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1. Incidence, symptom clusters and determinants of post-acute COVID symptoms: a population-based surveillance in community-dwelling users of the COVID RADAR app

Author: Mattijs E Numans, Frits R Rosendaal, Jessica C Kiefte-de Jong, Dennis O Mook-Kanamori, A van Hylckama Vlieg, Miriam L Haaksma, Willian J van Dijk, and Leo G Visser
Subjects: Medicine
Abstract: Objectives This study aims to describe the incidence, symptom clusters and determinants of post-acute COVID symptoms using data from the COVID RADAR app in the Netherlands.Design Prospective cohort.Setting General population in the Netherlands from April 2020 to February 2022.Participants A total of 1478 COVID RADAR app users, with data spanning 40 days before to 100 days after positive SARS-CoV-2 test.Outcome measures Incidence and duration of 10 new symptoms that developed during acute infection, defined as 10 days prior and 10 days after positive test. Clustering of these post-acute COVID symptoms and associations between factors known in the acute phase and 100-day symptom persistence.Results The most frequent post-acute symptoms were cough, loss of smell or taste and fatigue. At 100 days postinfection, 86 (8%) participants still experienced symptoms. Three post-acute COVID symptom clusters were identified: non-respiratory (headache and fatigue; 49% of participants with post-acute COVID symptoms); olfactory (15%) and respiratory (8%). Vaccination was associated with a lower risk of post-acute COVID symptoms 100 days after infection, although CIs were wide (OR: 0.5; 95% CI: 0.2 to 1.5), but not with non-respiratory symptoms (OR: 1.0; 95% CI: 0.3 to 4.4). Severe acute disease increased the risk of post-acute COVID symptoms (OR: 1.4; 95% CI: 1.2 to 1.5; per additional acute symptom).Conclusions In this cohort of infected community-dwelling app users, 5%–10% experienced post-acute COVID symptoms. The symptoms cluster in several distinct entities, which differ in incidence, patient characteristics and vaccination effects. This suggests multiple mechanisms underlying the development of post-acute COVID symptoms.
Published: 2024
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2. Dutch GPs’ perspectives on addressing obesity: a qualitative study

Author: Willemijn J van den Hout, Marieke A Adriaanse, Louise M Den Beer Poortugael, Dennis O Mook-Kanamori, Mattijs E Numans, and Petra G van Peet
Subjects: overweight, obesity, qualitative research, general practitioners, general practice, primary health care, Medicine (General), R5-920
Abstract: Background: Early diagnosis and treatment of obesity in primary care may help to tackle the obesity pandemic. Nonetheless, GPs frequently fail to address obesity and demonstrate limited adherence to guidelines. Aim: To explore Dutch GPs’ perspectives on addressing obesity regarding the following three target behaviours: discussing weight; diagnosing; and referring patients with obesity. Design & setting: A qualitative focus group study with Dutch GPs. Method: Six focus groups were conducted with a purposive sample of 21 GPs. Thematic analysis was performed using deductive coding, according to the Theoretical Domains Framework (TDF). Results: For discussing weight, the main barriers identified were a presented complaint unrelated to obesity (environmental context and resources), concerns about a negative response from the patient (beliefs about consequences), and worries about obesity being a sensitive subject to discuss (emotions). A long-term trustworthy relationship (social influences) facilitated discussing weight. For diagnosing patients with obesity, the main barriers were related to resources; for example, lack of (appropriate) measuring equipment and time (environmental context and resources). For referring patients with obesity, the main barriers were no referral options nearby (environmental context and resources), and doubts about the positive effects of the referral on weight change (beliefs about consequences). Conclusion: Different barriers for discussing weight, diagnosing, and referring patients with obesity were identified, underscoring the importance for tailored interventions to these specific behaviours. Improving knowledge and skills of GPs seems insufficient as this study showed that particular attention should be paid to establishing long-term relationships, addressing GPs' beliefs about consequences, and creating a supportive environment with sufficient time and resources.
Published: 2024
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3. Agreement between nicotine metabolites in blood and self-reported smoking status: The Netherlands Epidemiology of Obesity study

Author: Sofia Folpmers, Dennis O Mook-Kanamori, Renée de Mutsert, Frits R. Rosendaal, Ko Willems van Dijk, Diana van Heemst, Raymond Noordam, and Saskia le Cessie
Subjects: Smoking, Agreement, Nicotine metabolites, Self reported smoking status, Psychology, BF1-990, Social pathology. Social and public welfare. Criminology, HV1-9960
Abstract: Introduction: Self-report and nicotine detection are methods to measure smoking exposure and can both lead to misclassification. It is important to highlight discrepancies between these two methods in the context of epidemiological research. Objective: The aim of this cross-sectional study is to assess the agreements between self-reported smoking status and nicotine metabolite detection. Methods: Data of 599 participants from the Netherlands Epidemiology of Obesity study were used to compare serum metabolite levels of five nicotine metabolites (cotinine, hydroxy-cotinine, cotinine N-Oxide, norcotinine, 3-hydroxy-cotinine-glucuronide) between self-reported never smokers (n = 245), former smokers (n = 283) and current smokers (n = 71). We assessed whether metabolites were absent or present and used logistic regression to discriminate between current and never smokers based on nicotine metabolite information. A classification tree was derived to classify individuals into current smokers and non/former smokers based on metabolite information. Results: In 94% of the self-reported current smokers, at least one metabolite was present, versus in 19% of the former smokers and in 10% of the never smokers. In none of the never smokers, cotinine-n-oxide, 3-hydroxy-cotinine-n-glucorinide or norcotinine was present, while at least one of these metabolites was detected in 68% of the self-reported current smokers. The classification tree classified 95% of the participants in accordance to their self-reported smoking status. All self-reported smokers who were classified as non-smokers according to the metabolite profile, had reported to be occasional smokers. Conclusion: The agreement between self-reported smoking status and metabolite information was high. This indicates that self-reported smoking status is generally reliable.
Published: 2022
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4. Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

Author: Peitao Wu, Denis Rybin, Lawrence F Bielak, Mary F Feitosa, Nora Franceschini, Yize Li, Yingchang Lu, Jonathan Marten, Solomon K Musani, Raymond Noordam, Sridharan Raghavan, Lynda M Rose, Karen Schwander, Albert V Smith, Salman M Tajuddin, Dina Vojinovic, Najaf Amin, Donna K Arnett, Erwin P Bottinger, Ayse Demirkan, Jose C Florez, Mohsen Ghanbari, Tamara B Harris, Lenore J Launer, Jingmin Liu, Jun Liu, Dennis O Mook-Kanamori, Alison D Murray, Mike A Nalls, Patricia A Peyser, André G Uitterlinden, Trudy Voortman, Claude Bouchard, Daniel Chasman, Adolfo Correa, Renée de Mutsert, Michele K Evans, Vilmundur Gudnason, Caroline Hayward, Linda Kao, Sharon L R Kardia, Charles Kooperberg, Ruth J F Loos, Michael M Province, Tuomo Rankinen, Susan Redline, Paul M Ridker, Jerome I Rotter, David Siscovick, Blair H Smith, Cornelia van Duijn, Alan B Zonderman, D C Rao, James G Wilson, Josée Dupuis, James B Meigs, Ching-Ti Liu, and Jason L Vassy
Subjects: Medicine, Science
Abstract: Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p
Published: 2020
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5. Assessment of reproducibility and biological variability of fasting and postprandial plasma metabolite concentrations using 1H NMR spectroscopy.

Author: Ruifang Li-Gao, David A Hughes, Saskia le Cessie, Renée de Mutsert, Martin den Heijer, Frits R Rosendaal, Ko Willems van Dijk, Nicholas J Timpson, and Dennis O Mook-Kanamori
Subjects: Medicine, Science
Abstract: IntroductionIt is crucial to understand the factors that introduce variability before applying metabolomics to clinical and biomarker research.ObjectivesWe quantified technical and biological variability of both fasting and postprandial metabolite concentrations measured using 1H NMR spectroscopy in plasma samples.MethodsIn the Netherlands Epidemiology of Obesity study (n = 6,671), 148 metabolite concentrations (101 metabolites belonging to lipoprotein subclasses) were measured under fasting and postprandial states (150 minutes after a mixed liquid meal). Technical variability was evaluated among 265 fasting and 851 postprandial samples, with the identical blood plasma sample being measured twice by the same laboratory protocol. Biological reproducibility was assessed by measuring 165 individuals twice across time for evaluation of short- (3 years) biological variability. Intra-class coefficients (ICCs) were used to assess variability. The ICCs of the fasting metabolites were compared with the postprandial metabolites using two-sided paired Wilcoxon test separately for short- and long-term measurements.ResultsBoth fasting and postprandial metabolite concentrations showed high technical reproducibility using 1H NMR spectroscopy (median ICC = 0.99). Postprandial metabolite concentrations revealed slightly higher ICC scores than fasting ones in short-term repeat measures (median ICC in postprandial and fasting metabolite concentrations 0.72 versus 0.67, Wilcoxon p-value = 8.0×10-14). Variability did not increase further in a long-term repeat measure, with median ICC in postprandial of 0.64 and in fasting metabolite concentrations 0.66.ConclusionTechnical reproducibility is excellent. Biological reproducibility of postprandial metabolite concentrations showed a less or equal variability than fasting metabolite concentrations over time.
Published: 2019
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6. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

Author: Mary F Feitosa, Aldi T Kraja, Daniel I Chasman, Yun J Sung, Thomas W Winkler, Ioanna Ntalla, Xiuqing Guo, Nora Franceschini, Ching-Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan Marten, Solomon K Musani, Changwei Li, Amy R Bentley, Michael R Brown, Karen Schwander, Melissa A Richard, Raymond Noordam, Hugues Aschard, Traci M Bartz, Lawrence F Bielak, Rajkumar Dorajoo, Virginia Fisher, Fernando P Hartwig, Andrea R V R Horimoto, Kurt K Lohman, Alisa K Manning, Tuomo Rankinen, Albert V Smith, Salman M Tajuddin, Mary K Wojczynski, Maris Alver, Mathilde Boissel, Qiuyin Cai, Archie Campbell, Jin Fang Chai, Xu Chen, Jasmin Divers, Chuan Gao, Anuj Goel, Yanick Hagemeijer, Sarah E Harris, Meian He, Fang-Chi Hsu, Anne U Jackson, Mika Kähönen, Anuradhani Kasturiratne, Pirjo Komulainen, Brigitte Kühnel, Federica Laguzzi, Jian'an Luan, Nana Matoba, Ilja M Nolte, Sandosh Padmanabhan, Muhammad Riaz, Rico Rueedi, Antonietta Robino, M Abdullah Said, Robert A Scott, Tamar Sofer, Alena Stančáková, Fumihiko Takeuchi, Bamidele O Tayo, Peter J van der Most, Tibor V Varga, Veronique Vitart, Yajuan Wang, Erin B Ware, Helen R Warren, Stefan Weiss, Wanqing Wen, Lisa R Yanek, Weihua Zhang, Jing Hua Zhao, Saima Afaq, Najaf Amin, Marzyeh Amini, Dan E Arking, Tin Aung, Eric Boerwinkle, Ingrid Borecki, Ulrich Broeckel, Morris Brown, Marco Brumat, Gregory L Burke, Mickaël Canouil, Aravinda Chakravarti, Sabanayagam Charumathi, Yii-Der Ida Chen, John M Connell, Adolfo Correa, Lisa de Las Fuentes, Renée de Mutsert, H Janaka de Silva, Xuan Deng, Jingzhong Ding, Qing Duan, Charles B Eaton, Georg Ehret, Ruben N Eppinga, Evangelos Evangelou, Jessica D Faul, Stephan B Felix, Nita G Forouhi, Terrence Forrester, Oscar H Franco, Yechiel Friedlander, Ilaria Gandin, He Gao, Mohsen Ghanbari, Bruna Gigante, C Charles Gu, Dongfeng Gu, Saskia P Hagenaars, Göran Hallmans, Tamara B Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Makoto Hirata, Barbara V Howard, M Arfan Ikram, InterAct Consortium, Ulrich John, Tomohiro Katsuya, Chiea Chuen Khor, Tuomas O Kilpeläinen, Woon-Puay Koh, José E Krieger, Stephen B Kritchevsky, Michiaki Kubo, Johanna Kuusisto, Timo A Lakka, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Benjamin Lehne, Cora E Lewis, Yize Li, Shiow Lin, Jianjun Liu, Jingmin Liu, Marie Loh, Tin Louie, Reedik Mägi, Colin A McKenzie, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Lili Milani, Karen L Mohlke, Yukihide Momozawa, Mike A Nalls, Christopher P Nelson, Nona Sotoodehnia, Jill M Norris, Jeff R O'Connell, Nicholette D Palmer, Thomas Perls, Nancy L Pedersen, Annette Peters, Patricia A Peyser, Neil Poulter, Leslie J Raffel, Olli T Raitakari, Kathryn Roll, Lynda M Rose, Frits R Rosendaal, Jerome I Rotter, Carsten O Schmidt, Pamela J Schreiner, Nicole Schupf, William R Scott, Peter S Sever, Yuan Shi, Stephen Sidney, Mario Sims, Colleen M Sitlani, Jennifer A Smith, Harold Snieder, John M Starr, Konstantin Strauch, Heather M Stringham, Nicholas Y Q Tan, Hua Tang, Kent D Taylor, Yik Ying Teo, Yih Chung Tham, Stephen T Turner, André G Uitterlinden, Peter Vollenweider, Melanie Waldenberger, Lihua Wang, Ya Xing Wang, Wen Bin Wei, Christine Williams, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B Zonderman, Diane M Becker, Michael Boehnke, Donald W Bowden, John C Chambers, Ian J Deary, Tõnu Esko, Martin Farrall, Paul W Franks, Barry I Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Jost Bruno Jonas, Yoichiro Kamatani, Norihiro Kato, Jaspal S Kooner, Zoltán Kutalik, Markku Laakso, Cathy C Laurie, Karin Leander, Terho Lehtimäki, Lifelines Cohort Study, Patrik K E Magnusson, Albertine J Oldehinkel, Brenda W J H Penninx, Ozren Polasek, David J Porteous, Rainer Rauramaa, Nilesh J Samani, James Scott, Xiao-Ou Shu, Pim van der Harst, Lynne E Wagenknecht, Nicholas J Wareham, Hugh Watkins, David R Weir, Ananda R Wickremasinghe, Tangchun Wu, Wei Zheng, Claude Bouchard, Kaare Christensen, Michele K Evans, Vilmundur Gudnason, Bernardo L Horta, Sharon L R Kardia, Yongmei Liu, Alexandre C Pereira, Bruce M Psaty, Paul M Ridker, Rob M van Dam, W James Gauderman, Xiaofeng Zhu, Dennis O Mook-Kanamori, Myriam Fornage, Charles N Rotimi, L Adrienne Cupples, Tanika N Kelly, Ervin R Fox, Caroline Hayward, Cornelia M van Duijn, E Shyong Tai, Tien Yin Wong, Charles Kooperberg, Walter Palmas, Kenneth Rice, Alanna C Morrison, Paul Elliott, Mark J Caulfield, Patricia B Munroe, Dabeeru C Rao, Michael A Province, and Daniel Levy
Subjects: Medicine, Science
Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
Published: 2018
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7. The association between various smoking behaviors, cotinine biomarkers and skin autofluorescence, a marker for advanced glycation end product accumulation.

Author: Robert P van Waateringe, Marjonneke J Mook-Kanamori, Sandra N Slagter, Melanie M van der Klauw, Jana V van Vliet-Ostaptchouk, Reindert Graaff, Helen L Lutgers, Karsten Suhre, Mohammed M El-Din Selim, Dennis O Mook-Kanamori, and Bruce H R Wolffenbuttel
Subjects: Medicine, Science
Abstract: Skin autofluorescence, a biomarker for advanced glycation end products (AGEs) accumulation, has been shown to predict diabetes-related cardiovascular complications and is associated with several environmental and lifestyle factors. In the present study, we examined the association between various smoking behaviors and skin autofluorescence, as well as the association between several cotinine biomarkers and skin autofluorescence, using both epidemiological and metabolomics data.In a cross-sectional study, we evaluated participants from the LifeLines Cohort Study and the Qatar Metabolomics Study on Diabetes (QMDiab). In the LifeLines Cohort Study smoking behavior and secondhand smoking were assessed in 8,905 individuals including 309 individuals (3.5%) with type 2 diabetes. In QMDiab, cotinine biomarkers were measured in saliva, plasma and urine in 364 individuals of whom 188 (51%) had type 2 diabetes. Skin autofluorescence was measured non-invasively in all participants using the AGE Reader.Skin autofluorescence levels increased with a higher number of hours being exposed to secondhand smoking. Skin autofluorescence levels of former smokers approached levels of never smokers after around 15 years of smoking cessation. Urinary cotinine N-oxide, a biomarker of nicotine exposure, was found to be positively associated with skin autofluorescence in the QMDiab study (p = 0.03).In the present study, we have demonstrated that secondhand smoking is associated with higher skin autofluorescence levels whereas smoking cessation has a beneficial effect on skin autofluorescence. Finally, urinary cotinine N-oxide might be used as an alternative way for questionnaires to examine the effect of (environmental) tobacco smoking on skin autofluorescence.
Published: 2017
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8. Ethnicity and skin autofluorescence-based risk-engines for cardiovascular disease and diabetes mellitus.

Author: Muhammad Saeed Ahmad, Torben Kimhofer, Sultan Ahmad, Mohammed Nabil AlAma, Hala Hisham Mosli, Salwa Ibrahim Hindawi, Dennis O Mook-Kanamori, Katarína Šebeková, Zoheir Abdullah Damanhouri, and Elaine Holmes
Subjects: Medicine, Science
Abstract: Skin auto fluorescence (SAF) is used as a proxy for the accumulation of advanced glycation end products (AGEs) and has been proposed to stratify patients into cardiovascular disease (CVD) and diabetes mellitus (DM) risk groups. This study evaluates the effects of seven different ethnicities (Arab, Central-East African, Eastern Mediterranean, European, North African, South Asian and Southeast Asian) and gender on SAF as well as validating SAF assessment as a risk estimation tool for CVD and DM in an Arabian cohort. SAF data from self-reported healthy 2,780 individuals, collated from three independent studies, has been linear modelled using age and gender as a covariate. A cross-study harmonized effect size (Cohens'd) is provided for each ethnicity. Furthermore, new data has been collected from a clinically well-defined patient group of 235 individuals, to evaluate SAF as a clinical tool for DM and CVD-risk estimation in an Arab cohort. In an Arab population, SAF-based CVD and/or DM risk-estimation can be improved by referencing to ethnicity and gender-specific SAF values. Highest SAF values were observed for the North African population, followed by East Mediterranean, Arab, South Asian and European populations. The South Asian population had a slightly steeper slope in SAF values with age compared to other ethnic groups. All ethnic groups except Europeans showed a significant gender effect. When compared with a European group, effect size was highest for Eastern Mediterranean group and lowest for South Asian group. The Central-East African and Southeast Asian ethnicity matched closest to the Arab and Eastern Mediterranean ethnicities, respectively. Ethnic and gender-specific data improves performance in SAF-based CVD and DM risk estimation. The provided harmonized effect size allows a direct comparison of SAF in different ethnicities. For the first time, gender differences in SAF are described for North African and East Mediterranean populations.
Published: 2017
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9. Heritability estimates of body size in fetal life and early childhood.

Author: Dennis O Mook-Kanamori, Catharina E M van Beijsterveldt, Eric A P Steegers, Yurii S Aulchenko, Hein Raat, Albert Hofman, Paul H Eilers, Dorret I Boomsma, and Vincent W V Jaddoe
Subjects: Medicine, Science
Abstract: The objective was to estimate the heritability for height and weight during fetal life and early childhood in two independent studies, one including parent and singleton offsprings and one of mono- and dizygotic twins.This study was embedded in the Generation R Study (n = 3407, singletons) and the Netherlands Twin Register (n = 33694, twins). For the heritability estimates in Generation R, regression models as proposed by Galton were used. In the Twin Register we used genetic structural equation modelling. Parental height and weight were measured and fetal growth characteristics (femur length and estimated fetal weight) were measured by ultrasounds in 2(nd) and 3(rd) trimester (Generation R only). Height and weight were assessed at multiple time-points from birth to 36 months in both studies.Heritability estimates for length increased from 2(nd) to 3(rd) trimester from 13% to 28%. At birth, heritability estimates for length in singletons and twins were both 26% and 27%, respectively, and at 36 months, the estimates for height were 63% and 72%, respectively. Heritability estimates for fetal weight increased from 2(nd) to 3(rd) trimester from 17% to 27%. For birth weight, heritability estimates were 26% in singletons and 29% in twins. At 36 months, the estimate for twins was 71% and higher than for singletons (42%).Heritability estimates for height and weight increase from second trimester to infancy. This increase in heritability is observed in singletons and twins. Longer follow-up studies are needed to examine how the heritability develops in later childhood and puberty.
Published: 2012
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10. Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development.

Author: Ulla Sovio, Dennis O Mook-Kanamori, Nicole M Warrington, Robert Lawrence, Laurent Briollais, Colin N A Palmer, Joanne Cecil, Johanna K Sandling, Ann-Christine Syvänen, Marika Kaakinen, Lawrie J Beilin, Iona Y Millwood, Amanda J Bennett, Jaana Laitinen, Anneli Pouta, John Molitor, George Davey Smith, Yoav Ben-Shlomo, Vincent W V Jaddoe, Lyle J Palmer, Craig E Pennell, Tim J Cole, Mark I McCarthy, Marjo-Riitta Järvelin, Nicholas J Timpson, and Early Growth Genetics Consortium
Subjects: Genetics, QH426-470
Abstract: An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10(-20)) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10(-23)). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (-0.40% (95% CI: -0.74, -0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (-4.72% (-5.81, -3.63), p = 10(-17)), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.
Published: 2011
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11. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author: Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar
Subjects: Advanced and Specialized Nursing, Incidence, risk assessment, Smoking/epidemiology, intracranial aneurysm, genetic heterogeneity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Risk Factors, Intracranial Aneurysm/epidemiology, Humans, Subarachnoid Hemorrhage/epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, genetics, Neurology (clinical), aneurysmal subarachnoid hemorrhage, genetic, Cardiology and Cardiovascular Medicine
Abstract: Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
Published: 2023
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12. Association of mental health and negative life events with weight change in patients with overweight: A cohort study

Author: Willemijn J. van den Hout, Dennis O. Mook-Kanamori, Petra G. van Peet, Frederike L. Büchner, Bernet M. Elzinga, Frits R. Rosendaal, Renée de Mutsert, and Mattijs E. Numans
Subjects: Psychiatry and Mental health, Clinical Psychology
Published: 2023
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13. Hepatic triglyceride content is intricately associated with numerous metabolites and biochemical pathways

Author: Tariq O. Faquih, Jan Bert van Klinken, Ruifang Li‐Gao, Raymond Noordam, Diana van Heemst, Sebastiaan Boone, Patricia A. Sheridan, Gregory Michelotti, Hildo Lamb, Renée de Mutsert, Frits R. Rosendaal, Astrid van Hylckama Vlieg, Ko Willems van Dijk, Dennis O. Mook‐Kanamori, Laboratory Genetic Metabolic Diseases, Laboratory for General Clinical Chemistry, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: dysregulation, Hepatology, genetic targets, liver triglyceride content, metabolomics, pathway analysis
Abstract: Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of triglycerides in hepatocytes and is associated with insulin resistance, atherogenic dyslipidaemia and cardiometabolic diseases. Thus far, the extent of metabolic dysregulation associated with hepatic triglyceride accumulation has not been fully addressed. In this study, we aimed to identify metabolites associated with hepatic triglyceride content (HTGC) and map these associations using network analysis. Methods: To gain insight in the spectrum of metabolites associated with hepatic triglyceride accumulation, we performed a comprehensive plasma metabolomics screening of 1363 metabolites in apparently healthy middle aged (age 45–65) individuals (N = 496) in whom HTGC was measured by proton magnetic resonance spectroscopy. An atlas of metabolite–HTGC associations, based on univariate results, was created using correlation-based Gaussian graphical model (GGM) and genome scale metabolic model network analyses. Pathways associated with the clinical prognosis marker fibrosis 4 (FIB-4) index were tested using a closed global test. Results: Our analyses revealed that 118 metabolites were univariately associated with HTGC (p-value
Published: 2023

14. Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

Author: William J. Young, Jeffrey Haessler, Jan-Walter Benjamins, Linda Repetto, Jie Yao, Aaron Isaacs, Andrew R. Harper, Julia Ramirez, Sophie Garnier, Stefan van Duijvenboden, Antoine R. Baldassari, Maria Pina Concas, ThuyVy Duong, Luisa Foco, Jonas L. Isaksen, Hao Mei, Raymond Noordam, Casia Nursyifa, Anne Richmond, Meddly L. Santolalla, Colleen M. Sitlani, Negin Soroush, Sébastien Thériault, Stella Trompet, Stefanie Aeschbacher, Fariba Ahmadizar, Alvaro Alonso, Jennifer A. Brody, Archie Campbell, Adolfo Correa, Dawood Darbar, Antonio De Luca, Jean-François Deleuze, Christina Ellervik, Christian Fuchsberger, Anuj Goel, Christopher Grace, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Rebecca D. Jackson, Jan A. Kors, Maria Fernanda Lima-Costa, Allan Linneberg, Peter W. Macfarlane, Alanna C. Morrison, Pau Navarro, David J. Porteous, Peter P. Pramstaller, Alexander P. Reiner, Lorenz Risch, Ulrich Schotten, Xia Shen, Gianfranco Sinagra, Elsayed Z. Soliman, Monika Stoll, Eduardo Tarazona-Santos, Andrew Tinker, Katerina Trajanoska, Eric Villard, Helen R. Warren, Eric A. Whitsel, Kerri L. Wiggins, Dan E. Arking, Christy L. Avery, David Conen, Giorgia Girotto, Niels Grarup, Caroline Hayward, J.Wouter Jukema, Dennis O. Mook-Kanamori, Morten Salling Olesen, Sandosh Padmanabhan, Bruce M. Psaty, Cristian Pattaro, Antonio Luiz P. Ribeiro, Jerome I. Rotter, Bruno H. Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James G. Wilson, Michele Orini, Philippe Charron, Hugh Watkins, Charles Kooperberg, Henry J. Lin, James F. Wilson, Jørgen K. Kanters, Nona Sotoodehnia, Borbala Mifsud, Pier D. Lambiase, Larisa G. Tereshchenko, Patricia B. Munroe, Epidemiology, Department of Finance, Medical Informatics, Internal Medicine, Erasmus MC other, Cardiovascular Centre (CVC), Young, William J, Haessler, Jeffrey, Benjamins, Jan-Walter, Repetto, Linda, Yao, Jie, Isaacs, Aaron, Harper, Andrew R, Ramirez, Julia, Garnier, Sophie, van Duijvenboden, Stefan, Baldassari, Antoine R, Concas, Maria Pina, Duong, Thuyvy, Foco, Luisa, Isaksen, Jonas L, Mei, Hao, Noordam, Raymond, Nursyifa, Casia, Richmond, Anne, Santolalla, Meddly L, Sitlani, Colleen M, Soroush, Negin, Thériault, Sébastien, Trompet, Stella, Aeschbacher, Stefanie, Ahmadizar, Fariba, Alonso, Alvaro, Brody, Jennifer A, Campbell, Archie, Correa, Adolfo, Darbar, Dawood, De Luca, Antonio, Deleuze, Jean-Françoi, Ellervik, Christina, Fuchsberger, Christian, Goel, Anuj, Grace, Christopher, Guo, Xiuqing, Hansen, Torben, Heckbert, Susan R, Jackson, Rebecca D, Kors, Jan A, Lima-Costa, Maria Fernanda, Linneberg, Allan, Macfarlane, Peter W, Morrison, Alanna C, Navarro, Pau, Porteous, David J, Pramstaller, Peter P, Reiner, Alexander P, Risch, Lorenz, Schotten, Ulrich, Shen, Xia, Sinagra, Gianfranco, Soliman, Elsayed Z, Stoll, Monika, Tarazona-Santos, Eduardo, Tinker, Andrew, Trajanoska, Katerina, Villard, Eric, Warren, Helen R, Whitsel, Eric A, Wiggins, Kerri L, Arking, Dan E, Avery, Christy L, Conen, David, Girotto, Giorgia, Grarup, Niel, Hayward, Caroline, Jukema, J Wouter, Mook-Kanamori, Dennis O, Olesen, Morten Salling, Padmanabhan, Sandosh, Psaty, Bruce M, Pattaro, Cristian, Ribeiro, Antonio Luiz P, Rotter, Jerome I, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Verweij, Niek, Wilson, James G, Orini, Michele, Charron, Philippe, Watkins, Hugh, Kooperberg, Charle, Lin, Henry J, Wilson, James F, Kanters, Jørgen K, Sotoodehnia, Nona, Mifsud, Borbala, Lambiase, Pier D, Tereshchenko, Larisa G, and Munroe, Patricia B
Subjects: Electrocardiography/methods, General Physics and Astronomy, 610 Medicine & health, Arrhythmias, Cardiovascular, General Biochemistry, Genetics and Molecular Biology, cardiac arrhythmia, Electrocardiography, SDG 3 - Good Health and Well-being, Risk Factors, Cardiovascular Diseases/genetics, Genetics, Humans, Arrhythmias, Cardiac/genetics, Atrioventricular Block, Multidisciplinary, Human Genome, General Chemistry, Heart Disease, Cardiovascular Diseases, Cardiac, Biomarkers, Genome-Wide Association Study
Abstract: The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.
Published: 2023
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15. Normal range CAG repeat size variations in the HTT gene are associated with an adverse lipoprotein profile partially mediated by body mass index

Author: Tariq O Faquih, N Ahmad Aziz, Sarah L Gardiner, Ruifang Li-Gao, Renée de Mutsert, Yuri Milaneschi, Stella Trompet, J Wouter Jukema, Frits R Rosendaal, Astrid van Hylckama Vlieg, Ko Willems van Dijk, and Dennis O Mook-Kanamori
Subjects: ddc:570, Genetics, General Medicine, Molecular Biology, Genetics (clinical)
Abstract: Tandem cytosine-adenine-guanine (CAG) repeat sizes of 36 or more in the huntingtin gene (HTT) cause Huntington's disease (HD). Apart from neuropsychiatric complications, the disease is also accompanied by metabolic dysregulation and weight loss, which contribute to a progressive functional decline. Recent studies also reported an association between repeats below the pathogenic threshold (
Published: 2023
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16. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author: Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, Gina M. Peloso, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, HUSLAB, Epigenetics of Complex Diseases and Traits, Department of Medicine, Helsinki University Hospital Area, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Faculty Common Matters (Faculty of Social Sciences), Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Tampere University, Primary Health Care, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Epidemiology and Data Science, APH - Aging & Later Life, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Lee Kong Chian School of Medicine (LKCMedicine), Peloso, Gina M [0000-0002-5355-8636], Apollo - University of Cambridge Repository, Epidemiology, Department of Marketing Management, Erasmus MC other, Radiology & Nuclear Medicine, Kanoni, Stavroula, Graham, Sarah E, Wang, Yuxuan, Surakka, Ida, Ramdas, Shweta, Zhu, Xiang, Clarke, Shoa L, Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Zajac, Greg J M, Wu, Kuan-Han H, Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T, Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Havulinna, Aki S, Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A, Lingren, Todd, Feng, Qiping, Kullo, Iftikhar J, Narita, Akira, Takayama, Jun, Martin, Hilary C, Hunt, Karen A, Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Rasheed, Asif, Hindy, George, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian'An, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achillea, Hottenga, Jouke Jan, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Yousri, Noha A, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A, Yao, Jie, Manichaikul, Ani, Hwu, Chii-Min, Hung, Yi-Jen, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Mauro, Pala, Matteo, Flori, Mcdaid, Aaron F, Marques-Vidal, Pedro, Wielscher, Matthia, Trompet, Stella, Sattar, Naveed, Møllehave, Line T, Munz, Matthia, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Luka, Scholz, Marku, Galesloot, Tessel E, Bradfield, Jonathan P, Ruotsalainen, Sanni E, Daw, Ewarwick, Zmuda, Joseph M, Mitchell, Jonathan S, Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A, Vazquez-Moreno, Miguel, Feitosa, Mary F, Wojczynski, Mary K, Wang, Zhe, Preuss, Michael H, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W, Engmann, Jorgen, Tsao, Noah L, Verma, Anurag, Slieker, Roderick C, Lo, Ken Sin, Zilhao, Nuno R, Le, Phuong, Kleber, Marcus E, Delgado, Graciela E, Huo, Shaofeng, Ikeda, Daisuke D, Iha, Hiroyuki, Yang, Jian, Liu, Jun, Demirkan, Ayşe, Leonard, Hampton L, Marten, Jonathan, Frank, Mirjam, Schmidt, Börge, Smyth, Laura J, Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlo, Lyssenko, Valeriya, Nongmaithem, Suraj S, Bayyana, Swati, Stringham, Heather M, Irvin, Marguerite R, Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R H J, Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N, Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C, Wang, Ya Xing, Wei, Wen B, Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A, Banas, Bernhard, Nardone, Giuseppe Giovanni, Meidtner, Karina, Bielak, Lawrence F, Smith, Jennifer A, Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J, Pitkänen, Niina, Cade, Brian E, van der Laan, Sander W, Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Bentley, Amy R, Doumatey, Ayo P, Adeyemo, Adebowale A, Lee, Jong Young, Petersen, Eva R B, Nielsen, Aneta A, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W, Wang, Carol A, Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hidalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O, van Setten, Jessica, Li, Xiaoyin, Liang, Jingjing, Tang, Hua, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D, Reiner, Alexander P, Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C, Launer, Lenore J, Li, Huaixing, Nalls, Mike A, Raitakari, Olli T, Ichihara, Sahoko, Wild, Sarah H, Nelson, Christopher P, Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S, Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, de Kleijn, Dominique, de Borst, Gert J, Kim, Eung Kweon, Adams, Hieab H H, Ikram, M Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W, Kraaijeveld, Adriaan O, Beulens, Joline W J, Shu, Xiao-Ou, Rallidis, Loukianos S, Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W, Kähönen, Mika, Pérusse, Loui, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E, Mori, Trevor A, Lieb, Wolfgang, Franke, Andre, Ohlsson, Clae, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M, Stark, Klaus J, Zimmermann, Martina E, Völzke, Henry, Homuth, Georg, Evans, Michele K, Zonderman, Alan B, Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E, Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J, Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L R, Peyser, Patricia A, Kato, Norihiro, Schulze, Matthias B, Girotto, Giorgia, Böger, Carsten A, Jung, Bettina, Joshi, Peter K, Bennett, David A, De Jager, Philip L, Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morri, Caulfield, Mark J, Munroe, Patricia B, Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B, Samani, Nilesh J, Kaprio, Jaakko, Pajukanta, Päivi, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A, Adair, Linda S, Bechayda, Sonny Augustin, de Silva, H Janaka, Wickremasinghe, Ananda R, Krauss, Ronald M, Wu, Jer-Yuarn, Zheng, Wei, Hollander, Anneke Iden, Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G, Lind, Lar, Heng, Chew-Kiat, Nelson, Amanda E, Golightly, Yvonne M, Wilson, James F, Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J, Rao, D C, Arnett, Donna K, Hunt, Steven C, Walker, Mark, Koistinen, Heikki A, Chandak, Giriraj R, Mercader, Josep M, Costanzo, Maria C, Jang, Dongkeun, Burtt, Noël P, Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, Eshyong, van Dam, Rob M, Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F, Mcknight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, Mccarthy, Mark I, Palmer, Colin N A, Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M, Jin, Zi-Bing, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, Hart, Leen M 't, Elders, Petra J M, Damrauer, Scott M, Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D, Loos, Ruth J F, Province, Michael A, Parra, Esteban J, Cruz, Miguel, Psaty, Bruce M, Brandslund, Ivan, Pramstaller, Peter P, Rotimi, Charles N, Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F A, Kiemeney, Lambertus A L M, de Graaf, Jacqueline, Loeffler, Marku, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W, Linneberg, Allan, Jukema, J Wouter, Khera, Amit V, Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Francesco, Cucca, Mook-Kanamori, Dennis O, van Dijk, Ko Willem, Watkins, Hugh, Strachan, David P, Grarup, Niel, Sever, Peter, Poulter, Neil, Chuang, Lee-Ming, Rotter, Jerome I, Dantoft, Thomas M, Karpe, Fredrik, Neville, Matt J, Timpson, Nicholas J, Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Li, Hengtong, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T, Pedersen, Nancy L, Magnusson, Patrik K E, Boomsma, Dorret I, Willemsen, Allegonda H M, Cupples, Ladrienne, van Meurs, Joyce B J, Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J, Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C, Kooner, Jaspal S, de Vries, Paul S, Morrison, Alanna C, Hazelhurst, Scott, Ramsay, Michèle, North, Kari E, Daviglus, Martha, Kraft, Peter, Martin, Nicholas G, Whitfield, John B, Abbas, Shahid, Saleheen, Danish, Walters, Robin G, Holmes, Michael V, Black, Corri, Smith, Blair H, Baras, Ari, Justice, Anne E, Buring, Julie E, Ridker, Paul M, Chasman, Daniel I, Kooperberg, Charle, Tamiya, Gen, Yamamoto, Masayuki, van Heel, David A, Trembath, Richard C, Wei, Wei-Qi, Jarvik, Gail P, Namjou, Bahram, Hayes, M Geoffrey, Ritchie, Marylyn D, Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Kim, Bong-Jo, Thorsteinsdottir, Unnur, Stefansson, Kari, Zhang, Jifeng, Chen, Yeugene, Ho, Yuk-Lam, Lynch, Julie A, Rader, Daniel J, Tsao, Philip S, Chang, Kyong-Mi, Cho, Kelly, O'Donnell, Christopher J, Gaziano, John M, Wilson, Peter W F, Frayling, Timothy M, Hirschhorn, Joel N, Kathiresan, Sekar, Mohlke, Karen L, Sun, Yan V, Morris, Andrew P, Boehnke, Michael, Brown, Christopher D, Natarajan, Pradeep, Deloukas, Pano, Willer, Cristen J, Assimes, Themistocles L, and Peloso, Gina M
Subjects: Genome-wide association study, Medizin, Polymorphism, Single Nucleotide, Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Sex Characteristics, Phenotype, Lipids/genetics, Genetic Pleiotropy, Cholesterol, GWAS, Genetics, Lipids, Genetic, SDG 3 - Good Health and Well-being, Medicine [Science], 112 Statistics and probability, Medicinsk genetik, Genome-wide Association Study, Gwas, 1184 Genetics, developmental biology, physiology, 3126 Surgery, anesthesiology, intensive care, radiology, 3142 Public health care science, environmental and occupational health, 3141 Health care science, FOS: Biological sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 3111 Biomedicine, Medical Genetics
Abstract: Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756
Published: 2022
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17. The association between adiposity and atypical energy-related symptoms of depression: a role for metabolic dysregulations

Author: Tahani Alshehri, Dennis O Mook-Kanamori, Renée de Mutsert, Brenda WJH Penninx, Frits R Rosendaal, Saskia le Cessie, Yuri Milaneschi, Psychiatry, APH - Digital Health, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: Metabolic Syndrome, Behavioral Neuroscience, Endocrine and Autonomic Systems, Depression, Immunology, Body Fat Distribution, Homeostasis, Genetic risk score, Body Mass Index
Abstract: BackgroundAdiposity has been shown to be linked with atypical energy-related symptoms (AES) of depression. We used genomics to separate the effect of adiposity from that of metabolic dysregulations to examine whether the link between obesity and AES is dependent on the presence of metabolic dysregulations.MethodData were from NEO (n=5734 individuals) and NESDA (n=2238 individuals) cohorts, in which the Inventory of Depressive Symptomatology (IDS-SR30) was assessed. AES profile was based on four symptoms: increased appetite, increased weight, low energy level, and leaden paralysis. We estimated associations between AES and two genetic risk scores (GRS) indexing increasing total body fat with (metabolically unhealthy adiposity, GRS-MUA) and without (metabolically healthy adiposity, GRS-MHA) metabolic dysregulations.ResultsGRS-MUA and GRS-MHA were both associated with higher total body fat in NEO study, but divergently associated with biomarkers of metabolic health (e.g. fasting glucose and HDL) in both cohorts. In the pooled results, per standard deviation, GRS-MUA was specifically associated with a higher AES score (β=0.03, 95%CI: 0.01; 0.05), while there was no association between GRS-MHA and AES (β=-0.01, 95%CI: -0.03; 0.01).ConclusionThese results suggest that the established link between adiposity and AES profile emerges in the presence of metabolic dysregulations, which may represent the connecting substrate between the two conditions.
Published: 2022
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18. Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

Author: William J. Young, Najim Lahrouchi, Aaron Isaacs, ThuyVy Duong, Luisa Foco, Farah Ahmed, Jennifer A. Brody, Reem Salman, Raymond Noordam, Jan-Walter Benjamins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Linda Repetto, Maria Pina Concas, Marten E. van den Berg, Stefan Weiss, Antoine R. Baldassari, Traci M. Bartz, James P. Cook, Daniel S. Evans, Rebecca Freudling, Oliver Hines, Jonas L. Isaksen, Honghuang Lin, Hao Mei, Arden Moscati, Martina Müller-Nurasyid, Casia Nursyifa, Yong Qian, Anne Richmond, Carolina Roselli, Kathleen A. Ryan, Eduardo Tarazona-Santos, Sébastien Thériault, Stefan van Duijvenboden, Helen R. Warren, Jie Yao, Dania Raza, Stefanie Aeschbacher, Gustav Ahlberg, Alvaro Alonso, Laura Andreasen, Joshua C. Bis, Eric Boerwinkle, Archie Campbell, Eulalia Catamo, Massimiliano Cocca, Michael J. Cutler, Dawood Darbar, Alessandro De Grandi, Antonio De Luca, Jun Ding, Christina Ellervik, Patrick T. Ellinor, Stephan B. Felix, Philippe Froguel, Christian Fuchsberger, Martin Gögele, Claus Graff, Mariaelisa Graff, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Paul L. Huang, Heikki V. Huikuri, Nina Hutri-Kähönen, M. Arfan Ikram, Rebecca D. Jackson, Juhani Junttila, Maryam Kavousi, Jan A. Kors, Thiago P. Leal, Rozenn N. Lemaitre, Henry J. Lin, Lars Lind, Allan Linneberg, Simin Liu, Peter W. MacFarlane, Massimo Mangino, Thomas Meitinger, Massimo Mezzavilla, Pashupati P. Mishra, Rebecca N. Mitchell, Nina Mononen, May E. Montasser, Alanna C. Morrison, Matthias Nauck, Victor Nauffal, Pau Navarro, Kjell Nikus, Guillaume Pare, Kristen K. Patton, Giulia Pelliccione, Alan Pittman, David J. Porteous, Peter P. Pramstaller, Michael H. Preuss, Olli T. Raitakari, Alexander P. Reiner, Antonio Luiz P. Ribeiro, Kenneth M. Rice, Lorenz Risch, David Schlessinger, Ulrich Schotten, Claudia Schurmann, Xia Shen, M. Benjamin Shoemaker, Gianfranco Sinagra, Moritz F. Sinner, Elsayed Z. Soliman, Monika Stoll, Konstantin Strauch, Kirill Tarasov, Kent D. Taylor, Andrew Tinker, Stella Trompet, André Uitterlinden, Uwe Völker, Henry Völzke, Melanie Waldenberger, Lu-Chen Weng, Eric A. Whitsel, James G. Wilson, Christy L. Avery, David Conen, Adolfo Correa, Francesco Cucca, Marcus Dörr, Sina A. Gharib, Giorgia Girotto, Niels Grarup, Caroline Hayward, Yalda Jamshidi, Marjo-Riitta Järvelin, J. Wouter Jukema, Stefan Kääb, Mika Kähönen, Jørgen K. Kanters, Charles Kooperberg, Terho Lehtimäki, Maria Fernanda Lima-Costa, Yongmei Liu, Ruth J. F. Loos, Steven A. Lubitz, Dennis O. Mook-Kanamori, Andrew P. Morris, Jeffrey R. O’Connell, Morten Salling Olesen, Michele Orini, Sandosh Padmanabhan, Cristian Pattaro, Annette Peters, Bruce M. Psaty, Jerome I. Rotter, Bruno Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James F. Wilson, Dan E. Arking, Julia Ramirez, Pier D. Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-Cheh, Patricia B. Munroe, Cardiology, ACS - Heart failure & arrhythmias, Epidemiology, Radiology & Nuclear Medicine, Medical Informatics, Internal Medicine, Young, William J, Lahrouchi, Najim, Isaacs, Aaron, Duong, Thuyvy, Foco, Luisa, Ahmed, Farah, Brody, Jennifer A, Salman, Reem, Noordam, Raymond, Benjamins, Jan-Walter, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Repetto, Linda, Concas, Maria Pina, van den Berg, Marten E, Weiss, Stefan, Baldassari, Antoine R, Bartz, Traci M, Cook, James P, Evans, Daniel S, Freudling, Rebecca, Hines, Oliver, Isaksen, Jonas L, Lin, Honghuang, Mei, Hao, Moscati, Arden, Müller-Nurasyid, Martina, Nursyifa, Casia, Qian, Yong, Richmond, Anne, Roselli, Carolina, Ryan, Kathleen A, Tarazona-Santos, Eduardo, Thériault, Sébastien, van Duijvenboden, Stefan, Warren, Helen R, Yao, Jie, Raza, Dania, Aeschbacher, Stefanie, Ahlberg, Gustav, Alonso, Alvaro, Andreasen, Laura, Bis, Joshua C, Boerwinkle, Eric, Campbell, Archie, Catamo, Eulalia, Cocca, Massimiliano, Cutler, Michael J, Darbar, Dawood, De Grandi, Alessandro, De Luca, Antonio, Ding, Jun, Ellervik, Christina, Ellinor, Patrick T, Felix, Stephan B, Froguel, Philippe, Fuchsberger, Christian, Gögele, Martin, Graff, Clau, Graff, Mariaelisa, Guo, Xiuqing, Hansen, Torben, Heckbert, Susan R, Huang, Paul L, Huikuri, Heikki V, Hutri-Kähönen, Nina, Ikram, M Arfan, Jackson, Rebecca D, Junttila, Juhani, Kavousi, Maryam, Kors, Jan A, Leal, Thiago P, Lemaitre, Rozenn N, Lin, Henry J, Lind, Lar, Linneberg, Allan, Liu, Simin, Macfarlane, Peter W, Mangino, Massimo, Meitinger, Thoma, Mezzavilla, Massimo, Mishra, Pashupati P, Mitchell, Rebecca N, Mononen, Nina, Montasser, May E, Morrison, Alanna C, Nauck, Matthia, Nauffal, Victor, Navarro, Pau, Nikus, Kjell, Pare, Guillaume, Patton, Kristen K, Pelliccione, Giulia, Pittman, Alan, Porteous, David J, Pramstaller, Peter P, Preuss, Michael H, Raitakari, Olli T, Reiner, Alexander P, Ribeiro, Antonio Luiz P, Rice, Kenneth M, Risch, Lorenz, Schlessinger, David, Schotten, Ulrich, Schurmann, Claudia, Shen, Xia, Shoemaker, M Benjamin, Sinagra, Gianfranco, Sinner, Moritz F, Soliman, Elsayed Z, Stoll, Monika, Strauch, Konstantin, Tarasov, Kirill, Taylor, Kent D, Tinker, Andrew, Trompet, Stella, Uitterlinden, André, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Weng, Lu-Chen, Whitsel, Eric A, Wilson, James G, Avery, Christy L, Conen, David, Correa, Adolfo, Cucca, Francesco, Dörr, Marcu, Gharib, Sina A, Girotto, Giorgia, Grarup, Niel, Hayward, Caroline, Jamshidi, Yalda, Järvelin, Marjo-Riitta, Jukema, J Wouter, Kääb, Stefan, Kähönen, Mika, Kanters, Jørgen K, Kooperberg, Charle, Lehtimäki, Terho, Lima-Costa, Maria Fernanda, Liu, Yongmei, Loos, Ruth J F, Lubitz, Steven A, Mook-Kanamori, Dennis O, Morris, Andrew P, O'Connell, Jeffrey R, Olesen, Morten Salling, Orini, Michele, Padmanabhan, Sandosh, Pattaro, Cristian, Peters, Annette, Psaty, Bruce M, Rotter, Jerome I, Stricker, Bruno, van der Harst, Pim, van Duijn, Cornelia M, Verweij, Niek, Wilson, James F, Arking, Dan E, Ramirez, Julia, Lambiase, Pier D, Sotoodehnia, Nona, Mifsud, Borbala, Newton-Cheh, Christopher, Munroe, Patricia B, Cardiovascular Centre (CVC), Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Paediatrics, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Fysiologie, RS: Carim - B01 Blood proteins & engineering, RS: Carim - H08 Experimental atrial fibrillation, and Biochemie
Subjects: Male, Electrocardiography/methods, General Physics and Astronomy, 610 Medicine & health, Arrhythmias, 3121 Internal medicine, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, Electrocardiography, Humans, Arrhythmias, Cardiac/genetics, Genetic Testing, Medicinsk genetik, Multidisciplinary, Death, Sudden, Cardiac, Arrhythmias, Cardiac, General Chemistry, Sudden, Electrocardiogram, Death, Genetic markers, 3111 Biomedicine, 610 Medizin und Gesundheit, Cardiac, Medical Genetics
Abstract: The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
Published: 2022
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19. The effect of physical activity level and exercise training on the association between plasma branched-chain amino acids and intrahepatic lipid content in participants with obesity

Author: Froukje Vanweert, Dennis O. Mook-Kanamori, Esther Phielix, Renée de Mutsert, Patrick Schrauwen, Frits R. Rosendaal, Hildo J. Lamb, Sebastiaan C. Boone, Bram Brouwers, Matthijs K. C. Hesselink, Vera B. Schrauwen-Hinderling, Nutrition and Movement Sciences, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, Promovendi NTM, MUMC+: DA BV Research (9), and MUMC+: DA BV Klinisch Fysicus (9)
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Epidemiology, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), 030209 endocrinology & metabolism, Type 2 diabetes, Article, 03 medical and health sciences, 0302 clinical medicine, Valine, Non-alcoholic Fatty Liver Disease, Internal medicine, Medicine, Humans, Obesity, Exercise, Aged, chemistry.chemical_classification, Nutrition and Dietetics, business.industry, Fatty liver, Middle Aged, medicine.disease, Lipid Metabolism, Lipids, Physical activity level, Amino acid, 030104 developmental biology, Endocrinology, Cross-Sectional Studies, chemistry, Diabetes Mellitus, Type 2, Liver, Lipid content, Isoleucine, business, Amino Acids, Branched-Chain
Abstract: Aims To evaluate whether the association between plasma branched-chain amino acids (BCAA) and intrahepatic lipid (IHL) was affected by physical activity level. Furthermore, to investigate if a conventional exercise training program, a subcategory of physical activity, could lower plasma BCAA along with alterations in IHL content in patients with type 2 diabetes (T2DM) and people with nonalcoholic fatty liver (NAFL). Methods To investigate the effect of physical activity on the association between plasma BCAA and IHL content, linear regression analyses were performed in 1983 individuals from the Netherlands Epidemiology of Obesity (NEO) stratified by physical activity frequency. Furthermore, the effect of a 12-week supervised combined aerobic resistance-exercise program on plasma BCAA, insulin sensitivity (hyperinsulinemic–euglycemic clamp), and IHL (proton-magnetic resonance spectroscopy (1H-MRS)) was investigated in seven patients with T2DM, seven individuals with NAFL and seven BMI-matched control participants (CON). Results We observed positive associations between plasma valine, isoleucine and leucine level, and IHL content (1.29 (95% CI: 1.21, 1.38), 1.52 (95% CI: 1.43, 1.61), and 1.54 (95% CI: 1.44, 1.64) times IHL, respectively, per standard deviation of plasma amino acid level). Similar associations were observed in less active versus more active individuals. Exercise training did not change plasma BCAA levels among groups, but reduced IHL content in NAFL (from 11.6 ± 3.0% pre-exercise to 8.1 ± 2.0% post exercise, p p p Conclusions The association between plasma BCAA levels and IHL is not affected by physical activity level. Exercise training reduced IHL without affecting plasma BCAA levels in individuals with NAFL and CON. We conclude that exercise training-induced reduction in IHL content is not related to changes in plasma BCAA levels. Trial registration Trial registry number: NCT01317576.
Published: 2021

20. Association of measures of body fat with serum alpha-tocopherol and its metabolites in middle-aged individuals

Author: Leon G. Martens, Nadia Ashrafi, Kevin Mills, Frits R. Rosendaal, Jiao Luo, Diana van Heemst, Fleur L. Meulmeester, Hildo J. Lamb, Renée de Mutsert, Dennis O. Mook-Kanamori, Ko Willems van Dijk, and Raymond Noordam
Subjects: Male, medicine.medical_specialty, Subcutaneous adipose tissue, Epidemiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Urinary system, alpha-Tocopherol, Medicine (miscellaneous), Adipose tissue, 030209 endocrinology & metabolism, Urine, Intra-Abdominal Fat, 030204 cardiovascular system & hematology, Body Mass Index, Vitamin E metabolites, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Obesity, Adiposity, Netherlands, Nutrition and Dietetics, Mass spectrometry, business.industry, Vitamin E, Confounding, Age Factors, Alpha tocopherol, Middle Aged, medicine.disease, Cross-Sectional Studies, Endocrinology, chemistry, Visceral adipose tissue, Obesity, Abdominal, Female, Lipid Peroxidation, Cardiology and Cardiovascular Medicine, business, Body mass index, Biomarkers
Abstract: Background and aims: The accumulation of fat increases the formation of lipid perox-ides, which are partly scavenged by alpha-tocopherol (a-TOH). Here, we aimed to investigate the associations between different measures of (abdominal) fat and levels of urinary a-TOH metab-olites in middle-aged individuals. Methods and results: In this cross-sectional analysis in the Netherlands Epidemiology of Obesity study (N Z 511, 53% women; mean [SD] age of 55 [6.1] years), serum a-TOH and a-TOH metab-olites from 24-h urine were measured as alpha-tocopheronolactone hydroquinone (a-TLHQ, oxidized) and alpha-carboxymethyl-hydroxychroman (a-CEHC, enzymatically converted) using liquid-chromatography-tandem mass spectrometry. Body mass index and total body fat were measured, and abdominal subcutaneous and visceral adipose tissue (aSAT and VAT) were as-sessed using magnetic resonance imaging. Using multivariable-adjusted linear regression ana -lyses, we analysed the associations of BMI, TBF, aSAT and VAT with levels of urinary a-TOH metabolites, adjusted for confounders. We observed no evidence for associations between body fat measures and serum a-TOH. Higher BMI and TBF were associated with lower urinary levels of TLHQ (0.95 [95%CI: 0.90, 1.00] and 0.94 [0.88, 1.01] times per SD, respectively) and with lower TLHQ relative to CEHC (0.93 [0.90, 0.98] and 0.93 [0.87, 0.98] times per SD, respectively). We observed similar associations for VAT (TLHQ: 0.94 [0.89, 0.99] times per SD), but not for aSAT. Conclusions: Opposite to our research hypothesis, higher abdominal adiposity was moderately associated with lower levels of oxidized a-TOH metabolites, which might reflect lower vitamin E antioxidative activity in individuals with higher abdominal fat instead. (c) 2021 The Author(s). Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Published: 2021
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21. The Relation Between Adult Weight Gain, Adipocyte Volume, and the Metabolic Profile at Middle Age

Author: Costantinos Christodoulides, Inge Verkouter, Dennis O. Mook-Kanamori, Frits R. Rosendaal, Fredrik Karpe, Nellie Y. Loh, Peter L. Zock, Renée de Mutsert, Saskia le Cessie, Raymond Noordam, and Ko Willems van Dijk
Subjects: 0301 basic medicine, Male, Aging, Endocrinology, Diabetes and Metabolism, Biopsy, Clinical Biochemistry, 030204 cardiovascular system & hematology, Biochemistry, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Adipocyte, Adipocytes, Medicine, Netherlands, chemistry.chemical_classification, weight gain, Middle Aged, metabolomics, metabolic profile, Nutritional Biology, Metabolome, Female, medicine.symptom, AcademicSubjects/MED00250, Polyunsaturated fatty acid, medicine.medical_specialty, Lipoproteins, Abdominal Fat, Context (language use), body mass index, 03 medical and health sciences, Internal medicine, cohort study, Humans, Obesity, Online Only Articles, Clinical Research Articles, adipocyte volume, business.industry, Biochemistry (medical), Middle age, 030104 developmental biology, chemistry, Adipocyte hypertrophy, business, Weight gain, Body mass index, Lipoprotein
Abstract: Context Weight gain during adulthood increases cardiometabolic disease risk, possibly through adipocyte hypertrophy. Objective We aimed to study the specific metabolomic profile of adult weight gain, and to examine its association with adipocyte volume. Methods Nuclear magnetic resonance–based metabolomics were measured in the Netherlands Epidemiology of Obesity (NEO) study (n = 6347, discovery) and Oxford Biobank (n = 6317, replication). Adult weight gain was calculated as the absolute difference between body mass index (BMI) at middle age and recalled BMI at age 20 years. We performed linear regression analyses with both exposures BMI at age 20 years and weight gain, and separately with BMI at middle age in relation to 149 serum metabolomic measures, adjusted for age, sex, and multiple testing. Additionally, subcutaneous abdominal adipocyte biopsies were collected in a subset of the Oxford Biobank (n = 114) to estimate adipocyte volume. Results Mean (SD) weight gain was 4.5 (3.7) kg/m2 in the NEO study and 3.6 (3.7) kg/m2 in the Oxford Biobank. Weight gain, and not BMI at age 20 nor middle age, was associated with concentrations of 7 metabolomic measures after successful replication, which included polyunsaturated fatty acids, small to medium low-density lipoproteins, and total intermediate-density lipoprotein. One SD weight gain was associated with 386 μm3 (95% CI, 143-629) higher median adipocyte volume. Adipocyte volume was associated with lipoprotein particles specific for adult weight gain. Conclusion Adult weight gain is associated with specific metabolomic alterations of which the higher lipoprotein concentrations were likely contributed by larger adipocyte volumes, presumably linking weight gain to cardiometabolic disease.
Published: 2021

22. De SARS-CoV-2-antigeentest is niet accuraat genoeg

Author: Nathalie van Burgel, Bart Torensma, H. Essers, Febe Smits, Rolf H.H. Groenwold, Mattijs E. Numans, Frits R. Rosendaal, Maurine Leversteijn-Van Hall, Dennis O. Mook-Kanamori, and Robert Jansen
Subjects: Gynecology, 03 medical and health sciences, 2019-20 coronavirus outbreak, medicine.medical_specialty, 030505 public health, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Medicine, 0305 other medical science, Family Practice, business, Onderzoek
Abstract: Samenvatting Met een antigeensneltest kan een besmetting met SARS-CoV-2 binnen enkele minuten worden aangetoond. Wij onderzochten de validiteit van zo’n antigeentest in de eerstelijns spoedzorg bij patiënten met matig-ernstige corona-achtige klachten. De onderzochte antigeentest bleek een sensitiviteit te hebben van 65,7% en een negatief voorspellende waarde van 95-98%. Het is daarom aan te raden om een negatieve sneltestuitslag bij patiënten die klachten hebben altijd te bevestigen met een PCR-test.
Published: 2021

23. Multi-ancestry genome-wide association study improves resolution of genes, pathways and pleiotropy for lung function and chronic obstructive pulmonary disease

Author: Nick Shrine, Abril G Izquierdo, Jing Chen, Richard Packer, Robert J Hall, Anna L Guyatt, Chiara Batini, Rebecca J Thompson, Chandan Pavuluri, Vidhi Malik, Brian D Hobbs, Matthew Moll, Wonji Kim, Ruth Tal-Singer, Per Bakke, Katherine A Fawcett, Catherine John, Kayesha Coley, Noemi Nicole Piga, Alfred Pozarickij, Kuang Lin, Iona Y Millwood, Zhengming Chen, Liming Li, Sara RA Wielscher, Lies Lahousse, Guy Brusselle, Andre G Uitterlinden, Ani Manichaikul, Elizabeth C Oelsner, Stephen S Rich, R. Graham Barr, Shona M Kerr, Veronique Vitart, Michael R Brown, Matthias Wielscher, Medea Imboden, Ayoung Jeong, Traci M Bartz, Sina A Gharib, Claudia Flexeder, Stefan Karrasch, Christian Gieger, Annette Peters, Beate Stubbe, Xiaowei Hu, Victor E Ortega, Deborah A Meyers, Eugene R Bleecker, Stacey B Gabriel, Namrata Gupta, Albert Vernon Smith, Jian’an Luan, Jing-Hua Zhao, Ailin F Hansen, Arnulf Langhammer, Cristen Willer, Laxmi Bhatta, David Porteous, Blair H Smith, Archie Campbell, Tamar Sofer, Jiwon Lee, Martha L Daviglus, Bing Yu, Elise Lim, Hanfei Xu, George T O’Connor, Gaurav Thareja, Omar M E., Hamdi Mbarek, Karsten Suhre, Raquel Granell, Tariq O Faquih, Pieter S Hiemstra, Annelies M Slats, Benjamin H Mullin, Jennie Hui, Alan James, John Beilby, Karina Patasova, Pirro Hysi, Jukka T Koskela, Annah B Wyss, Jianping Jin, Sinjini Sikdar, Mikyeong Lee, Sebastian May-Wilson, Nicola Pirastu, Katherine A Kentistou, Peter K Joshi, Paul RHJ Timmers, Alexander T Williams, Robert C Free, Xueyang Wang, John L Morrison, Frank D Gilliland, Zhanghua Chen, Carol A Wang, Rachel E Foong, Sarah E Harris, Adele Taylor, Paul Redmond, James P Cook, Anubha Mahajan, Lars Lind, Teemu Palviainen, Terho Lehtimäki, Olli T Raitakari, Jaakko Kaprio, Taina Rantanen, Kirsi H Pietiläinen, Simon R Cox, Craig E Pennell, Graham L Hall, W. James Gauderman, Chris Brightling, James F Wilson, Tuula Vasankari, Tarja Laitinen, Veikko Salomaa, Dennis O Mook-Kanamori, Nicholas J Timpson, Eleftheria Zeggini, Josée Dupuis, Caroline Hayward, Ben Brumpton, Claudia Langenberg, Stefan Weiss, Georg Homuth, Carsten Oliver Schmidt, Nicole Probst-Hensch, Marjo-Riitta Jarvelin, Alanna C Morrison, Ozren Polasek, Igor Rudan, Joo-Hyeon Lee, Ian Sayers, Emma L Rawlins, Frank Dudbridge, Edwin K Silverman, David P Strachan, Robin G Walters, Andrew P Morris, Stephanie J London, Michael H Cho, Louise V Wain, Ian P Hall, and Martin D Tobin
Abstract: Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Published: 2022
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24. [Code dark grey in hospitals: short hospital admission and high mortality due to COVID-19]

Author: Dennis O, Mook-Kanamori, Frits R, Rosendaal, Saskia, le Cessie, Marino, van Zelst, and Bob, Siegerink
Subjects: Hospitalization, SARS-CoV-2, COVID-19, Humans, Hospital Mortality, Pandemics, Hospitals
Abstract: During the COVID-19 pandemic, we have experienced several waves in which the number of hospital beds occupied by patients with COVID-19 has varied greatly. In December 2022, hospitals were under a tremendous pressure, and were forced to upgrade their capacity to phase 2D ("Code Dark Grey"). This is the last phase prior to phase 3 ("Code Black"), in which we would be unable to treat all patients and would be forced to triage based on medical and non-medical characteristics of the patients. In this brief analysis, we demonstrate that phase 2D is characterized by a relatively short mean period of hospital admission and a higher hospital mortality.
Published: 2022

25. Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism

Author: Nicholas J. Timpson, Ko Willems van Dijk, David A. Hughes, Frits R. Rosendaal, Jan B. van Klinken, Dennis O. Mook-Kanamori, Ruifang Li-Gao, Renée de Mutsert, Laboratory Genetic Metabolic Diseases, Laboratory for General Clinical Chemistry, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Male, medicine.medical_specialty, Genotyping Techniques, Endocrinology, Diabetes and Metabolism, Metabolite, Genome-wide association study, Biology, chemistry.chemical_compound, Metabolomics, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Meals, Genetic association, Aged, Netherlands, Lipid metabolism, Middle Aged, medicine.disease, Lipid Metabolism, Postprandial Period, Solutions, Postprandial, Endocrinology, Glucose, chemistry, Melatonin receptor 1B, Metabolome, Carbohydrate Metabolism, Female, Insulin Resistance, Genome-Wide Association Study
Abstract: Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We set out to examine the genetics of variation in concentrations of postprandial metabolites (t=150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity study (N=5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (beta (SE): -0.23 (0.03), P-value: 2.15×10-19). In addition, ANKRD55 locus led by rs458741:C showed strong associations to extremely large VLDL particle (XXLVLDL) response (with XXLVLDLC: beta (SE): 0.17 (0.03) P-value: 5.76×10-10 and with XXLVLDLCE: beta (SE): 0.17 (0.03), P-value: 9.74×10-10), which also revealed strong associations to body composition and diabetes in the UK Biobank (p-values-8). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-β, ISI matsuda index and HbA1c in the NEO study further implied the role of chylomicron synthesis in diabetes (with FDR corrected q-valueANKRD55 locus underlying diabetes.
Published: 2021
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26. Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses

Author: Robert A. Schoevers, Mohsen Ghanbari, Annemarie I. Luik, Bastiaan T. Heijmans, Nienke R. Biermasz, Brenda W.J.H. Penninx, Carisha S. Thesing, Aeilko H. Zwinderman, Ruifang Li-Gao, Kaitlin H Wade, Frits R. Rosendaal, Dorret I. Boomsma, M. Arfan Ikram, Marian Beekman, Dennis O. Mook-Kanamori, Lisanne S. Vijfhuizen, P. Eline Slagboom, Debbie A Lawlor, Matthew Lee, Naveed Sattar, Matt J. Neville, Stella Trompet, J. Wouter Jukema, L.H. Lumey, Diana van Heemst, Ian Ford, Renée de Mutsert, Rima Mustafa, Patrick C.N. Rensen, Xiang Zhang, M.M. Bos, Abbas Dehghan, Carolien A. Wijsman, Gonneke Willemsen, Gisela M. Terwindt, Irene de Boer, Raymond Noordam, Ko Willems van Dijk, René Pool, Fredrik Karpe, Arn M. J. M. van den Maagdenberg, Neil Goulding, Rebecca C Richmond, Simon P. Mooijaart, Amy Hofman, Constantinos Christodoulides, Chihua Li, Mariska Bot, Neurosurgery, ANS - Neurodegeneration, ANS - Systems & Network Neuroscience, Epidemiology and Data Science, APH - Methodology, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Epidemiology, Biological Psychology, APH - Health Behaviors & Chronic Diseases, and APH - Personalized Medicine
Subjects: medicine.medical_specialty, Epidemiology, lcsh:Medicine, Physiology, Coronary Artery Disease, Polymorphism, Single Nucleotide, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Metabolic Diseases, SDG 3 - Good Health and Well-being, Risk Factors, Mendelian randomization, medicine, Insomnia, Humans, Metabolomics, Isoleucine, sleep, Aged, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Creatinine, business.industry, lcsh:R, Chronotype, General Medicine, Mendelian Randomization Analysis, R1, Confidence interval, 3. Good health, Cross-Sectional Studies, Phenotype, chemistry, Human and Animal Physiology, Cohort, Fysiologie van Mens en Dier, medicine.symptom, business, Sleep, Body mass index, 030217 neurology & neurosurgery, Research Article, Genome-Wide Association Study
Abstract: Background Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD)[95% confidence interval (CI) − 0.12, − 0.03] in AMV and − 0.03SD [− 0.07, − 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (− 0.04SD [− 0.08, 0.00] in AMV and − 0.05SD [− 0.09, − 0.02] in MR), and lower phospholipids in very large HDL particles (− 0.04SD [− 0.08, 0.002] in AMV and − 0.05SD [− 0.08, − 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. Conclusions Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.
Published: 2021
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27. Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

Author: Peter W. Macfarlane, Niels Grarup, Ruth J. F. Loos, Marcus Dörr, Peter P. Pramstaller, Torben Hansen, James F. Wilson, Lu-Chen Weng, Eduardo Tarazona-Santos, Honghuang Lin, Yong Qian, Jeffrey R. O'Connell, Maria Pina Concas, Claudia Schurmann, Michele Orini, Joshua C. Bis, Archie Campbell, Susan R. Heckbert, Jie Yao, Eulalia Catamo, Claus Graff, James G. Wilson, Pashupati P. Mishra, Massimo Mangino, Martina Müller-Nurasyid, Borbala Mifsud, Linda Repetto, Stephan B. Felix, Julia Ramirez, Rebecca D. Jackson, Eric Boerwinkle, Monika Stoll, Elsayed Z. Soliman, Maryam Kavousi, David J. Porteous, Nina Mononen, Dan E. Arking, Laura Andreasen, Lorenz Risch, Antonio Luiz Pinho Ribeiro, Pier D. Lambiase, Mika Kähönen, Xia Shen, Kenneth Rice, Eric A. Whitsel, Nona Sotoodehnia, Victor Nauffal, Konstantin Strauch, Jørgen K. Kanters, Henry Völzke, Daniel S. Evans, Jonas L. Isaksen, Alessandro De Grandi, Hao Mei, Alexander P. Reiner, Christy L. Avery, Thiago P. Leal, Alanna C. Morrison, Christian Fuchsberger, M. Arfan Ikram, Moritz Sinner, Yongmei Liu, Bruno H. Stricker, Francesco Cucca, Allan Linneberg, Patricia B. Munroe, Christina Ellervik, Olli T. Raitakari, Melanie Waldenberger, Reem Salman, Xiuqing Guo, Sandosh Padmanabhan, ThuyVy Duong, Dawood Darbar, Stefan Weiss, Arden Moscati, Alvaro Alonso, Cornelia M. van Duijn, Gianfranco Sinagra, Luisa Foco, Matthias Nauck, Kathleen A. Ryan, Kjell Nikus, Gustav Ahlberg, Helen R. Warren, Kent D. Taylor, Niek Verweij, Rebecca Freudling, Cristian Pattaro, Michael Preuss, Charles Kooperberg, Anne Richmond, David Conen, Oliver Hines, Juhani Junttila, Leo-Pekka Lyytikäinen, Nina Hutri-Kähönen, Kirill V. Tarasov, Ulrich Schotten, M. Benjamin Shoemaker, Marten E. van den Berg, Jerome I. Rotter, Michael J. Cutler, Adolfo Correa, Bruce M. Psaty, Caroline Hayward, Yalda Jamshidi, Pau Navarro, J W Benjamins, Patrick T. Ellinor, Massimo Mezzavilla, William J Young, Stefan Kääb, Lars Lind, Antonio De Luca, Heikki V. Huikuri, Marjo-Riitta Järvelin, Guillaume Paré, Stefan van Duijvenboden, Uwe Völker, Maria Fernanda Lima-Costa, Philippe Froguel, Jan A. Kors, Annette Peters, David Schlessinger, Christopher Newton-Cheh, J. Wouter Jukema, Andrew Tinker, Dennis O. Mook-Kanamori, Antoine R Baldassari, Stefanie Aeschbacher, Mariaelisa Graff, Najim Lahrouchi, Henry J. Lin, Giorgia Girotto, Giulia Pelliccione, Jeffrey Haessler, Aaron Isaacs, Rebecca N. Mitchell, Carolina Roselli, Massimiliano Cocca, Sina A. Gharib, Rozenn N. Lemaitre, Raymond Noordam, Morten S. Olesen, Steven A. Lubitz, Jun Ding, May E. Montasser, Jennifer A. Brody, Stella Trompet, Traci M. Bartz, Dania Raza, Thomas Meitinger, Andrew P. Morris, James P. Cook, Sébastien Thériault, Martin Gögele, André G. Uitterlinden, Pim van der Harst, Alan Pittman, Farah Ahmed, Simin Liu, Casia Nursyifa, Paul L. Huang, Kristen K. Patton, and Terho Lehtimäki
Subjects: medicine.medical_specialty, business.industry, Locus (genetics), Atrial fibrillation, medicine.disease, QT interval, Genetic architecture, Sudden cardiac death, QRS complex, Internal medicine, cardiovascular system, medicine, Cardiology, Repolarization, cardiovascular diseases, business, Ventricular depolarization
Abstract: The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
Published: 2021

28. Genome Wide Association Metanalysis Of Skull Bone Mineral Density Identifies Loci Relevant For Osteoporosis And Craniosynostosis

Author: Kun Zhu, Scott Wilson, Prokic I, Stuart H. Ralston, Karasik D, Raimo Joro, Ohlsson C, Andre G. Uitterlinden, Dennis O. Mook-Kanamori, Stykársdóttir U, Gautvik Km, Benjamin H. Mullin, Linda Broer, van Duijn Cm, Pawlak Ma, Struan F.A. Grant, Tim D. Spector, Carol A. Wang, van der Velde N, Shochat-Carvalho C, Richards Jb, Alessandra Chesi, Eric S. Orwoll, Carolina Medina-Gomez, Tarunveer S. Ahluwalia, John P. Walsh, James F. Wilson, John P. Kemp, Katharina E. Schraut, Erika Kague, David M. Evans, Fernando Rivadeneira, Daniel S. Evans, Kari Stefansson, Maria Nethander, Ruifang Li-Gao, van de Peppel J, Cheryl L. Ackert-Bicknell, Evans Te, Klaus Bønnelykke, Katerina Trajanoska, M. A. Ikram, Janine F. Felix, Gudmar Thorleifsson, van Schoor N, Babette S. Zemel, Jonathan H Tobias, Zillikens Mc, Prijatelj, Adams Hh, Maria J. Knol, Mattias Lorentzon, Hans Bisgaard, van der Eerden B, Timo A. Lakka, and Reppe S
Subjects: Bone growth, Genetics, Skull, medicine.anatomical_structure, Craniofacial abnormality, Intramembranous ossification, Osteoporosis, medicine, Genome-wide association study, Craniofacial, Biology, medicine.disease, Craniosynostosis
Abstract: Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of genes important to bone biology in general, and particularly for identifying components unique to intramembranous ossification, which cannot be captured at other skeletal sites. We assessed genetic determinants of SK-BMD in 43,800 individuals, identifying 59 genome-wide significant loci (4 novel), explaining 12.5% of its variance. Pathway and enrichment analyses of the association signals resulted in clustering within gene-sets involved in regulating the development of the skeleton; overexpressed in the musculoskeletal system; and enriched in enhancer and transcribed regions in osteoblasts. From the four novel loci (mapping to ZIC1, PRKAR1A, ATP6V1C1, GLRX3), two (ZIC1 and PRKAR1A) have previously been related to craniofacial developmental defects. Functional validation of skull development in zebrafish revealed abnormal cranial bone initiation that culminated in ectopic sutures and reduced BMD in mutated zic1 and atp6v1c1 fish and asymmetric bone growth and elevated BMD in mutated prkar1a fish. We confirmed a role of ZIC1 loss-of-function in suture patterning and discovered ATP6V1C1 gene associated with suture development. In light of the evidence presented suggesting that SK-BMD is genetically related to craniofacial abnormalities, our study opens new avenues to the understanding of the pathophysiology of craniofacial defects and towards the effective pharmacological treatment of bone diseases.
Published: 2021
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29. A tangled start

Author: Josja A. de Ridder, Dennis O. Mook-Kanamori, Bernet M. Elzinga, Philip Spinhoven, Brenda W.J.H. Penninx, Mona Shahab, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Digital Health
Subjects: Adult, Adolescent, Poison control, Anxiety, Affect (psychology), Young Adult, Childhood maltreatment, Intimate relationships, Anxious attachment, Injury prevention, Developmental and Educational Psychology, medicine, Attachment theory, Humans, Child Abuse, Child, Avoidant attachment, Aged, Alcohol Use Disorders Identification Test, Psychopathology, Alcohol dependence, Mediation, Middle Aged, Anxiety Disorders, Object Attachment, Psychiatry and Mental health, Alcoholism, Pediatrics, Perinatology and Child Health, medicine.symptom, Psychology, Clinical psychology
Abstract: Background: Adults with a history of childhood maltreatment are more likely to experience distrust, feel distant from others, and develop an insecure attachment style which may also affect relationship quality. Furthermore, childhood maltreatment has been linked to several mental health problems; including, depression, anxiety, and alcohol dependance severity, that are also known to relationship quality.Objective: The current study was designed to investigate to what extent childhood maltreatment is associated with adult insecure attachment and intimate relationships and whether this association is mediated by psychopathology.Participants and Method: In a study comprised of 2035 adults aged 18–65, we investigated whether childhood maltreatment was associated with insecure adult attachment styles and the quality of intimate relationships and whether this was mediated by depression, anxiety, and alcohol dependence severity (based on repeated assessments of the Inventory of Depressive Symptomatology-Self Report, Beck Anxiety Index, and Alcohol Use Disorders Identification Test respectively).Results: The path model showed an acceptable fit, RMSEA = 0.05, and suggested full mediation of the association of childhood maltreatment with quality of intimate relationships by depression severity and a) anxious attachment (β = −4.0 ∗ 10−2; 95% CI = −5.5 ∗ 10−2, −2.7 ∗ 10−2) and b) avoidant attachment (β = −7.2 ∗ 10−2; 95% CI = −9.6 ∗ 10−2, −4.9 ∗ 10−2). Anxiety and alcohol dependence severity were not significant mediators. Conclusions: Childhood maltreatment is associated with a lower quality of intimate relationships, which is fully mediated by depression severity and insecure attachment styles.
Published: 2021
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30. Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function

Author: George T. O'Connor, Natalie Terzikhan, Albert V. Smith, Georg Homuth, Nick Shrine, Raymond Noordam, Stephen B. Kritchevsky, Patricia A. Cassano, Matthias Wielscher, Tobias Bonten, Yongmei Liu, Kurt Lohman, Traci M. Bartz, Elizabeth C. Oelsner, John M. Starr, Sarah E. Harris, Ani Manichaikul, Stefan Weiss, Lies Lahousse, Stefan Karrasch, Tianzhong Yang, Josée Dupuis, Alanna C. Morrison, Holger Schulz, Stephen S. Rich, Han Chen, Ian P. Hall, Sven Gläser, Sina A. Gharib, Victoria E. Jackson, Christian Gieger, Kent D. Taylor, Ruifang Li-Gao, Marjo-Riitta Järvelin, Annette Peters, Ralf Ewert, Bruce M. Psaty, Dennis O. Mook-Kanamori, Peng Wei, Ian J. Deary, Guy Brusselle, Jiayi Xu, Claudia Flexeder, Stephanie J. London, R. G. Barr, Colleen M. Sitlani, Martin D. Tobin, and Epidemiology
Subjects: Male, Vital capacity, LOCI, Datasets as Topic, Diseases, Genome-wide association study, Receptors, G-Protein-Coupled, Pulmonary function testing, DESIGN, Risk Factors, Forced Expiratory Volume, Medicine and Health Sciences, Lung, POPULATION, Aged, 80 and over, Genetics, education.field_of_study, Multidisciplinary, Exons, Middle Aged, LUNG-FUNCTION, ENVIRONMENT INTERACTION, Cohort, Medicine, HEART, Female, HEALTH, Adult, Science, Population, Biology, PROFILE, Polymorphism, Single Nucleotide, Article, Cigarette Smoking, Humans, COHORT, GENOME-WIDE ASSOCIATION, education, Gene, Aged, Genetic association, Cyclic Nucleotide Phosphodiesterases, Type 3, Minor allele frequency, Feasibility Studies, Gene-Environment Interaction, FOLLOW-UP, Genome-Wide Association Study
Abstract: Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.
Published: 2021
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31. The association of plasma fatty acids with hand and knee osteoarthritis: the NEO study

Author: R. de Mutsert, Andreea Ioan-Facsinay, Margreet Kloppenburg, Dennis O. Mook-Kanamori, M. Loef, K. Willems van Dijk, and F. R. Rosendaal
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Hand Joints, Population, Biomedical Engineering, Osteoarthritis, Gastroenterology, Fatty Acids, Monounsaturated, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Humans, Knee, Orthopedics and Sports Medicine, education, 030203 arthritis & rheumatology, chemistry.chemical_classification, Meal, education.field_of_study, business.industry, Fatty Acids, food and beverages, Fatty acid, Fasting, Middle Aged, Osteoarthritis, Knee, Hand, Postprandial Period, medicine.disease, Lipids, Logistic Models, 030104 developmental biology, Knee pain, Postprandial, chemistry, Saturated fatty acid, Fatty Acids, Unsaturated, Female, medicine.symptom, business, human activities, Polyunsaturated fatty acid
Abstract: Objective: To investigate the association of postprandial and fasting plasma saturated fatty acid (SFAs), monounsaturated fatty acid (MUFAs) and polyunsaturated fatty acid (PUFAs) concentrations with hand and knee osteoarthritis (OA).Design: In the population-based NEO study clinical hand and knee OA were defined by the ACR classification criteria. Structural knee OA was defined on MRI. Hand and knee pain was determined by Australian/Canadian Hand Osteoarthritis Index (AUSCAN) and KOOS, respectively. Plasma was sampled fasted and 150 min after a standardized meal, and subsequently analysed using a nuclear magnetic resonance platform. Logistic regression analyses were used to investigate the association of total fatty acid, SFA, MUFA, total PUFA, omega-3 PUFA and omega-6 PUFA concentrations with clinical hand and knee OA, structural knee OA and hand and knee pain. Fatty acid concentrations were standardized (mean 0, SD 1). Analyses were stratified by sex and corrected for age, education, ethnicity and total body fat percentage.Results: Of the 5,328 participants (mean age 56 years, 58% women) 7% was classified with hand OA, 10% with knee OA and 4% with concurrent hand and knee OA. In men, postprandial SFAs (OR (95% CI)) 1.23 (1.00; 1.50), total PUFAs 1.26 (1.00; 1.58) and omega-3 PUFAs 1.24 (1.01; 1.52) were associated with hand OA. SFAs and PUFAs were associated with structural, but not clinical knee OA. Association of fasting fatty acid concentrations were weaker than postprandial concentrations.Conclusion: Plasma postprandial SFA and PUFA levels were positively associated with clinical hand and structural knee OA in men, but not in women. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Published: 2020
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32. Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

Author: Michiel L. Bots, Annette Peters, Jennifer A. Brody, Pim van der Harst, Niek Verweij, Torben Hansen, Lu-Chen Weng, Marco V Perez, Honghuang Lin, Nona Sotoodehnia, Katharina Schramm, Dennis O. Mook-Kanamori, Marcus Dörr, Susan R. Heckbert, Henry J. Lin, Jie Yao, Paul L. Huang, Melanie Waldenberger, Bruno H. Stricker, Cornelia M. van Duijn, Jelena Kornej, Kent D. Taylor, Stephan B. Felix, Julia Ramirez, Xiuqing Guo, Peter van der Meer, Patrick T. Ellinor, Emelia J. Benjamin, Amelia W. Hall, Martina Müller-Nurasyid, Steven A. Lubitz, Alexander Teumer, Ilonca Vaartjes, Niels Grarup, Kathryn L. Lunetta, Marten E. van den Berg, Aaron Isaacs, Uwe Völker, Bruce M. Psaty, Jan A. Kors, Alvaro Alonso, Seung Hoan Choi, Rudolf A. de Boer, Allan Linneberg, Sandosh Padmanabhan, Helen R. Warren, Jerome I. Rotter, Nathan A. Bihlmeyer, Man Li, Jeffrey Haessler, Charles Kooperberg, Moritz F. Sinner, Sean J. Jurgens, Folkert W. Asselbergs, Dan E. Arking, Ruifang Li-Gao, Jessica van Setten, Patricia B. Munroe, Jørgen K. Kanters, Stefan Kääb, Fysiologie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Erasmus MC other, Medical Informatics, Internal Medicine, Epidemiology, and Cardiology
Subjects: 0301 basic medicine, PROTEIN, population, 030204 cardiovascular system & hematology, Cardiovascular, Electrocardiography, 0302 clinical medicine, MYH6, Atrial Fibrillation, 2.1 Biological and endogenous factors, Connectin, atrial fibrillation, Aetiology, Exome, MYOSIN HEAVY-CHAIN, RISK, education.field_of_study, NAV1.8 Voltage-Gated Sodium Channel/genetics, Connectin/genetics, Atrial fibrillation, General Medicine, ASSOCIATION, Heart Disease, Duration (music), Cardiology, EXPRESSION, medicine.medical_specialty, HMGA2, Population, INDEXES, Quantitative Trait Loci, Transcription Factors/genetics, Electrophysiology, Genetic, Genome-wide Association Studies, Article, NAV1.8 Voltage-Gated Sodium Channel, 03 medical and health sciences, Myosin Heavy Chains/genetics, Clinical Research, Internal medicine, Cardiac conduction, Cardiac Myosins/genetics, P wave duration, medicine, Genetics, Humans, education, RECURRENCE, Homeodomain Proteins, Myosin Heavy Chains, business.industry, Human Genome, Genetic Variation, medicine.disease, electrophysiology, Atrial Fibrillation/ethnology, 030104 developmental biology, genome-wide association studies, Homeodomain Proteins/genetics, genetic, business, Cardiac Myosins, exome, Transcription Factors, Genome-Wide Association Study
Abstract: Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci ( TTN , CAND2 , SCN10A , PITX2 , CAV1 , SYNPO2L , SOX5 , TBX5, MYH6, RPL3L ). The top variants at known sarcomere genes ( TTN, MYH6 ) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A ) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.
Published: 2020

33. Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration

Author: Sina A. Gharib, Kenneth Rice, Donna K. Arnett, Tõnu Esko, Annemarie I. Luik, Niki Dimou, Dabeeru C. Rao, Pamela J. Schreiner, Melissa A. Richard, Reedik Mägi, Nicholette D. Palmer, Stefan Weiss, Han Chen, Solomon K. Musani, W. James Gauderman, Christian Gieger, Kari E. North, Salman M. Tajuddin, Diana van Heemst, Rainer Rauramaa, Stephen B. Kritchevsky, Henry Völzke, Minjung Kho, Michele K. Evans, Ruth J. F. Loos, Correa Adolfo, Pedro Marques-Vidal, Diane M. Becker, Claude Bouchard, José Haba-Rubio, Georg Homuth, Kurt Lohman, Nora Franceschini, Caizheng Yu, Peter Vollenweider, Ervin F. Fox, Thomas Meitinger, Karen Schwander, Heming Wang, Morris A. Swertz, Aldi T. Kraja, José Eduardo Krieger, Xiuqing Guo, Tangchun Wu, Raymond Noordam, Yongmei Liu, Michael R. Brown, Patrick C.N. Rensen, Annette Peters, Jingmin Liu, Tuomo Rankinen, Robert B. Wallance, Timo A. Lakka, Stephen S. Rich, Yun Ju Sung, Meian He, Till Roenneberg, Wanqing Wen, Dennis O. Mook-Kanamori, M. A. Province, Evangelos Evangelou, L. Adrienne Cupples, Maxime M Bos, Paul S. de Vries, Hans J. Grabe, Lisa R. Yanek, Jiwon Lee, Mario Sims, Bruce M. Psaty, Treva Rice, Tanika N. Kelly, Brenda W.J.H. Penninx, Brigitte Kühnel, Maria E. Graff, Alexandre C. Pereira, Daniel J. Gottlieb, Charles N. Rotimi, Lynne E. Wagenknecht, Ashley van der Spek, Lisa W. Martin, Jeffrey R. O'Connell, Changwei Li, James E. Hixson, Chuan Gao, Alisa K. Manning, Sharon L.R. Kardia, Stella Aslibekyan, Andres Metspalu, Sami Heikkinen, Maris Alver, Xiao-Ou Shu, Amy R. Bentley, Susan Redline, Konstantin Strauch, Tamara B. Harris, Yuri Milaneschi, L.F. Bielak, Marjan Ilkov, Myriam Fornage, Ilja M. Nolte, André G. Uitterlinden, Dina Vojinovic, Hugues Aschard, Paul Elliott, Kent D. Taylor, Najaf Amin, James M. Shikany, Yong-Bing Xiang, Jerome I. Rotter, Vilmundur Gudnason, Cornelia M. van Duijn, Ko Willems van Dijk, Andrea R. V. R. Horimoto, Jonathan Marten, Olli T. Raitakari, Vincent Laville, Pirjo Komulainen, Zhe Wang, Traci M. Bartz, Mary F. Feitosa, Mike A. Nalls, Eric Boerwinkle, Alanna C. Morrison, Melanie Waldenberger, Alexander P. Reiner, Christie M. Ballantyne, Wei Zheng, Raphael Heinzer, M. Arfan Ikram, Colleen M. Sitlani, Lisa de las Fuentes, Patricia B. Munroe, Patricia A. Peyser, Brian E. Cade, Tamar Sofer, Xiaofeng Zhu, Nienke R. Biermasz, Harold Snieder, Elise Lim, Tuomas O. Kilpeläinen, Ching-Ti Liu, Terho Lehtimäki, Thomas W. Winkler, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Stephen Sidney, Alan B. Zonderman, Charles Kooperberg, Leiden University Medical Center (LUMC), Universiteit Leiden, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Universität Regensburg (UR), National Institutes of Health [Bethesda] (NIH), University of Copenhagen = Københavns Universitet (UCPH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), The University of Texas Health Science Center at Houston (UTHealth), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Massachusetts General Hospital [Boston], Harvard T.H. Chan School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), University of Mississippi Medical Center (UMMC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Alabama at Birmingham [ Birmingham] (UAB), University of Washington [Seattle], Universidade de São Paulo Medical School (FMUSP), Icelandic Heart Association [Kopavogur, Iceland] (IHA), University of Michigan [Ann Arbor], University of Michigan System, University of Georgia [USA], School of Public Health [Boston], Boston University [Boston] (BU), Wake Forest University, Pennington Biomedical Research Center, Louisiana State University (LSU), University of Edinburgh, University of Tartu, Imperial College London, University of Ioannina, Huazhong University of Science and Technology [Wuhan] (HUST), Helmholtz Zentrum München = German Research Center for Environmental Health, Fimlab Laboratories [Tampere, Finland], University of Tampere [Finland], Lausanne University Hospital, University of Groningen [Groningen], This project was supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF–6110-00183) and the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848 and NNF15CC0018486). Diana van Heemst was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). Susan Redline was supported in part by NIH R35HL135818 and HL11338., European Project: 602757,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,HUMAN(2013), Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, University of Copenhagen = Københavns Universitet (KU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Helmholtz-Zentrum München (HZM), Van Duijn, CM, Wang, Heming [0000-0002-1486-7495], Bentley, Amy R [0000-0002-0827-9101], Schwander, Karen [0000-0002-0193-4134], Manning, Alisa [0000-0003-0247-902X], Aschard, Hugues [0000-0002-7554-6783], Richard, Melissa [0000-0003-0129-9860], de Las Fuentes, Lisa [0000-0002-4689-325X], Feitosa, Mary [0000-0002-0933-2410], van der Spek, Ashley [0000-0001-7136-0159], Wang, Zhe [0000-0002-8046-4969], Marten, Jonathan [0000-0001-6916-2014], Laville, Vincent [0000-0003-4946-698X], Evangelou, Evangelos [0000-0002-5488-2999], He, Meian [0000-0002-2096-921X], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Marques-Vidal, Pedro [0000-0002-4548-8500], Nolte, Ilja M [0000-0001-5047-4077], Palmer, Nicholette D [0000-0001-8883-2511], Snieder, Harold [0000-0003-1949-2298], Weiss, Stefan [0000-0002-3553-4315], Yanek, Lisa R [0000-0001-7117-1075], Adolfo, Correa [0000-0002-9501-600X], Dimou, Niki [0000-0003-1678-9328], Heikkinen, Sami [0000-0002-6083-2402], Ikram, M Arfan [0000-0003-0372-8585], Krieger, Jose E [0000-0001-5464-1792], Lee, Jiwon [0000-0002-4079-7494], Liu, Jingmin [0000-0003-0001-6013], Martin, Lisa W [0000-0003-4352-0914], Metspalu, Andres [0000-0002-3718-796X], Rensen, Patrick CN [0000-0002-8455-4988], Rich, Stephen S [0000-0003-3872-7793], Rotter, Jerome I [0000-0001-7191-1723], Sofer, Tamar [0000-0001-8520-8860], Taylor, Kent D [0000-0002-2756-4370], Uitterlinden, André G [0000-0002-7276-3387], van Dijk, Ko Willems [0000-0002-2172-7394], Elliott, Paul [0000-0002-7511-5684], Esko, Tõnu [0000-0003-1982-6569], Grabe, Hans J [0000-0003-3684-4208], Zheng, Wei [0000-0003-1226-070X], Bouchard, Claude [0000-0002-0048-491X], Gudnason, Vilmundur [0000-0001-5696-0084], Loos, Ruth JF [0000-0002-8532-5087], Cupples, L Adrienne [0000-0003-0273-7965], Munroe, Patricia B [0000-0002-4176-2947], Liu, Ching-Ti [0000-0002-0703-0742], Apollo - University of Cambridge Repository, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Home Office, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), and UK DRI Ltd
Subjects: Male, 0301 basic medicine, Epidemiology, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Svefnrannsóknir, 0302 clinical medicine, MESH: Aged, 80 and over, Polymorphism (computer science), lcsh:Science, MESH: Phylogeny, Phylogeny, Aged, 80 and over, Genetics, MESH: Aged, [STAT.AP]Statistics [stat]/Applications [stat.AP], Multidisciplinary, MESH: Middle Aged, medicine.diagnostic_test, MESH: Polymorphism, Single Nucleotide, Chromosome Mapping, Middle Aged, Explained variation, Lipids, Sleep in non-human animals, Blóðfita, ddc, 3. Good health, MESH: Young Adult, Female, lipids (amino acids, peptides, and proteins), Erfðarannsóknir, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, Adolescent, MESH: Sleep, Science, Biology, Polymorphism, Single Nucleotide, MESH: Genetic Loci, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Phylogenetics, Svefn, medicine, Humans, SNP, Dyslipidaemias, Aged, MESH: Adolescent, MESH: Humans, Faraldsfræði, PCSK9, MESH: Adult, General Chemistry, MESH: Lipids, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Sleep, Lipid profile, MESH: Chromosome Mapping, MESH: Female, 030217 neurology & neurosurgery
Abstract: Publisher's version (útgefin grein)., Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles., This project was supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF–6110-00183) and the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848 and NNF15CC0018486). Diana van Heemst was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). Susan Redline was supported in part by NIH R35HL135818 and HL11338. Study-specific acknowledgements can be found in the Supplementary Notes 2 and 4. The data on coronary artery disease have been contributed by the Myocardial Infarction Genetics and CARDIoGRAM investigators, and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG.
Published: 2019
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34. Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group

Author: David J. Stott, Christopher J. O'Donnell, Nuno R. Zilhão, Eric A. Whitsel, Fangui Sun, Leslie A. Lange, Xiuqing Guo, Kerri L. Wiggins, Hanfei Xu, Aishwarya Sundaresan, Dennis O. Mook-Kanamori, Christy L. Avery, Albert V. Smith, Xiaohui Li, Til Stürmer, Ayush Giri, Raymond Noordam, Joshua C. Bis, Walter Palmas, Adolfo Correa, Laura M. Raffield, Peter Rossing, Rikki M. Tanner, Tarunveer S. Ahluwalia, James A. Stewart, Helen R. Warren, Jie Yao, Colleen M. Sitlani, Vilmundur Gudnason, Adrienne Cupples, James S. Floyd, Bruce M. Psaty, Jerome I. Rotter, Marguerite R. Irvin, Jacklyn N. Hellwege, Donna K. Arnett, Adriana M. Hung, Ching-Ti Liu, Nita A. Limdi, Stella Trompet, Todd L. Edwards, Lenore J. Launer, J. Wouter Jukema, and Ian Ford
Subjects: Male, Pharmacogenomic Variants, Drug Resistance, Blood Pressure, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular, Logistic regression, DNA Methyltransferase 3A, 0302 clinical medicine, Risk Factors, DNA (Cytosine-5-)-Methyltransferases, 0303 health sciences, blood pressure, Single Nucleotide, Middle Aged, severe hypertension, DNA-Binding Proteins, Europe, Female, medicine.medical_specialty, hypertension, Clinical Sciences, Myosin Type V, Locus (genetics), Single-nucleotide polymorphism, Brief Communication, Polymorphism, Single Nucleotide, Risk Assessment, White People, 03 medical and health sciences, Clinical Research, Internal medicine, Genetics, Internal Medicine, medicine, Humans, Polymorphism, Antihypertensive Agents, Aged, 030304 developmental biology, genome-wide association study, Myosin Heavy Chains, business.industry, Human Genome, Neuropeptides, Odds ratio, United States, Confidence interval, Black or African American, Blood pressure, Cardiovascular System & Hematology, Genetic Loci, Pharmacogenetics, Case-Control Studies, treatment-resistant hypertension, Dystrophin-Associated Proteins, business, Transcription Factors
Abstract: BACKGROUND Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS We conducted a case–control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal ( RESULTS The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10−8) and in the race-combined analysis (P = 1.5 × 10−9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6–0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
Published: 2019
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35. Genome-Wide Association Study on the Early-Phase Insulin Response to a Liquid Mixed Meal: Results From the NEO Study

Author: Frits R. Rosendaal, Ruifang Li-Gao, Ko Willems van Dijk, Astrid van Hylckama Vlieg, Eelco J.P. de Koning, Dennis O. Mook-Kanamori, Françoise Carlotti, Renée de Mutsert, J. Wouter Jukema, and Hubrecht Institute for Developmental Biology and Stem Cell Research
Subjects: Blood Glucose, Male, 0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Genome-wide association study, Type 2 diabetes, Biology, ABO Blood-Group System, 03 medical and health sciences, Endocrinology, 0302 clinical medicine, ABO blood group system, Internal medicine, Insulin Secretion, Internal Medicine, medicine, Humans, Insulin, Glucose homeostasis, Allele, Meals, Aged, Fasting, Middle Aged, Postprandial Period, medicine.disease, Diabetes and Metabolism, Minor allele frequency, 030104 developmental biology, Postprandial, Diabetes Mellitus, Type 2, Female, Genome-Wide Association Study
Abstract: Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm–transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (β: −6.5% [minor allele frequency (MAF) 0.32, P = 3.3 × 10−8]) located in the ABO gene reached genome-wide significant level (P < 5 × 10−8) and was also replicated successfully (β: −7.8% [MAF 0.32, P = 7.2 × 10−5]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic β-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic β-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early-phase insulin secretion.
Published: 2019
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36. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
Subjects: Gerontology, Aging, Far East, Endocrinology, Diabetes and Metabolism, Menopause, Premature, Genome-wide association study, VARIANTS, Primary Ovarian Insufficiency, Inbred C57BL, Bioinformatics, DISEASE, Healthy Aging, genetics of ovarian aging, Fragile X Mental Retardation Protein, Mice, Endocrinology, Medicine, EARLY MENOPAUSE, media_common, RISK, Multidisciplinary, Asia, Eastern, Reproduction, Longevity, Middle Aged, Europe, MENDELIAN RANDOMIZATION, Medical genetics, Female, ICEP, Menopause, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Fertility, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Inbred C57BL, Ovary, Uterus, Type 2, medicine.medical_specialty, media_common.quotation_subject, MEDLINE, Biology, Premature ovarian insufficiency, Article, genome-wide meta-analysis, SDG 3 - Good Health and Well-being, GERMLINE, Diabetes Mellitus, Genetic predisposition, Ovarian reserve, Premature, business.industry, Human genetics, CHROMOSOME SYNAPSIS, DNA-DAMAGE, Ageing, EXPRESSION ANALYSIS, business, MEIOTIC CELL-CYCLE
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.
Published: 2021
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37. Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations

Author: Nicholas J. Wareham, Carol A. Wang, Daniel I. Chasman, Yasmin Mossavar-Rahmani, Jordi Merino, Ruifang Li-Gao, Jessica C. Kiefte-de Jong, Rozenn N. Lemaitre, Paul M. Ridker, Kent D. Taylor, Gina M. Peloso, Achilleas N. Pitsillides, Craig E. Pennell, Wendy H. Oddy, Linda Snetselaar, Kim V.E. Braun, Nathan L. Tintle, Alice H. Lichtenstein, Nita G. Forouhi, James B. Meigs, Alexis C. Wood, M. Arfan Ikram, Fumiaki Imamura, Melanie Guirette, Jason Westra, Jorma Viikari, Frits R. Rosendall, Kristin L. Young, Dennis O. Mook-Kanamori, Renée de Mutsert, Jian'an Luan, Mika Helminen, Dariush Mozaffarian, Jerome I. Rotter, Niina Pitkänen, Danielle E. Haslam, Olli T. Raitakari, Steven Rich, JoAnn E. Manson, Trudy Voortman, Nicola M. McKeown, Mariaelisa Graff, Mohsen Ghanbari, Josée Dupuis, Mark A. Herman, Kari E. North, Terho Lehtimäki, Caren E. Smith, Bruce M. Psaty, Hassan S. Dashti, Samia Mora, Traci M. Bartz, André G. Uitterlinden, Kara A Livingston, Mika Kähönen, Lisa W. Martin, Imamura, Fumiaki [0000-0002-6841-8396], Luan, Jian'an [0000-0003-3137-6337], Forouhi, Nita [0000-0002-5041-248X], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Tampere University, Department of Clinical Physiology and Nuclear Medicine, Clinical Medicine, Tays Research Services, Health Sciences, and Department of Clinical Chemistry
Subjects: 0301 basic medicine, Male, carbohydrates, Cardiovascular, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, genetics, 030212 general & internal medicine, Sugar-Sweetened Beverages, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, General Medicine, Single Nucleotide, Middle Aged, Cholesterol, nutrition, Biochemistry, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, epidemiology, Adult, HDL, Locus (genetics), Polymorphism, Single Nucleotide, 03 medical and health sciences, Meta-Analysis as Topic, Genetics, Humans, triglyceride, Polymorphism, Sugar, Carbohydrate-responsive element-binding protein, Transcription factor, Triglycerides, Triglyceride, Human Genome, Cholesterol, HDL, dyslipidemia, Original Articles, Carbohydrate, 3141 Health care science, stomatognathic diseases, 030104 developmental biology, chemistry, sugars, 3111 Biomedicine
Abstract: Supplemental Digital Content is available in the text., Background: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia. Methods: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake. Results: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16–3.07] mg/dL per allele; P
Published: 2021

38. Urinary oxidized, but not enzymatic vitamin E metabolites are inversely associated with measures of glucose homeostasis in middle-aged healthy individuals

Author: Diana van Heemst, Fleur L. Meulmeester, Nadia Ashrafi, Dennis O. Mook-Kanamori, Frits R. Rosendaal, Kevin Mills, Raymond Noordam, Jiao Luo, Renée de Mutsert, Ko Willems van Dijk, Saskia le Cessie, and Leon G. Martens
Subjects: Blood Glucose, Male, 0301 basic medicine, Metabolite, medicine.medical_treatment, Urine, Critical Care and Intensive Care Medicine, Glucose homeostasis, Body Mass Index, Lipid peroxidation, chemistry.chemical_compound, 0302 clinical medicine, Homeostasis, Vitamin E, Prospective Studies, Netherlands, education.field_of_study, Nutrition and Dietetics, Middle Aged, Healthy Volunteers, Postprandial, Female, Oxidation-Reduction, Vitamin E, Alpha-tocopherol, Glucose homeostasis, Insulin resistance, medicine.medical_specialty, Population, 030209 endocrinology & metabolism, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, Humans, Chromans, education, Aged, 030109 nutrition & dietetics, business.industry, medicine.disease, Cross-Sectional Studies, Endocrinology, chemistry, Linear Models, Alpha-tocopherol, Lipid Peroxidation, Propionates, alpha-Tocopherol, business
Abstract: Background & aims: Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (alpha-tocopherol, alpha-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between alpha-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population. Methods: This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. alpha-TOH metabolites in blood (alpha-TOH and alpha-CEHC-SO3) and urine [sulfate (SO3) and glucuronide (GLU) of both alpha-TLHQ (oxidized) and alpha-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MSeMS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of alpha-TOH metabolites and measures of glucose homeostasis. Results: We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood alpha-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (alpha-TLHQ-SO3/GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher alpha-TLHQ-SO3 was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary alpha-TLHQ to alpha-CEHC ratio as a measure of oxidized-over-enzymatic conversion of alpha-TOH. Conclusion: Higher urinary levels of oxidized alpha-TOH metabolites as well as higher oxidized-to-enzymatic alpha-TOH metabolite ratio, but not circulating alpha-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating alpha-TOH, estimates of the conversion of alpha-TOH might be informative in relation to health and disease. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/
Published: 2021

39. BS8 Genetically-determined serum calcium levels influence markers of ventricular repolarisation: a mendelian randomisation study

Author: Dennis O. Mook-Kanamori, Patricia B. Munroe, Diana van Heemst, William J Young, Pier D. Lambiase, J. Wouter Jukema, Andrew Tinker, Julia Ramirez, Stefan van Duijvenboden, Michele Orini, Helen R. Warren, and Raymond Noordam
Subjects: education.field_of_study, medicine.medical_specialty, biology, business.industry, Population, Serum albumin, chemistry.chemical_element, Genome-wide association study, Calcium, medicine.disease, Sudden cardiac death, QRS complex, chemistry, Internal medicine, biology.protein, Cardiology, Medicine, Risk factor, business, education, Predictive testing
Abstract: Introduction Electrocardiographic (ECG) markers of ventricular depolarisation and repolarisation are associated with an increased risk of arrhythmia and sudden cardiac death. Our prior work indicated lower serum calcium concentrations are associated with longer QT and JT intervals in the general population. Here, we investigate whether serum calcium is a causal risk factor for changes in ECG measures using Mendelian Randomisation (MR). Methods We performed a new genome-wide association study (GWAS) for serum calcium in >300,000 European-ancestry participants from UK-Biobank. Independent lead variants were extracted to be used as instrumental variables (figure 1). Two-sample MR analyses were performed to approximate the causal effect of serum calcium on QT, JT and QRS intervals using an inverse-weighted method in 76,226 UK-Biobank participants with ECG data, not contributing to the serum calcium GWAS. A secondary analysis wase performed using lead variants from a calcium GWAS corrected for serum albumin. Sensitivity analyses were performed using contemporary methods to test for the presence of horizontal pleiotropy. Results 205 independent lead calcium-associated variants were used as instrumental variables for Mendelian Randomisation. A decrease of 0.1 mmol/L genetically-determined serum calcium, was associated with longer QT (3.01ms (95% CI 2.03, 3.99)) and JT (2.89ms (1.91, 3.87)) intervals. A weak association was observed for QRS duration in secondary analyses only (0.39ms (0.08, 0.69)). Results were concordant in all sensitivity analyses. Conclusion These analyses support a causal effect of serum calcium levels on ventricular repolarisation, in a middle-aged population of European-ancestry where serum calcium concentrations are likely stable and chronic. Modulation of calcium concentration may therefore directly influence cardiovascular disease risk. Further research into the effects of serum calcium concentration on arrhythmogenesis is warranted and calcium variants could be considered for inclusion in genetic risk score models for predictive testing. Conflict of Interest None
Published: 2021
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40. Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling

Author: Maik Pietzner, Mohsen Ghanbari, Fredrik Karpe, Nicolien A. van Vliet, P. Eline Slagboom, Dennis O. Mook-Kanamori, Paul Elliott, Kathrin Budde, Jennifer Meessen, Constantinos Christodoulides, J. Wouter Jukema, E. Houtman, Yuri Milaneschi, Ingrid Meulenbelt, Brenda W.J.H. Penninx, Naveed Sattar, Martin Jaeger, Marian Beekman, Stella Trompet, M.M. Bos, Antonius E. van Herwaarden, Romana T. Netea-Maier, Ko Willems van Dijk, Matt J. Neville, Ibrahim Karaman, Fariba Ahmadizar, Simon P. Mooijaart, Rima Mustafa, H. Eka D. Suchiman, Margreet Kloppenburg, Layal Chaker, He Gao, Diana van Heemst, Raymond Noordam, Mihai G. Netea, Robin P. Peeters, Henry Völzke, Abbas Dehghan, Ruifang Li-Gao, Mariska Bot, Carisha S. Thesing, Marina Evangelou, Christian Delles, M. Arfan Ikram, Epidemiology, Internal Medicine, Home Office, Medical Research Council (MRC), Imperial College Healthcare NHS Trust- BRC Funding, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Consortium, BBMRI Metabolomics, Noordam, Raymond [0000-0001-7801-809X], and Apollo - University of Cambridge Repository
Subjects: Male, endocrine system diseases, Thyroid hormones, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Physiology, RATIONALE, Thyrotropin, Disease, 030204 cardiovascular system & hematology, Coronary artery disease, SERUM, 0302 clinical medicine, SUBCLINICAL HYPOTHYROIDISM, DESIGN, THYROID-HORMONES, EPIDEMIOLOGY, Euthyroid, 11 Medical and Health Sciences, 0303 health sciences, medicine.diagnostic_test, Thyroid, OBJECTIVES, General Medicine, Middle Aged, Lipids, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], medicine.anatomical_structure, Cardiovascular Diseases, Cohort, Medicine, Female, HEALTH, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Research Article, Adult, endocrine system, Reference range, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], BBMRI Metabolomics Consortium, 03 medical and health sciences, Young Adult, Medicine, General & Internal, SDG 3 - Good Health and Well-being, General & Internal Medicine, Mendelian randomization, medicine, Humans, Metabolomics, 030304 developmental biology, Aged, Science & Technology, business.industry, Mendelian Randomization Analysis, medicine.disease, Thyroxine, Lipid profile, business
Abstract: Background Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. Methods Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. Results Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99–1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96–1.04; p value 0.59). Conclusions Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk.
Published: 2021
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41. Agreement of aptamer proteomics with standard methods for measuring venous thrombosis biomarkers

Author: Trevor Baglin, Astrid van Hylckama Vlieg, Frits R. Rosendaal, Ko Willems van Dijk, Tariq Faquih, and Dennis O. Mook-Kanamori
Subjects: Oncology, medicine.medical_specialty, Aptamer, Complex disease, aptamers, Thrombophilia, Fibrinogen, Proteomics, proteomics, Internal medicine, medicine, Diseases of the blood and blood-forming organs, immunoassay, business.industry, Brief Report, biomarkers, Hematology, Standard methods, nucleotide, medicine.disease, blood coagulation factors, Venous thrombosis, venous thrombosis, RC633-647.5, business, Venous thromboembolism, medicine.drug
Abstract: Background Venous thromboembolism (VTE) is a complex disease with an incidence rate of about 1 in 1000 per year. Despite the availability of validated biomarkers for VTE, unprovoked events account for 50% of first events. Therefore, emerging high‐throughput proteomics are promising methods for the expansion of VTE biomarkers. One such promising high‐throughput platform is SomaScan, which uses a large library of synthetic oligonucleotide ligands known as aptamers to measure thousands of proteins. Objective The aim of this study was to evaluate the viability of the aptamer‐based SomaScan platform for VTE studies by examining its agreement with standard laboratory methods. Methods We examined the agreement between eight established VTE biomarkers measured by SomaScan and standard laboratory immunoassay and viscosity‐based instruments in 54 individuals (27 cases and 27 controls) from the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism study. We performed the agreement analysis by using a regression model and predicting the estimates and the 95% prediction interval (PI) of the laboratory instrument values using SomaScan values. Results SomaScan measurements exhibited overall poor agreement, particularly for D‐dimer (average fit, 492.7 ng/mL; 95% PI, 110.0‐1998.2) and fibrinogen (average fit, 3.3 g/L; 95% PI, 2.0‐4.7). Conclusion Our results indicate that SomaScan measurement had poor agreement with the standard laboratory measurements. These results may explain why some genome‐wide association studies with VTE proteins measured by SomaScan did not confirm previously identified loci. Therefore, SomaScan should be considered with caution in VTE studies.
Published: 2021

42. The trans-ancestral genomic architecture of glycemic traits

Author: Albertine J. Oldehinkel, Wieland Kiess, Xueling Sim, Norihiro Kato, Philippe Froguel, Astrid van Hylckama Vlieg, Josée Dupuis, Nanette R. Lee, Symen Ligthart, Harry Campbell, Marta E. Alarcón-Riquelme, P. Eline Slagboom, Massimo Mangino, Tian Xie, Niek Verweij, James B. Meigs, Chaolong Wang, Michael Y. Tsai, Erik Ingelsson, Colin N. A. Palmer, Erik B. van den Akker, Fumihiko Matsuda, Rainer Rauramaa, Yi-Cheng Chang, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Sven Bergmann, Ya X. Wang, Ching-Ti Liu, Annette Schürmann, Michael Boehnke, David J. Porteous, Kazuya Setoh, Qibin Qi, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Claire J. Steves, Jun Liu, Leslie A. Lange, Noël P. Burtt, Diana Kuh, Cassandra N. Spracklen, Ken K. Ong, Charumathi Sabanayagam, Jost B. Jonas, Ele Ferrannini, Lawrence J. Beilin, Qing Duan, Blair H. Smith, Isobel D. Stewart, Alexander P. Reiner, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, E. Shyong Tai, Mark I. McCarthy, Anna L. Gloyn, D.I. Boomsma, Dennis Raven, Nicholas J. Timpson, Rona J. Strawbridge, George Dedoussis, Susan Redline, Jaeyoung Hong, Harald Grallert, Jagadish Vangipurapu, Rico Rueedi, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Johannes Waage, Jin Fang Chai, Yii-Der Ida Chen, Graciela E. Delgado, Thibaud S. Boutin, Yang Hai, Yoriko Heianza, Wei Zhao, Andres Metspalu, Tien Yin Wong, Mila Desi Anasanti, Inger Njølstad, Hans Bisgaard, Valeriya Lyssenko, Denis Rybin, Wanqing Wen, Torben Hansen, James F. Wilson, Sameline Grimsgaard, Annette Peters, Michele K. Evans, Damia Noce, Sarah C. Nelson, May E. Montasser, Nan Wang, Geltrude Mingrone, Gudny Eiriksdottir, Nicholas J. Wareham, Fouad Kandeel, Linda S. Adair, Kelvin Lam, Jaana Lindström, Eco J. C. de Geus, Debbie A Lawlor, Sara M. Willems, Xu Lin, Harold Snieder, Matt J. Neville, Naveed Sattar, Chelsea K. Raulerson, Paul M. Ridker, Jer-Yuarn Wu, Weihua Zhang, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Elena Tremoli, Toru Nabika, Jing Hua Zhao, Vilmundur Gudnason, Tao Huang, Robert C. Kaplan, Sohee Han, Mohammad Hadi Zafarmand, Aaron Leong, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Ivana Kolcic, Franco Giulianini, Tao Wang, Lu Qi, Stephan J. L. Bakker, Laura J Corbin, Zoltán Kutalik, Bruna Gigante, Willa A. Hsueh, Peter J. van der Most, Tin Louie, Yujie Wang, Stella Trompet, Fernando Rivideneira, Yasumasa Ohyagi, Lynne E. Wagenknecht, Jerry L. Nadler, Michael Stumvoll, Mark O. Goodarzi, Sahoko Ichihara, Jeffrey R. O'Connell, Tomohiro Katsuya, Giorgio Pistis, Alice Stanton, Sirkka Keinänen-Kiukaanniemi, Momoko Horikoshi, Honglan Li, Tanja G. M. Vrijkotte, Caroline Hayward, Karen L. Mohlke, Carola Marzi, Girish N. Nadkarni, Laura J. Rasmussen-Torvik, Alain G. Bertoni, Andrew R. Wood, Annique Claringbould, Mi Yeong Hwang, Hugh Watkins, Heikki A. Koistinen, Mattias Frånberg, Jani Heikkinen, Elizabeth Selvin, Donald W. Bowden, Abbas Dehghan, Christian Fuchsberger, Audrey Y. Chu, Kent D. Taylor, Katherine A. Kentistou, Johanna Kuusisto, Jingyi Tan, Huaixing Li, Eric Boerwinkle, Catharina A. Hartman, Archie Campbell, Kari E. North, Oluf Pedersen, Sölve Elmståhl, Emil V. R. Appel, Chang-Hsun Hsieh, Dennis O. Mook-Kanamori, Rob M. van Dam, Pontiano Kaleebu, Corri Black, Jennifer A. Brody, Bengt Sennblad, Shaofeng Huo, M. Larissa Avilés-Santa, Ruth J. F. Loos, Patricia B. Munroe, Chien-Hsiun Chen, Liang Sun, Zorayr Arzumanyan, Rebecca Rohde, Yasuharu Tabara, Albert V. Smith, Betina H. Thuesen, Niels Grarup, Jorgen Engmann, Tatijana Zemunik, M. Arfan Ikram, Marit E. Jørgensen, Christian Herder, Ching-Yu Cheng, Serena Sanna, Damiano Baldassarre, Tarunveer S. Ahluwalia, Mark J. Caulfield, Anne Ndungu, Carl D. Langefeld, Lisa R. Yanek, Luigi Ferrucci, Ananda R. Wickremasinghe, Raymond Noordam, Trevor A. Mori, Tom Wilsgaard, Mika Kivimäki, Rita R. Kalyani, Alan B. Zonderman, Veronique Vitart, Patricia A. Peyser, Shuiqing Lai, Richa Saxena, Li-Ching Chang, Karin Leander, Wei Huang, Peter Vollenweider, Tanya M. Teslovich, Ying Wu, Shufa Du, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Stephen C. J. Parker, Tamar Sofer, Winfried März, Sharon L.R. Kardia, Peter K. Joshi, Neil R. Robertson, Anny H. Xiang, Fumihiko Takeuchi, N. Amin, Jouke-Jan Hottenga, Carol A. Wang, Stefan Gustafsson, Jung Ho Gong, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Gonneke Willemsen, Michael A. Province, Aliki-Eleni Farmaki, Segun Fatumo, Antje Körner, Pim van der Harst, Marie Loh, Kei Hang Katie Chan, Gonçalo R. Abecasis, Nicholette D. Palmer, Simin Liu, Ishminder K. Kooner, Javier Gayán, Arne Astrup, Laura J. Scott, Erwin P. Bottinger, Andrew Wong, Inga Prokopenko, Ping An, Markku Laakso, Matthias Blüher, Susan R. Heckbert, Thomas A. Buchanan, Tatsuaki Matsubara, Andrew P. Morris, Brian H. Chen, Kristi Läll, Teresa Tusie, Timo A. Lakka, Jie Yao, Michael Preuss, Teemu Kuulasmaa, Carlos Lorenzo, Stephen S. Rich, Marie Lauzon, Laura M. Raffield, Pankow S. James, Takahisa Kawaguchi, Kathleen A. Ryan, Wei Zheng, Igor Rudan, Thomas Sparsø, Hugoline G. de Haan, Sandosh Padmanabhan, Richard M. Watanabe, Alicia Huerta-Chagoya, Anette P. Gjesing, Andrew A. Hicks, Richard N. Bergman, Mitsuhiro Yokota, Heather M. Stringham, Bruce M. Psaty, Jian'an Luan, Anuj Goel, Eleanor Wheeler, Masahiro Nakatochi, Young-Jin Kim, Xiao-Ou Shu, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Mari Nelis, Adolfo Correa, Jaspal S. Kooner, Michiya Igase, Anubha Mahajan, Peter E. H. Schwarz, Craig E. Pennell, Claudia Schurmann, Xiaoran Chai, Ji Chen, Lori L. Bonnycastle, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Ilja M. Nolte, Gaëlle Marenne, Timothy M. Frayling, Bong-Jo Kim, Kerrin S. Small, Cecilia M. Lindgren, Bernhard O. Böhm, Shih-Yi Lin, Katharina E. Schraut, Cornelia M. van Duijn, Sanghoon Moon, Mark Walker, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Ko Willems van Dijk, Ozren Polasek, W. Craig Johnson, Dermot F. Reilly, Inês Barroso, Anke Tönjes, Manjinder S. Sandhu, Wen B. Wei, Jose C. Florez, Lorraine Southam, Leif Groop, Lawrence F. Bielak, Peter Kovacs, Jianjun Liu, Jouko Saramies, Helen R. Warren, Man Li, Daniel I. Chasman, Eleftheria Zeggini, Xiaoshuai Zhang, Loic Yengo, Shi Jinxiu, Jirong Long, Xiuqing Guo, Meena Kumari, Leslie J. Raffel, Jill M. Norris, Henrik Vestergaard, Jing He, Peter P. Pramstaller, Diana van Heemst, Kevin Sandow, Marjo-Ritta Jarvelin, Carlos A. Aguilar-Salinas, Peitao Wu, Hortensia Moreno-Macías, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Bernardo L. Horta, Heming Wang, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Rozenn N. Lemaitre, Paul R. H. J. Timmers, Timo Saaristo, Jaakko Tuomilehto, Reedik Mägi, Debashree Ray, J. Wouter Jukema, Claudia Langenberg, Marcus E. Kleber, Francis S. Collins, Klaus Bønnelykke, Lenore J. Launer, Arushi Varshney, Anders Hamsten, European Commission, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanger Institute, Wellcome Trust, Marenne, Gaëlle [0000-0002-4363-7170], Varshney, Arushi [0000-0001-9177-9707], Corbin, Laura J [0000-0002-4032-9500], Parker, Stephen CJ [0000-0001-8122-0117], Langenberg, Claudia [0000-0002-5017-7344], Wheeler, Eleanor [0000-0002-8616-6444], Morris, Andrew P [0000-0002-6805-6014], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Lifelines Cohort Study, Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), de Haan, H.G., van den Akker, E., van der Most, P.J., de Geus, EJC, van Dam, R.M., van Heemst, D., van Hylckama Vlieg, A., van Willems van Dijk, K., de Silva, H.J., van der Harst, P., van Duijn, C., Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology, Helsinki University Hospital Area, University of Helsinki, Clinicum, Department of Public Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Physiology, AMS - Musculoskeletal Health, AMS - Tissue Function & Regeneration, APH - Mental Health, Nutrition and Health, APH - Methodology, Epidemiology and Data Science, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Public and occupational health, Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Cardiovascular Centre (CVC)
Subjects: Blood Glucose, Disease risk, Multifactorial Inheritance, Glycated Hemoglobin A, [SDV]Life Sciences [q-bio], Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), LOCI, Genome-wide association study, Type 2 diabetes, VARIANTS, GLUCOSE, Epigenesis, Genetic, chemistry.chemical_compound, 0302 clinical medicine, Mechanisms, WIDE ASSOCIATION, genetics, Gene-expression, HEMOGLOBIN, ComputingMilieux_MISCELLANEOUS, 11 Medical and Health Sciences, GENE-EXPRESSION, Genetics, Genetics & Heredity, 0303 health sciences, INSULIN-RESISTANCE, Genome, Loci, 1184 Genetics, developmental biology, physiology, Variants, ALSPAC, Physical Chromosome Mapping, Life Sciences & Biomedicine, Human, Quantitative Trait Loci, Wide association study, Biology, Quantitative trait locus, Article, White People, diseases, MECHANISMS, Quantitative Trait, 03 medical and health sciences, Insulin resistance, Quantitative Trait, Heritable, SDG 3 - Good Health and Well-being, Genetic, Lifelines Cohort Study, Diabetes mellitus, medicine, Humans, Hemoglobin, Heritable, METAANALYSIS, Alleles, 030304 developmental biology, Genetic association, Glycemic, Glycated Hemoglobin, Science & Technology, Genome, Human, Whites, Gene Expression Profiling, DISEASE RISK, Settore MED/13 - ENDOCRINOLOGIA, Insulin-resistance, 06 Biological Sciences, medicine.disease, Glucose, chemistry, Blood Glucose/genetics, European Continental Ancestry Group/genetics, Genome-Wide Association Study, Glycated Hemoglobin A/metabolism, Multifactorial Inheritance/genetics, Quantitative Trait Loci/genetics, Glycated hemoglobin, 030217 neurology & neurosurgery, Meta analysis, Epigenesis, Developmental Biology
Abstract: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.
Published: 2021
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43. Genetic insights into the biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Daniel I. Chasman, Rehannah Borup, Anne B. Newman, Kristina W. Olsen, Lude Franke, Stefania Bandinelli, Nora Franceschini, Celine M. Vachon, Nicholas J. Timpson, James F. Wilson, Micaella Joaquim, Christa Meisinger, Felix R. Day, Charles Kooperberg, Qin Wang, Pascal Timshel, Dennis O. Mook-Kanamori, Luigi Ferrucci, Jennifer A. Smith, Miriam Dwek, Pascal Guénel, Claus Yding Andersen, Peter A. Fasching, Sven Bergmann, Thomas Meitinger, Nicholas Bowker, Jane L. Tarry-Adkins, Jeremy A. Daniel, Katharina E. Schraut, Mikael Eriksson, Amruta Shrikhande, Jacques E. Rossouw, Amber N. Wilcox, Simon S. Cross, Stasa Stankovic, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Annette Peters, David Schlessinger, Sheila Ulivi, Mònica Ferrer-Roda, Immaculata De Vivo, Michela Traglia, Jessica Tyrrell, Paul R. H. J. Timmers, Rico Rueedi, Ko Willems van Dijk, N. Charlotte Onland-Moret, Doris Stöckl, Anthony J. Swerdlow, Paul M. Ridker, Zoltán Kutalik, Patrick Deelen, Gerardo Heiss, Marie Louise Grøndahl, Alison M. Dunning, Dale R. Nyholt, Nicholas J. Wareham, Reedik Mägi, Stephen J. Chanock, Martina La Bianca, Ozren Polasek, Daniel F. Gudbjartsson, Rebecca D. Jackson, Alison D. Murray, Lynda M. Rose, Hironori Abe, Joanne M. Murabito, Henry Völzke, Daniela Ruggiero, Dorret I. Boomsma, Harald Grallert, Stefania Benonisdottir, Javier Martin Gonzalez, Esther M. John, Natalia Perjakova, Georgia Chenevix-Trench, John R. B. Perry, Jenny Chang-Claude, Archie Campbell, Teresa Nutile, Ellen W. Demerath, Robin N Beaumont, Jouke J. Hottenga, Albert V. Smith, David Karasik, Linda Broer, Raymond Noordam, Wei He, Niclas Håkansson, Catherine E. Aiken, Robert Karlsson, Christopher A. Haiman, Massimo Mangino, Melissa C. Southey, Sharon L.R. Kardia, Nicholas G. Martin, Jodie N. Painter, Peter K. Joshi, Gonneke Willemsen, Lenore J. Launer, Alicja Wolk, Konstantin Strauch, Stig E. Bojesen, Manjeet K. Bolla, Allison W. Kurian, Renée de Mutsert, Joop S.E. Laven, Antonella Mulas, Igor Rudan, Vallari Shukla, Kathyrn L Lunetta, Susan E. Ozanne, Loic Le Marchand, Jenny A. Visser, Gad Rennert, Jennifer A. Brody, Paul D.P. Pharoah, Tune H. Pers, Sara Lindström, Ignasi Roig, Angela Cox, Unnur Þorsteinsdottir, Graham G. Giles, Toshiko Tanaka, Eva Hoffmann, Melissa A. Troester, Claudia Langenberg, Serena Sanna, Julie E. Buring, Anna Pujol, Mike A. Nalls, Kamila Czene, Tõnu Esko, Jian'an Luan, Lili Milani, Iffat Rahman, Sarah E. Medland, Caterina Barbieri, Emil Peter Trane Hertz, Behrooz Z. Alizadeh, David G. Hunter, Sandra Turon, Antonietta Robino, Marina Ciullo, Barbara McKnight, Chunyan He, Bruce H. R. Wolffenbuttel, David R. Weir, Daniela Toniolo, Ulrike Peters, George Davey-Smith, Saleh Shekari, Caroline Hayward, Elinor J. Sawyer, Patrick Sulem, Simin Liu, Tanguy Corre, Susan M. Ring, Peter Kraft, Alexander Teumer, Marjanka K. Schmidt, André G. Uitterlinden, Arto Mannermaa, Kristan J. Aronson, Heiko Becher, John L. Hopper, Alpa V. Patel, Joyce B. J. van Meurs, kConFab Investigators, Hamdi Mbarek, Frits R. Rosendaal, Minouk J. Schoemaker, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Nancy L. Pedersen, Jessica D. Faul, Patrik K. E. Magnusson, Jingmei Li, Christopher G. Scott, Joe Dennis, Genevieve Lachance, Ajuna Azad, Yongmei Liu, Elnaz Naderi, Andrew R. Wood, Yan Huang, Anna Murray, Annique Claringbould, Stephen Burgess, Jose E. Castelao, Brumat Marco, Eco J. C. de Geus, Veronique Vitart, Ken K. Ong, Kari Stefansson, Blair H. Smith, Francesco Cucca, Grant W. Montgomery, Emmanouil Saloustros, Andrés J. López-Contreras, Jonathan Marten, Håkan Olsson, Dale P. Sandler, Alice M. Arnold, Ana Martínez-Marchal, Tim D. Spector, Chloé Sarnowski, John J. Spinelli, Vilmundur Gudnason, Frank B. Hu, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Eric Boerwinkle, Matthias W. Beckmann, Jazib Hussain, Uwe Völker, Peter Vollenweider, Douglas F. Easton, Irene L. Andrulis, Harry Campbell, Manuela Gago-Dominguez, Cari M. Kitahara, Yvonne T. van der Schouw, Eleonora Porcu, Annika Lindblom, Martha S. Linet, Meir J. Stampfer, Eulalia Catamo, Roger L. Milne, Ivana Kolcic, Annelie Augustinsson, Cinzia Sala, Debbie A Lawlor, Cristina Menni, Timothy M. Frayling, Lauren R. Teras, Marek Zygmunt, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Per Hall, Rossella Sorice, Wei Zhao, Andres Metspalu, Katherine S. Ruth, Andrew F. Olshan, Massimo Mezzavilla, Murielle Bochud, and Christian Gieger
Subjects: media_common.quotation_subject, Genetic predisposition, Longevity, Fertility, Disease, Biology, Premature ovarian insufficiency, Bioinformatics, Ovarian reserve, FMR1, Human genetics, media_common
Abstract: Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ∼200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenicFMR1premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Published: 2021
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44. Metabolomics dissection of depression heterogeneity and related cardiometabolic risk

Author: Tahani Alshehri, Richard Dinga, Dennis O. Mook-Kanamori, Brenda W.J.H. Penninx, Frits R. Rosendaal, Saskia le Cessie, Ko Willems van Dijk, Yuri Milaneschi, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: Oncology, medicine.medical_specialty, media_common.quotation_subject, Population, Adipose tissue, Body fat distribution, body mass index, metabolic syndrome, 03 medical and health sciences, Metabolomics, 0302 clinical medicine, Internal medicine, medicine, education, Applied Psychology, Depression (differential diagnoses), media_common, education.field_of_study, business.industry, 220 Statistical Imaging Neuroscience, Appetite, medicine.disease, metabolomics, 030227 psychiatry, Dissection, Psychiatry and Mental health, Cohort, depression, Major depressive disorder, Metabolic syndrome, business, Body mass index, 030217 neurology & neurosurgery
Abstract: BackgroundA recent hypothesis postulates the existence of an ‘immune-metabolic depression’ (IMD) dimension characterized by metabolic dysregulations. Combining data on metabolomics and depressive symptoms, we aimed to identify depressions associated with an increased risk of adverse metabolic alterations.MethodClustering data were from 1094 individuals with major depressive disorder in the last 6 months and measures of 149 metabolites from a 1H-NMR platform and 30 depressive symptoms (IDS-SR30). Canonical correlation analyses (CCA) were used to identify main independent metabolite-symptom axes of variance. Then, for the replication, we examined the association of the identified dimensions with metabolites from the same platform and cardiometabolic diseases in an independent population-based cohort (n = 6572).ResultsCCA identified an overall depression dimension and a dimension resembling IMD, in which symptoms such as sleeping too much, increased appetite, and low energy level had higher relative loading. In the independent sample, the overall depression dimension was associated with lower cardiometabolic risk, such as (i.e. per s.d.) HOMA-1B −0.06 (95% CI −0.09 – −0.04), and visceral adipose tissue −0.10 cm2 (95% CI −0.14 – −0.07). In contrast, the IMD dimension was associated with well-known cardiometabolic diseases such as higher visceral adipose tissue 0.08 cm2 (95% CI 0.04–0.12), HOMA-1B 0.06 (95% CI 0.04–0.09), and lower HDL-cholesterol levels −0.03 mmol/L (95% CI −0.05 – −0.01).ConclusionsCombining metabolomics and clinical symptoms we identified a replicable depression dimension associated with adverse metabolic alterations, in line with the IMD hypothesis. Patients with IMD may be at higher cardiometabolic risk and may benefit from specific treatment targeting underlying metabolic dysregulations.
Published: 2021
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45. Genetically-Determined Serum Calcium Levels and Markers of Ventricular Repolarisation: A Mendelian Randomization Study in the UK Biobank

Author: William J Young, Patricia B. Munroe, Helen R. Warren, Diana van Heemst, Stefan van Duijvenboden, J. Wouter Jukema, Andrew Tinker, Dennis O. Mook-Kanamori, Pier D. Lambiase, Raymond Noordam, Julia Ramirez, and Michele Orini
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Ventricular Repolarization, electrocardiography, chemistry.chemical_element, electrolyte, 030204 cardiovascular system & hematology, Calcium, Sudden cardiac death, 03 medical and health sciences, action potential, 0302 clinical medicine, Internal medicine, Mendelian randomization, Humans, Medicine, Repolarization, Aged, calcium, medicine.diagnostic_test, business.industry, Original Articles, General Medicine, Mendelian Randomization Analysis, Middle Aged, medicine.disease, Biobank, United Kingdom, cardiovascular diseases, 3. Good health, Long QT Syndrome, 030104 developmental biology, Increased risk, chemistry, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Cardiology, Female, business, Electrocardiography
Abstract: Supplemental Digital Content is available in the text., Background: ECG markers of ventricular depolarization and repolarization are associated with an increased risk of arrhythmia and sudden cardiac death. Our prior work indicated lower serum calcium concentrations are associated with longer QT and JT intervals in the general population. Here, we investigate whether serum calcium is a causal risk factor for changes in ECG measures using Mendelian randomization (MR). Methods: Independent lead variants from a newly performed genome-wide association study for serum calcium in >300 000 European-ancestry participants from UK Biobank were used as instrumental variables. Two-sample MR analyses were performed to approximate the causal effect of serum calcium on QT, JT, and QRS intervals using an inverse-weighted method in 76 226 participants not contributing to the serum calcium genome-wide association study. Sensitivity analyses including MR-Egger, weighted-median estimator, and MR pleiotropy residual sum and outlier were performed to test for the presence of horizontal pleiotropy. Results: Two hundred five independent lead calcium-associated variants were used as instrumental variables for MR. A decrease of 0.1 mmol/L serum calcium was associated with longer QT (3.01 ms [95% CI, 2.03 to 3.99]) and JT (2.89 ms [1.91 to 3.87]) intervals. A weak association was observed for QRS duration (secondary analyses only). Results were concordant in all sensitivity analyses. Conclusions: These analyses support a causal effect of serum calcium levels on ventricular repolarization, in a middle-aged population of European-ancestry where serum calcium concentrations are likely stable and chronic. Modulation of calcium concentration may, therefore, directly influence cardiovascular disease risk.
Published: 2021
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46. Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Author: Daniel I. Chasman, Torben Hansen, Rebecca S. Fine, Kari E. North, Harald Grallert, Jeffrey Haesser, Jie Yao, Arund D. Pradhan, Peter Kovacs, Mariaelisa Graff, Rebecca D. Jackson, Zoltán Kutalik, James G. Wilson, Neil Robertson, Mika Kähönen, Linda S. Adair, Jennifer Kriebel, Ruth J. F. Loos, Massimo Mangino, Jayne F. Martin Carli, Yiying Zhang, M. Arfan Ikram, Paraskevi Christofidou, Linda Broer, Paul M. Ridker, Barbara McKnight, Satu Männistö, Sophia Metz, Tea Skaaby, Jette Bork-Jensen, Craig E. Pennell, Sophie Molnos, Michael A. Province, Xiuqing Guo, Laura B. L. Wittemans, Stephen J. Lye, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Tim Kacprowski, America A. Sandoval-Zárate, Hermina Jakupović, Tuomas O. Kilpeläinen, Michael Preuss, Jaeyoung Hong, Cristina Venturini, Ying Wu, Germán D. Carrasquilla, Ivana Prokic, Mary F. Feitosa, Melissa E. Garcia, Paul L. Auer, Leslie A. Lange, Leo-Pekka Lyytikäinen, Kristin L. Young, Tugce Karaderi, Alexander P. Reiner, Tim D. Spector, Anubha Mahajan, Claudia Schurmann, Jerome I. Rotter, Rudolph L. Leibel, Georg Homuth, Claudia A. Doege, Hakon Hakonarson, Nicholas J. Wareham, Najaf Amin, Shuai Wang, Matthias Blüher, Ayse Demirkan, Andrew P. Morris, Charles A. LeDuc, Claudia Langenberg, Hanieh Yaghootkar, Mike A. Nalls, Erik Ingelsson, Dennis O. Mook-Kanamori, Jorge R. Kizer, Carolina Medina-Gomez, Timothy M. Frayling, Colleen M. Sitlani, David A. Mackey, Bruce M. Psaty, Matthias Nauck, Struan F.A. Grant, Konstantin Strauch, Olli T. Raitakari, Alexander Teumer, Mark Walker, Jonathan P. Bradfield, Judith B. Borja, Karen L. Mohlke, Lars Lind, André G. Uitterlinden, Renée de Mutsert, Ruifang Li-Gao, Cassandra N. Spracklen, Jin Li, Anne E. Justice, Cecilia M. Lindgren, Kaiying Guo, Terho Lehtimäki, Pekka Jousilahti, Yingchang Lu, Yii-Der Ida Chen, Sara M. Willems, Tamara B. Harris, Matthew A. Allison, Carol A. Wang, Niels Grarup, Lam Opal Huang, Veikko Salomaa, Jian'an Luan, Robert A. Scott, Kent D. Taylor, James B. Meigs, Ophthalmology, Epidemiology, Internal Medicine, Clinical Genetics, Department of Organisation and Personnel Management, Health Services Management & Organisation (HSMO), Yaghootkar, Hanieh [0000-0001-9672-9477], Kilpeläinen, Tuomas O [0000-0002-8349-3028], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Leptin, Models, Molecular, medicine.medical_specialty, Genotype, Protein Conformation, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Genome-wide association study, KLF14, Biology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Missense mutation, Humans, Allele, Exome, Adiposity, 2. Zero hunger, Racial Groups, digestive, oral, and skin physiology, Gene Expression Regulation, Developmental, Genetic Variation, Genetics/Genomes/Proteomics/Metabolomics, medicine.disease, Obesity, 030104 developmental biology, Endocrinology, hormones, hormone substitutes, and hormone antagonists
Abstract: Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10-16, n=3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.
Published: 2020

47. On-site rapid molecular testing, mobile sampling teams and eHealth to support primary care physicians during the COVID-19 pandemic

Author: R.W. Jansen, S. Kiani deh Kiani, L. Janssens, B.C. Mourik, Mariet C.W. Feltkamp, Stefan A. Boers, Aloys C.M. Kroes, Dennis O. Mook-Kanamori, and N.N. Cheung
Subjects: GeneXpert MTB/RIF, Coronavirus disease 2019 (COVID-19), Referral, business.industry, Pandemic, medicine, eHealth, Sampling (statistics), Medical emergency, medicine.disease, business, Turnaround time, Test (assessment)
Abstract: ObjectivesWe evaluated the effects of on-site rapid molecular testing at a drive-through sampling facility, deployment of mobile sampling teams and implementation of an online eHealth platform as supportive measures for general practitioners (GPs) during the COVID-19 pandemic.MethodsAn eHealth platform was developed that allowed GPs to either refer patients to a drive-through sampling facility or to request a home visit by a sampling team. Nasopharyngeal swab samples from patients marked as urgent (n=333) were tested immediately on-site using a GeneXpert System. Non-urgent samples (n=1,460) were sent once a day to a university hospital laboratory for routine testing. Time stamps starting from referral to the moment of test report sent were recorded to calculate the turnaround time.ResultsThe eHealth platform was rapidly adopted and used by a total of 517 GPs to test 1,793 patients in a period of 13 weeks. On-site rapid molecular testing reduced the median turnaround time to 03h:41m compared to 29h:15m for routine testing. Positive SARS-CoV-2 test results were identified amongst 84/1,477 (5.7%) and 33/316 (10.4%) patients sampled at the drive-through or at home, respectively. In the age category of >80 years, 80.4% of patients were tested by a mobile sampling team.ConclusionsThe combination of rapid molecular testing and eHealth reduced the time between referral and results sent back to the GP to less than four hours. In addition, mobile sampling teams helped in reaching non-mobile, elderly patient populations with a higher prevalence of COVID-19.
Published: 2020
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48. A Workflow for Missing Values Imputation of Untargeted Metabolomics Data

Author: Diana van Heemst, Gabi Kastenmüller, Saskia le Cessie, Jiao Luo, Frits R. Rosendaal, Ko Willems van Dijk, Dennis O. Mook-Kanamori, Raymond Noordam, Maarten van Smeden, Jan Krumsiek, Tariq Faquih, and Astrid van Hylckama Vlieg
Subjects: 0301 basic medicine, Multivariate statistics, Imputation, K-nearest Neighbors, Metabolon, Multiple Imputation Using Chained Equations, Simulation, Untargeted Metabolomics, Workflow, workflow, Endocrinology, Diabetes and Metabolism, lcsh:QR1-502, imputation, 01 natural sciences, Biochemistry, Article, lcsh:Microbiology, metabolon, Correlation, 010104 statistics & probability, 03 medical and health sciences, Metabolomics, Statistics, Imputation (statistics), 0101 mathematics, Molecular Biology, Mathematics, k-nearest neighbors, Missing data, simulation, untargeted metabolomics, multiple imputation using chained equations, 030104 developmental biology, Untargeted metabolomics, Sample size determination
Abstract: Metabolomics studies have seen a steady growth due to the development and implementation of affordable and high-quality metabolomics platforms. In large metabolite panels, measurement values are frequently missing and, if neglected or sub-optimally imputed, can cause biased study results. We provided a publicly available, user-friendly R script to streamline the imputation of missing endogenous, unannotated, and xenobiotic metabolites. We evaluated the multivariate imputation by chained equations (MICE) and k-nearest neighbors (kNN) analyses implemented in our script by simulations using measured metabolites data from the Netherlands Epidemiology of Obesity (NEO) study (n = 599). We simulated missing values in four unique metabolites from different pathways with different correlation structures in three sample sizes (599, 150, 50) with three missing percentages (15%, 30%, 60%), and using two missing mechanisms (completely at random and not at random). Based on the simulations, we found that for MICE, larger sample size was the primary factor decreasing bias and error. For kNN, the primary factor reducing bias and error was the metabolite correlation with its predictor metabolites. MICE provided consistently higher performance measures particularly for larger datasets (n &gt, 50). In conclusion, we presented an imputation workflow in a publicly available R script to impute untargeted metabolomics data. Our simulations provided insight into the effects of sample size, percentage missing, and correlation structure on the accuracy of the two imputation methods.
Published: 2020

49. Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author: Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie CY Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian’an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, null FinnGen, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin NA Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I McCarthy, and Andrew P Morris
Subjects: 0303 health sciences, Transferability, Translation (biology), Type 2 diabetes, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Global health, medicine, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.
Published: 2020
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50. Cholesteryl Ester Transfer Protein as a Drug Target for Cardiovascular Disease

Author: Dennis O. Mook-Kanamori, Nora Franceschini, Jackie F. Price, Pimphen Charoen, Reecha Sofat, Amand F. Schmidt, Alun D. Hughes, Aroon D. Hingorani, Nicholas B Hunt, María Gordillo-Marañón, Mika Kivimäki, Goya Wannamethee, Juan-Pablo Casas, Andrew Wong, Claudia Giambartolomei, Magdalena Zwierzyna, Debbie A Lawlor, Olia Papacosta, Joshua C. Bis, Tom R. Gaunt, Nishi Chaturvedi, Chris Finan, Fotios Drenos, and Christopher J. O'Donnell
Subjects: biology, business.industry, Dalcetrapib, Torcetrapib, Pharmacology, chemistry.chemical_compound, chemistry, Drug development, Anacetrapib, Mendelian randomization, Cholesterylester transfer protein, biology.protein, Medicine, business, CETP inhibitor, Evacetrapib
Abstract: Drug development of cholesteryl ester transfer protein (CETP) inhibition to prevent coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and Mendelian randomization (MR) results. Findings from meta-analyses of CETP inhibitor trials (≥ 24 weeks follow-up) were used to judge between-compound heterogeneity in treatment effects. Genetic data were extracted on 190+ pharmacologically relevant outcomes; spanning 480,698-21,770 samples and 74,124-4,373 events. Drug target MR of protein concentration was used to determine the on-target effects of CETP inhibition and compared to that of PCSK9 modulation. Fifteen eligible CETP inhibitor trials of four compounds were identified, enrolling 79,961 participants. There was a high degree of heterogeneity in effects on lipids, lipoproteins, blood pressure, and clinical events. For example, dalcetrapib and evacetrapib showed a neutral effect, torcetrapib increased, and anacetrapib decreased cardiovascular disease (CVD); heterogeneity p-value < 0.001. In drug target MR analysis, lower CETP concentration (per μg/ml) was associated with CHD (odds ratio 0.95; 95%CI 0.91; 0.99), heart failure (0.95; 95%CI 0.92; 0.99), chronic kidney disease (0.94 95%CI 0.91; 0.98), and age-related macular degeneration (1.69; 95%CI 1.44; 1.99). Lower PCSK9 concentration was associated with a lower risk of CHD, heart failure, atrial fibrillation and stroke, and increased risk of Alzheimer’s disease and asthma. In conclusion, previous failures of CETP inhibitors are likely compound related. CETP inhibition is expected to reduce risk of CHD, heart failure, and kidney disease, but potentially increase risk of age-related macular disease.
Published: 2020
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