10, Greifswald University Hospital11, Texas Biomedical Research Institute12, University of Maryland, Baltimore13, Wake Forest University14, University of Iceland15, Medical College of Wisconsin16, Uppsala University17, University of Bern18, University of Michigan19, Veterans Health Administration20, University of Texas at Brownsville21, Stanford University22, University of Liverpool23, University of Mississippi24, University of California, San Diego25, Broad Institute26
TL;DR: Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis.
Abstract: Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
University of Mainz1, Erasmus University Rotterdam2, University of Lübeck3, Greifswald University Hospital4, Boston University5, University of Greifswald6, University of Washington7, University of Alabama at Birmingham8, Northwestern University9, Karolinska Institutet10, University of Kiel11, Medical University of Graz12, Royal College of Surgeons in Ireland13, University of Göttingen14, University of Iceland15, Uppsala University16, Imperial College London17, Martin Luther University of Halle-Wittenberg18, Broad Institute19, Lund University20, Harvard University21, Columbia University22, University of Mississippi23, University of Texas Health Science Center at Houston24, University of Pennsylvania25, Heidelberg University26, National Institutes of Health27, Medical College of Wisconsin28, Charité29, University of Groningen30, University College London31, University of Tampere32, University of Veterinary Medicine Vienna33, University of Oxford34, Hammersmith Hospital35, University of Liverpool36, Ludwig Maximilian University of Munich37, National Research Council38, University of Turku39, University of California, Los Angeles40, University of Miami41, University of Exeter42, University College Dublin43, University of KwaZulu-Natal44, Synlab Group45, Group Health Cooperative46, United States Department of Veterans Affairs47, Technische Universität München48, Stanford University49
TL;DR: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac architecture and warrant follow-up in future functional studies.
Abstract: BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.
01 Jan 2017
TL;DR: In this paper, the authors used GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI.
Abstract: Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
University of Regensburg1, University of Groningen2, Greifswald University Hospital3, Harvard University4, National Institutes of Health5, Johns Hopkins University6, University of Utah7, University of Verona8, University of Trieste9, Washington University in St. Louis10, University of Freiburg11, Loyola University Chicago12, University of Iceland13, University of Newcastle14, University of Lausanne15, University of Texas Health Science Center at Houston16, Regeneron17, Mount Sinai Hospital18, Pasteur Institute19, National Research Council20, Northwestern University21, Erasmus University Rotterdam22, Wake Forest University23, Uppsala University24, University of Tartu25, French Institute of Health and Medical Research26, University of Bordeaux27, Medical University of Graz28, University of Basel29, Swiss Tropical and Public Health Institute30, Technische Universität München31, University of Ulm32, Heidelberg University33, Karolinska Institutet34, Icahn School of Medicine at Mount Sinai35, Université Paris-Saclay36, University of Sydney37, University of Greifswald38, VU University Amsterdam39, University of Turku40, Ludwig Maximilian University of Munich41, Boston University42, Broad Institute43, Geisinger Medical Center44
TL;DR: A GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate in 110,517 European ancestry participants using 1000 Genomes imputed data identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS, which highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.
Abstract: HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.
TL;DR: It is shown that the underlying cause of catatonic signs is the low-grade inflammation of white matter tracts, which marks a final common pathway in Cnp-deficient and other mutant mice with minor myelin abnormalities.
Abstract: The underlying cellular mechanisms of catatonia, an executive "psychomotor" syndrome that is observed across neuropsychiatric diseases, have remained obscure. In humans and mice, reduced expression of the structural myelin protein CNP is associated with catatonic signs in an age-dependent manner, pointing to the involvement of myelin-producing oligodendrocytes. Here, we showed that the underlying cause of catatonic signs is the low-grade inflammation of white matter tracts, which marks a final common pathway in Cnp-deficient and other mutant mice with minor myelin abnormalities. The inhibitor of CSF1 receptor kinase signaling PLX5622 depleted microglia and alleviated the catatonic symptoms of Cnp mutants. Thus, microglia and low-grade inflammation of myelinated tracts emerged as the trigger of a previously unexplained mental condition. We observed a very high (25%) prevalence of individuals with catatonic signs in a deeply phenotyped schizophrenia sample (n = 1095). Additionally, we found the loss-of-function allele of a myelin-specific gene (CNP rs2070106-AA) associated with catatonia in 2 independent schizophrenia cohorts and also associated with white matter hyperintensities in a general population sample. Since the catatonic syndrome is likely a surrogate marker for other executive function defects, we suggest that microglia-directed therapies may be considered in psychiatric disorders associated with myelin abnormalities.
QIMR Berghofer Medical Research Institute1, Brigham and Women's Hospital2, VU University Medical Center3, University of Southern California4, University of Queensland5, Queensland University of Technology6, Virginia Commonwealth University7, University of Sydney8, Leiden University Medical Center9, University of California, Irvine10, German Center for Neurodegenerative Diseases11, Greifswald University Hospital12, Health Science University13, Charité14, University Hospital Heidelberg15, University Medical Center Freiburg16, University of Bonn17, University of Marburg18, University of Lübeck19, Warneford Hospital20, University of New South Wales21
TL;DR: This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date and highlights the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.
Abstract: The aetiology of suicidal behaviour is complex, and knowledge about its neurobiological mechanisms is limited. Neuroimaging methods provide a noninvasive approach to explore the neural correlates of suicide vulnerability in vivo. The ENIGMA-MDD Working Group is an international collaboration evaluating neuroimaging and clinical data from thousands of individuals collected by research groups from around the world. Here we present analyses in a subset sample (n=3097) for whom suicidality data were available. Prevalence of suicidal symptoms among major depressive disorder (MDD) cases ranged between 29 and 69% across cohorts. We compared mean subcortical grey matter volumes, lateral ventricle volumes and total intracranial volume (ICV) in MDD patients with suicidal symptoms (N=451) vs healthy controls (N=1996) or MDD patients with no suicidal symptoms (N=650). MDD patients reporting suicidal plans or attempts showed a smaller ICV (P=4.12 × 10-3) or a 2.87% smaller volume compared with controls (Cohen's d=-0.284). In addition, we observed a nonsignificant trend in which MDD cases with suicidal symptoms had smaller subcortical volumes and larger ventricular volumes compared with controls. Finally, no significant differences (P=0.28-0.97) were found between MDD patients with and those without suicidal symptoms for any of the brain volume measures. This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date. Our results did not replicate previous reports of association between subcortical brain structure and suicidality and highlight the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.
TL;DR: In a white German population, the prevalence of fatty liver diseases and liver iron overload is 42.2% and 17.4% respectively, whereas liver fat is associated with predictors related to the metabolic syndrome, liver iron content is mainly associated with mean serum corpuscular hemoglobin.
Abstract: Hepatic steatosis had a prevalence of 42.2% (1082 of 2561), whereas liver iron overload was found in 17.4% (447 of 2561) of participants; although liver fat content is associated with changes connected with the metabolic syndrome, liver iron content is associated with mean serum corpuscular hemoglobin, male sex, and age.
TL;DR: The results suggest that there is a causal effect of BMI on serum testosterone in men, and population level interventions to reduce BMI are expected to increase serumosterone in men.
Abstract: Context Obesity in men is associated with low serum testosterone and both are associated with several diseases and increased mortality. Objectives Examine the direction and causality of the relationship between body mass index (BMI) and serum testosterone. Design Bi-directional Mendelian randomization (MR) analysis on prospective cohorts. Setting Five cohorts from Denmark, Germany and Sweden (Inter99, SHIP, SHIP Trend, GOOD and MrOS Sweden). Participants 7446 Caucasian men, genotyped for 97 BMI-associated SNPs and three testosterone-associated SNPs. Main outcome measures BMI and serum testosterone adjusted for age, smoking, time of blood sampling and site. Results 1 SD genetically instrumented increase in BMI was associated with a 0.25 SD decrease in serum testosterone (IV ratio: -0.25, 95% CI: -0.42-0.09, p = 2.8∗10-3). For a body weight reduction altering the BMI from 30 to 25 kg/m2, the effect would equal a 13% increase in serum testosterone. No association was seen for genetically instrumented testosterone with BMI, a finding that was confirmed using large-scale data from the GIANT consortium (n = 104349). Conclusions Our results suggest that there is a causal effect of BMI on serum testosterone in men. Population level interventions to reduce BMI are expected to increase serum testosterone in men. (Less)
Trinity College, Dublin1, Otto-von-Guericke University Magdeburg2, Greifswald University Hospital3, University of Melbourne4, VU University Medical Center5, University of Cape Town6, German Center for Neurodegenerative Diseases7, University of California, Irvine8, University of Southern California9, University of Potsdam10, University of Sydney11, University of the Sunshine Coast12, University of Regensburg13, Charité14, University Hospital Heidelberg15, University of Münster16, University Medical Center Freiburg17, University of Marburg18, University of Lübeck19, University of Adelaide20, University Medical Center Groningen21
TL;DR: All subcategories of childhood adversity were negatively associated with caudate volumes in females - in particular emotional neglect and physical neglect (independently from age, ICV, imaging site and MDD diagnosis), and there was no interaction effect between childhood adversity andMDD diagnosis on subcortical brain volumes.
TL;DR: This study aimed to confirm existing assumptions about the associations of circulating chemerin with inflammatory and metabolic parameters in a large population‐based study.
Abstract: Objective
This study aimed to confirm existing assumptions about the associations of circulating chemerin with inflammatory and metabolic parameters in a large population-based study.
Methods
Data of 3,986 subjects from the Study of Health in Pomerania were analyzed. Residual method was used to investigate the different associations of visceral (VAT) and subcutaneous adipose tissue (SAT) with serum chemerin levels. Multivariable regression models were applied to examine the association of chemerin with high-sensitivity C-reactive protein, fibrinogen, glucose, glycated hemoglobin, lipid profile, blood pressure, diabetes, dyslipidemia, and hypertension.
Results
Positive associations with chemerin were observed for VAT and SAT with a stronger relation found for VAT. After adjustment for waist circumference, increased chemerin levels were related to higher inflammatory cytokines and glycated hemoglobin and an unfavorable lipid profile. Logistic regression revealed positive associations of chemerin with dyslipidemia [highest vs. lowest quartile: odds ratio (OR) 1.56 (95% confidence interval (CI) 1.25-1.94)] and hypertension [OR 1.31 (95% CI 1.03-1.68)].
Conclusions
Chemerin levels are significantly linked to inflammation and metabolic syndrome. The majority of the detected associations persisted even after adjustment for waist circumference, suggesting that the relation of chemerin with the analyzed traits cannot be solely explained by an accumulation of adipose tissue.
Virginia Commonwealth University1, Charité2, University of Queensland3, VU University Amsterdam4, Max Planck Society5, VU University Medical Center6, University of Münster7, University of Edinburgh8, King's College London9, Aarhus University10, QIMR Berghofer Medical Research Institute11, Cardiff University12, University of Bonn13, Harvard University14, Broad Institute15, SUNY Downstate Medical Center16, Heidelberg University17, Trinity College, Dublin18, Greifswald University Hospital19, Kaiser Permanente20, Washington University in St. Louis21, University of Basel22, University of Sydney23, University of Greifswald24, University of Southern California25, Janssen Pharmaceutica26, Columbia University27, Aarhus University Hospital28, University of Liverpool29, Queensland University of Technology30, Florida Atlantic University31, University of Iowa32, University of Granada33, University of Groningen34, Group Health Cooperative35, Leiden University Medical Center36, University of York37, Stanford University38, University of Oxford39, Wellcome Trust Centre for Human Genetics40, Karolinska Institutet41
TL;DR: A partially shared polygenic basis of MDD in East Asian and European populations is successfully demonstrated and this findings support a complex etiology for MDD and possible population differences in predisposing genetic factors.
Abstract: Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.
TL;DR: Investigation of epidemiologic associations between periodontitis and the incidence of non-alcoholic fatty liver disease among 2,623 participants of the Study of Health in Pomerania found history ofperiodontitis may be a risk factor for NAFLD.
Abstract: Background
Non-alcoholic fatty liver disease (NAFLD) affects 20-30% of adults with risk factors like obesity and insulin resistance putatively acting through chronic low-grade inflammation. Because periodontitis elicits low-grade inflammation, we hypothesized that it could contribute to NAFLD occurrence. Objective
To investigate epidemiologic associations between periodontitis and the incidence of NAFLD among 2,623 participants of the Study of Health in Pomerania
Methods
Periodontitis at baseline was defined as the percentage of sites (0%, 1-30%, ≥30%) with 1) clinical attachment level (CAL) ≥3mm; 2) probing pocket depth (PD) ≥4mm. Incident NAFLD was defined as a significant increase in liver echogenicity on ultrasound relative to the kidneys, with the diaphragm indistinct OR the echogenic walls of the portal veins invisible
Results
After a median 7·7 years of follow-up, 605 incident NAFLD cases occurred at a rate of 32·5 cases per 1,000 person-years. Relative to participants without CAL ≥3mm, NAFLD incidence was elevated slightly in participants with 1-<30% of sites affected, and moderately in participants with ≥30% of sites affected (multivariable-adjusted incidence rate ratio= 1.28, 95% CI, 0.84, 1.95 and 1·60, 95% CI, 1·05-2·43) respectively. A similar dose-response relationship was not observed for PD
Conclusion
History of periodontitis may be a risk factor for NAFLD.
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TL;DR: Integrative analyses of different types of physiological data provided converging evidence indicating that oral contraceptives may cause effects analogous to chronic psychological stressors regarding the regulation of the HPA axis, potentially explaining conflicting results in the literature.
Abstract: Using oral contraceptives has been implicated in the aetiology of stress-related disorders like depression. Here, we followed the hypothesis that oral contraceptives deregulate the HPA-axis by elevating circulating cortisol levels. We report for a sample of 233 pre-menopausal women increased circulating cortisol levels in those using oral contraceptives. For women taking oral contraceptives, we observed alterations in circulating phospholipid levels and elevated triglycerides and found evidence for increased glucocorticoid signalling as the transcript levels of the glucocorticoid-regulated genes DDIT4 and FKBP5 were increased in whole blood. The effects were statistically mediated by cortisol. The associations of oral contraceptives with higher FKBP5 mRNA and altered phospholipid levels were modified by rs1360780, a genetic variance implicated in psychiatric diseases. Accordingly, the methylation pattern of FKBP5 intron 7 was altered in women taking oral contraceptives depending on the rs1360780 genotype. Moreover, oral contraceptives modified the association of circulating cortisol with depressive symptoms, potentially explaining conflicting results in the literature. Finally, women taking oral contraceptives displayed smaller hippocampal volumes than non-using women. In conclusion, the integrative analyses of different types of physiological data provided converging evidence indicating that oral contraceptives may cause effects analogous to chronic psychological stressors regarding the regulation of the HPA axis.
TL;DR: Greater cardiorespiratory fitness but not domain-specific physical activity was associated with a lower incidence of major depressive disorder and clinical anxiety and was more strongly related to the co-occurrence of MDD and anxiety than depression or anxiety alone.
Abstract: OBJECTIVE: Physical activity and cardiorespiratory fitness may help prevent depression and anxiety. Previous studies have been limited by error-prone measurements. We examined whether self-reported physical activity domains and peak exercise capacity (peakVO₂) are associated with incident and recurrent major depressive disorder (MDD), depressive symptoms, and anxiety disorders. METHODS: This was a prospective population-based study of 1,080 adult men and women (25-83 years) with a median follow-up of 4.5 years and measures of physical activity during leisure time, sports, and work (Baecke questionnaire); a measure of depressive symptoms (Beck Depression Inventory II); symptom-limited cycle ergometer testing (peakVO₂, oxygen uptake at anaerobic threshold [[email protected]/* */], maximum power output at peak exertion); and a structured psychiatric interview (Munich Composite International Diagnostic Interview). Baseline data were collected between 2002 and 2006, and follow-up data, between 2007 and 2010. RESULTS: After adjustment for age, sex, education, smoking, alcohol consumption, and waist circumference, the relative risks for incident MDD per standard deviation (SD) increase in leisure-time physical activity, physical activity during sport, physical activity at work, peakVO₂, [email protected]/* */, and maximum power output were 1.002 (95% confidence interval, 0.90 to 1.12), 1.02 (0.90 to 1.15), 0.94 (0.80 to 1.10), 0.71 (0.52 to 0.98), 0.83 (0.66 to 1.04), and 0.71 (0.52 to 0.96), respectively. PeakVO₂, [email protected]/* */, and maximum power output were associated with recurrent MDD, depressive symptoms, and anxiety. PeakVO₂ was more strongly related to the co-occurrence of MDD and anxiety (adjusted odds ratio [OR] = 0.45 [0.24 to 0.84]) than depression or anxiety alone (OR = 0.71 [0.53 to 0.94]). CONCLUSIONS: Greater cardiorespiratory fitness but not domain-specific physical activity was associated with a lower incidence of MDD and clinical anxiety. Language: en
TL;DR: A two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine among participants of European ancestry from the CKDGen Consortium identifies novel genes with potential roles in kidney formation.
Abstract: Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
TL;DR: The findings suggest that prediabetes might have harmful effects on the kidney.
Abstract: Background and Aims We investigated the associations of serum fasting (FG) and 2-h postload (2HG) glucose from an oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), fasting insulin and the homeostasis model assessment-insulin resistance index (HOMA-IR) with urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). Methods and Results We performed cross-sectional analyses of 2713 subjects (1429 women; 52.7%) without known type 2 diabetes, aged 31–82 years, from the KORA (Cooperative Health Research in the Augsburg Region) F4-Study. FG, 2HG, HbA1c, fasting insulin, HOMA-IR and glucose tolerance categories were analyzed for association with ACR and eGFR in multivariable adjusted linear and median regression models, and with isolated microalbuminuria (i-MA), isolated reduced kidney function (i-RKF) and chronic kidney disease (CKD, defined as MA and/or RKF) in multivariable adjusted logistic regression models. Among the 2713 study participants, 28% revealed prediabetes (isolated impaired fasting glucose [i-IFG], isolated glucose tolerance [i-IGT] or both by American Diabetes Association definition), 4.2% had unknown type 2 diabetes, 6.5% had i-MA, 3.1% i-RKF and 10.9% CKD. In multivariable adjusted analysis, all continuous variables (FG, 2HG, HbA1c, fasting insulin and HOMA-IR) were associated with i-MA, i-RKF and CKD. The odds ratios (ORs) for i-MA and CKD were 1.54 (95% confidence interval: 1.02–2.33) and 1.58 (1.10–2.25) for individuals with i-IFG. Moreover, the OR for i-RKF was 2.57 (1.31–5.06) for individuals with IFG + IGT. Conclusion Our findings suggest that prediabetes might have harmful effects on the kidney.
TL;DR: It is shown in two independent human samples that a single normal AMBRA1 genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower AMBra1 mRNA expression in peripheral blood mononuclear cells relative to female GG carriers, and suggest Ambra1 heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.
Abstract: Ambra1 is linked to autophagy and neurodevelopment. Heterozygous Ambra1 deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of AMBRA1 for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal AMBRA1 genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower AMBRA1 mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by in silico analysis. Searching for further autism-relevant characteristics in Ambra1+/- mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an in vivo readout of neuronal excitation-inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of AMBRA1/Ambra1 partial loss-of-function genotypes for female autistic traits. Moreover, they suggest Ambra1 heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.
University of Bristol1, University of Copenhagen2, Bispebjerg Hospital3, University of South Australia4, Norwegian University of Science and Technology5, National Institute for Health and Welfare6, Robertson Centre for Biostatistics7, Leiden University Medical Center8, University of Duisburg-Essen9, University of Glasgow10, Ludwig Maximilian University of Munich11, Technische Universität München12, University of Southern Denmark13, University College London14, University of Essex15, University of Greifswald16, Greifswald University Hospital17, Aalborg University18, National Institutes of Health19, University of Helsinki20
TL;DR: This paper examined the causal effect of smoking on hay fever and asthma by using the smokingassociated single nucleotide polymorphism (SNP) rs16969968/rs1051730.
Abstract: Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76; P < 0·001) and allergic sensitization (OR = 0·74, 95% CI: 0·64, 0·86; P < 0·001), but similar asthma risk (OR = 1·00, 95% CI: 0·91, 1·09; P = 0·967). Mendelian randomization analyses in current smokers showed a slightly lower risk of hay fever (OR = 0·958, 95% CI: 0·920, 0·998; P = 0·041), a lower risk of allergic sensitization (OR = 0·92, 95% CI: 0·84, 1·02; P = 0·117), but higher risk of asthma (OR = 1·06, 95% CI: 1·01, 1·11; P = 0·020) per smoking-increasing allele. Our results suggest that smoking may be causally related to a higher risk of asthma and a slightly lower risk of hay fever. However, the adverse events associated with smoking limit its clinical significance.