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1. Association between long-term use of calcium channel blockers (CCB) and the risk of breast cancer: a retrospective longitudinal observational study protocol

Author

Christopher M Reid, Rachael Moorin, Sallie-Anne Pearson, Max K Bulsara, David B Preen, Gita Mishra, David Youens, Jeffery David Hughes, Ninh Thi Ha, Bruno H Stricker, Rikje Ruiter, Cameron Wright, Chau Ho, Walter P Abhayaratna, Christobel M Saunders, and Frank J A van Rooij

Subjects
Medicine
Abstract

Introduction Calcium channel blockers (CCB), a commonly prescribed antihypertensive (AHT) medicine, may be associated with increased risk of breast cancer. The proposed study aims to examine whether long-term CCB use is associated with the development of breast cancer and to characterise the dose–response nature of any identified association, to inform future hypertension management.Methods and analysis The study will use data from 2 of Australia’s largest cohort studies; the Australian Longitudinal Study on Women’s Health, and the 45 and Up Study, combined with the Rotterdam Study. Eligible women will be those with diagnosed hypertension, no history of breast cancer and no prior CCB use at start of follow-up (2004–2009). Cumulative dose-duration exposure to CCB and other AHT medicines will be captured at the earliest date of: the outcome (a diagnosis of invasive breast cancer); a competing risk event (eg, bilateral mastectomy without a diagnosis of breast cancer, death prior to any diagnosis of breast cancer) or end of follow-up (censoring event). Fine and Gray competing risks regression will be used to assess the association between CCB use and development of breast cancer using a generalised propensity score to adjust for baseline covariates. Time-varying covariates related to interaction with health services will also be included in the model. Data will be harmonised across cohorts to achieve identical protocols and a two-step random effects individual patient-level meta-analysis will be used.Ethics and dissemination Ethical approval was obtained from the following Human research Ethics Committees: Curtin University (ref No. HRE2022-0335), NSW Population and Health Services Research Ethics Committee (2022/ETH01392/2022.31), ACT Research Ethics and Governance Office approval under National Mutual Acceptance for multijurisdictional data linkage research (2022.STE.00208). Results of the proposed study will be published in high-impact journals and presented at key scientific meetings.Trial registration number NCT05972785.

Published
2024
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2. Associations of autozygosity with a broad range of human phenotypes

Author

David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O’connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J. C. Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K. E. Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J. F. Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R. B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, and James F Wilson

Subjects
Science
Abstract

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Published
2019
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3. Meta-GWAS Accuracy and Power (MetaGAP) Calculator Shows that Hiding Heritability Is Partially Due to Imperfect Genetic Correlations across Studies.

Author

Ronald de Vlaming, Aysu Okbay, Cornelius A Rietveld, Magnus Johannesson, Patrik K E Magnusson, André G Uitterlinden, Frank J A van Rooij, Albert Hofman, Patrick J F Groenen, A Roy Thurik, and Philipp D Koellinger

Subjects
Genetics, QH426-470
Abstract

Large-scale genome-wide association results are typically obtained from a fixed-effects meta-analysis of GWAS summary statistics from multiple studies spanning different regions and/or time periods. This approach averages the estimated effects of genetic variants across studies. In case genetic effects are heterogeneous across studies, the statistical power of a GWAS and the predictive accuracy of polygenic scores are attenuated, contributing to the so-called 'missing heritability'. Here, we describe the online Meta-GWAS Accuracy and Power (MetaGAP) calculator (available at www.devlaming.eu) which quantifies this attenuation based on a novel multi-study framework. By means of simulation studies, we show that under a wide range of genetic architectures, the statistical power and predictive accuracy provided by this calculator are accurate. We compare the predictions from the MetaGAP calculator with actual results obtained in the GWAS literature. Specifically, we use genomic-relatedness-matrix restricted maximum likelihood to estimate the SNP heritability and cross-study genetic correlation of height, BMI, years of education, and self-rated health in three large samples. These estimates are used as input parameters for the MetaGAP calculator. Results from the calculator suggest that cross-study heterogeneity has led to attenuation of statistical power and predictive accuracy in recent large-scale GWAS efforts on these traits (e.g., for years of education, we estimate a relative loss of 51-62% in the number of genome-wide significant loci and a relative loss in polygenic score R2 of 36-38%). Hence, cross-study heterogeneity contributes to the missing heritability.

Published
2017
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4. Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts.

Author

Dariush Mozaffarian, Hassan S Dashti, Mary K Wojczynski, Audrey Y Chu, Jennifer A Nettleton, Satu Männistö, Kati Kristiansson, Mägi Reedik, Jari Lahti, Denise K Houston, Marilyn C Cornelis, Frank J A van Rooij, Maria Dimitriou, Stavroula Kanoni, Vera Mikkilä, Lyn M Steffen, Marcia C de Oliveira Otto, Lu Qi, Bruce Psaty, Luc Djousse, Jerome I Rotter, Kennet Harald, Markus Perola, Harri Rissanen, Antti Jula, Fischer Krista, Evelin Mihailov, Mary F Feitosa, Julius S Ngwa, Luting Xue, Paul F Jacques, Mia-Maria Perälä, Aarno Palotie, Yongmei Liu, Nike A Nalls, Luigi Ferrucci, Dena Hernandez, Ani Manichaikul, Michael Y Tsai, Jessica C Kiefte-de Jong, Albert Hofman, André G Uitterlinden, Loukianos Rallidis, Paul M Ridker, Lynda M Rose, Julie E Buring, Terho Lehtimäki, Mika Kähönen, Jorma Viikari, Rozenn Lemaitre, Veikko Salomaa, Paul Knekt, Andres Metspalu, Ingrid B Borecki, L Adrienne Cupples, Johan G Eriksson, Stephen B Kritchevsky, Stefania Bandinelli, David Siscovick, Oscar H Franco, Panos Deloukas, George Dedoussis, Daniel I Chasman, Olli Raitakari, and Toshiko Tanaka

Subjects
Medicine, Science
Abstract

BACKGROUND:Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences. OBJECTIVE:To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption. DESIGN:We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts. RESULTS:Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA. CONCLUSIONS:These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.

Published
2017
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5. The molecular genetic architecture of self-employment.

Author

Matthijs J H M van der Loos, Cornelius A Rietveld, Niina Eklund, Philipp D Koellinger, Fernando Rivadeneira, Gonçalo R Abecasis, Georgina A Ankra-Badu, Sebastian E Baumeister, Daniel J Benjamin, Reiner Biffar, Stefan Blankenberg, Dorret I Boomsma, David Cesarini, Francesco Cucca, Eco J C de Geus, George Dedoussis, Panos Deloukas, Maria Dimitriou, Guðny Eiriksdottir, Johan Eriksson, Christian Gieger, Vilmundur Gudnason, Birgit Höhne, Rolf Holle, Jouke-Jan Hottenga, Aaron Isaacs, Marjo-Riitta Järvelin, Magnus Johannesson, Marika Kaakinen, Mika Kähönen, Stavroula Kanoni, Maarit A Laaksonen, Jari Lahti, Lenore J Launer, Terho Lehtimäki, Marisa Loitfelder, Patrik K E Magnusson, Silvia Naitza, Ben A Oostra, Markus Perola, Katja Petrovic, Lydia Quaye, Olli Raitakari, Samuli Ripatti, Paul Scheet, David Schlessinger, Carsten O Schmidt, Helena Schmidt, Reinhold Schmidt, Andrea Senft, Albert V Smith, Timothy D Spector, Ida Surakka, Rauli Svento, Antonio Terracciano, Emmi Tikkanen, Cornelia M van Duijn, Jorma Viikari, Henry Völzke, H-Erich Wichmann, Philipp S Wild, Sara M Willems, Gonneke Willemsen, Frank J A van Rooij, Patrick J F Groenen, André G Uitterlinden, Albert Hofman, and A Roy Thurik

Subjects
Medicine, Science
Abstract

Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (σ(g)(2)/σ(P)(2) = 25%, h(2) = 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p

Published
2013
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6. Serum uric acid and chronic kidney disease: the role of hypertension.

Author

Sanaz Sedaghat, Ewout J Hoorn, Frank J A van Rooij, Albert Hofman, Oscar H Franco, Jacqueline C M Witteman, and Abbas Dehghan

Subjects
Medicine, Science
Abstract

BackgroundThere are inconsistent findings on the role of hyperuricemia as an independent risk factor for chronic kidney disease (CKD). Hypertension has been implicated as a factor influencing the association between serum uric acid and CKD. In this population-based study we investigated the association between serum uric acid and decline in renal function and tested whether hypertension moderates this association.MethodsWe included 2601 subjects aged 55 years and over from the Rotterdam Study. Serum uric acid and estimated glomerular filtration rate (eGFR) were assessed at baseline. After average 6.5 years of follow-up, second eGFR was assessed. CKD was defined as eGFRResultsEach unit (mg/dL) increase in serum uric acid was associated with 0.19 ml/min per 1.73 m(2) faster annual decline in eGFR. While the association between serum uric acid and incidence of CKD was not significant in our study population (Hazard Ratio: 1.12, 95% confidence interval [CI]: 0.98-1.28), incorporating our results in a meta-analysis with eleven published studies revealed a significant association (Relative Risk: 1.18, 95%CI: 1.15-1.22). In the stratified analyses, we observed that the associations of serum uric acid with eGFR decline and incident CKD were stronger in hypertensive subjects (P for interaction = 0.046 and 0.024, respectively).ConclusionsOur findings suggest that hyperuricemia is independently associated with a decline in renal function. Stronger association in hypertensive individuals may indicate that hypertension mediates the association between serum uric acid and CKD.

Published
2013
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7. Multiple loci are associated with white blood cell phenotypes.

Author

Michael A Nalls, David J Couper, Toshiko Tanaka, Frank J A van Rooij, Ming-Huei Chen, Albert V Smith, Daniela Toniolo, Neil A Zakai, Qiong Yang, Andreas Greinacher, Andrew R Wood, Melissa Garcia, Paolo Gasparini, Yongmei Liu, Thomas Lumley, Aaron R Folsom, Alex P Reiner, Christian Gieger, Vasiliki Lagou, Janine F Felix, Henry Völzke, Natalia A Gouskova, Alessandro Biffi, Angela Döring, Uwe Völker, Sean Chong, Kerri L Wiggins, Augusto Rendon, Abbas Dehghan, Matt Moore, Kent Taylor, James G Wilson, Guillaume Lettre, Albert Hofman, Joshua C Bis, Nicola Pirastu, Caroline S Fox, Christa Meisinger, Jennifer Sambrook, Sampath Arepalli, Matthias Nauck, Holger Prokisch, Jonathan Stephens, Nicole L Glazer, L Adrienne Cupples, Yukinori Okada, Atsushi Takahashi, Yoichiro Kamatani, Koichi Matsuda, Tatsuhiko Tsunoda, Toshihiro Tanaka, Michiaki Kubo, Yusuke Nakamura, Kazuhiko Yamamoto, Naoyuki Kamatani, Michael Stumvoll, Anke Tönjes, Inga Prokopenko, Thomas Illig, Kushang V Patel, Stephen F Garner, Brigitte Kuhnel, Massimo Mangino, Ben A Oostra, Swee Lay Thein, Josef Coresh, H-Erich Wichmann, Stephan Menzel, JingPing Lin, Giorgio Pistis, André G Uitterlinden, Tim D Spector, Alexander Teumer, Gudny Eiriksdottir, Vilmundur Gudnason, Stefania Bandinelli, Timothy M Frayling, Aravinda Chakravarti, Cornelia M van Duijn, David Melzer, Willem H Ouwehand, Daniel Levy, Eric Boerwinkle, Andrew B Singleton, Dena G Hernandez, Dan L Longo, Nicole Soranzo, Jacqueline C M Witteman, Bruce M Psaty, Luigi Ferrucci, Tamara B Harris, Christopher J O'Donnell, and Santhi K Ganesh

Subjects
Genetics, QH426-470
Abstract

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

Published
2011
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8. Identification of nine novel loci associated with white blood cell subtypes in a Japanese population.

Author

Yukinori Okada, Tomomitsu Hirota, Yoichiro Kamatani, Atsushi Takahashi, Hiroko Ohmiya, Natsuhiko Kumasaka, Koichiro Higasa, Yumi Yamaguchi-Kabata, Naoya Hosono, Michael A Nalls, Ming Huei Chen, Frank J A van Rooij, Albert V Smith, Toshiko Tanaka, David J Couper, Neil A Zakai, Luigi Ferrucci, Dan L Longo, Dena G Hernandez, Jacqueline C M Witteman, Tamara B Harris, Christopher J O'Donnell, Santhi K Ganesh, Koichi Matsuda, Tatsuhiko Tsunoda, Toshihiro Tanaka, Michiaki Kubo, Yusuke Nakamura, Mayumi Tamari, Kazuhiko Yamamoto, and Naoyuki Kamatani

Subjects
Genetics, QH426-470
Abstract

White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P

Published
2011
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9. Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels.

Author

Tamra E Meyer, Germaine C Verwoert, Shih-Jen Hwang, Nicole L Glazer, Albert V Smith, Frank J A van Rooij, Georg B Ehret, Eric Boerwinkle, Janine F Felix, Tennille S Leak, Tamara B Harris, Qiong Yang, Abbas Dehghan, Thor Aspelund, Ronit Katz, Georg Homuth, Thomas Kocher, Rainer Rettig, Janina S Ried, Christian Gieger, Hanna Prucha, Arne Pfeufer, Thomas Meitinger, Josef Coresh, Albert Hofman, Mark J Sarnak, Yii-Der Ida Chen, André G Uitterlinden, Aravinda Chakravarti, Bruce M Psaty, Cornelia M van Duijn, W H Linda Kao, Jacqueline C M Witteman, Vilmundur Gudnason, David S Siscovick, Caroline S Fox, Anna Köttgen, Genetic Factors for Osteoporosis Consortium, and Meta Analysis of Glucose and Insulin Related Traits Consortium

Subjects
Genetics, QH426-470
Abstract

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p

Published
2010
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10. Common and Rare Variants Genetic Association Analysis of Circulating Neutrophil Extracellular Traps

Author

Samantha J. Donkel, Eliana Portilla Fernández, Shahzad Ahmad, Fernando Rivadeneira, Frank J. A. van Rooij, M. Arfan Ikram, Frank W. G. Leebeek, Moniek P. M. de Maat, and Mohsen Ghanbari

Subjects
genome-wide association studies, genetics, exome sequencing, neutrophil extracellular traps, NETs, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionNeutrophils contribute to host defense through different mechanisms, including the formation of neutrophil extracellular traps (NETs). The genetic background and underlying mechanisms contributing to NET formation remain unclear.Materials and MethodsWe performed a genome-wide association study (GWAS) and exome-sequencing analysis to identify common and rare genetic variants associated with plasma myeloperoxidase (MPO)-DNA complex levels, a biomarker for NETs, in the population-based Rotterdam Study cohort. GWAS was performed using haplotype reference consortium(HRC)-imputed genotypes of common variants in 3,514 individuals from the first and 2,076 individuals from the second cohort of the Rotterdam Study. We additionally performed exome-sequencing analysis in 960 individuals to investigate rare variants in candidate genes.ResultsThe GWAS yielded suggestive associations (p-value < 5.0 × 10−6) of SNPs annotated to four genes. In the exome-sequencing analysis, a variant in TMPRSS13 gene was significantly associated with MPO-DNA complex levels (p-value < 3.06×10−8). Moreover, gene-based analysis showed ten genes (OR10H1, RP11-461L13.5, RP11-24B19.4, RP11-461L13.3, KHDRBS1, ZNF200, RP11-395I6.1, RP11-696P8.2, RGPD1, AC007036.5) to be associated with MPO-DNA complex levels (p-value between 4.48 × 10−9 and 1.05 × 10−6). Pathway analysis of the identified genes showed their involvement in cellular development, molecular transport, RNA trafficking, cell-to-cell signaling and interaction, cellular growth and proliferation. Cancer was the top disease linked to the NET-associated genes.ConclusionIn this first GWAS and exome-sequencing analysis of NETs levels, we found several genes that were associated with NETs. The precise mechanism of how these genes may contribute to neutrophil function or the formation of NETs remains unclear and should be further investigated in experimental studies.

Published
2021
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11. Design, implementation and initial findings of COVID-19 research in the Rotterdam Study

Author

Michelle M. J. Mens, Luba M. Pardo, S Geurts, Eric F. Thee, Premysl Velek, Frank J. A. van Rooij, Jolande Verkroost-van Heemst, Marije J. Splinter, Silvan Licher, Annechien E. G. Haarman, Niels Schaft, Maud de Feijter, Brenda C.T. Kieboom, Natalie Terzikhan, M. Arfan Ikram, Epidemiology, General Practice, Ophthalmology, and Dermatology

Subjects
Adult, Male, medicine.medical_specialty, Design, Epidemiology, Population, Disease, Population-based, Cohort Studies, Rotterdam Study, SDG 3 - Good Health and Well-being, Surveys and Questionnaires, Health care, Prevalence, Methods, Medicine, Humans, Prospective Studies, education, Pandemics, Aged, Netherlands, Aged, 80 and over, education.field_of_study, business.industry, SARS-CoV-2, Public health, COVID-19, Middle Aged, New Study, Mental health, Risk factors, Family medicine, Epidemiologic Research Design, Population Surveillance, Female, business, Cohort study
Abstract

The Rotterdam Study is an ongoing prospective, population-based cohort study that started in 1989 in the city of Rotterdam, the Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. It focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. In response to the COVID-19 pandemic, a substudy was designed and embedded within the Rotterdam Study. On the 20th of April, 2020, all living non-institutionalized participants of the Rotterdam Study (n = 8732) were invited to participate in this sub-study by filling out a series of questionnaires administered over a period of 8 months. These questionnaires included questions on COVID-19 related symptoms and risk factors, characterization of lifestyle and mental health changes, and determination of health care seeking and health care avoiding behavior during the pandemic. As of May 2021, the questionnaire had been sent out repeatedly for a total of six times with an overall response rate of 76%. This article provides an overview of the rationale, design, and implementation of this sub-study nested within the Rotterdam Study. Finally, initial results on participant characteristics and prevalence of COVID-19 in this community-dwelling population are shown. Supplementary Information The online version contains supplementary material available at 10.1007/s10654-021-00789-7.

Published
2021

12. Ascertainment of cancer in longitudinal research

Author

M. Arfan Ikram, Frank J. A. van Rooij, Rikje Ruiter, Sanne B. Schagen, Jolande Verkroost-van Heemst, Kimberly D. van der Willik, Otto Visser, Bruno H. Stricker, Karin C A A Timmermans, Sander J Hogewoning, Psychology Other Research (FMG), Brain and Cognition, Brein en Cognitie (Psychologie, FMG), and Epidemiology

Subjects
Male, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Concordance, Population, Cohort Studies, 03 medical and health sciences, Rotterdam Study, 0302 clinical medicine, SDG 3 - Good Health and Well-being, International Classification of Diseases, Internal medicine, Neoplasms, Epidemiology, medicine, Humans, cancer registration, Registries, Medical diagnosis, education, Aged, Netherlands, Aged, 80 and over, education.field_of_study, accuracy, business.industry, Data Collection, Incidence, misclassification, Middle Aged, Cancer registry, Oncology, 030220 oncology & carcinogenesis, Hematologic Neoplasms, Etiology, Female, epidemiology, business, Cancer Epidemiology, Cohort study
Abstract

Complete and accurate registration of cancer is needed to provide reliable data on cancer incidence and to investigate aetiology. Such data can be derived from national cancer registries, but also from large population‐based cohort studies. Yet, the concordance and discordance between these two data sources remain unknown. We evaluated completeness and accuracy of cancer registration by studying the concordance between the population‐based Rotterdam Study (RS) and the Netherlands Cancer Registry (NCR) between 1989 and 2012 using the independent case ascertainment method. We compared all incident cancers in participants of the RS (aged ≥45 years) to registered cancers in the NCR in the same persons based on the date of diagnosis and the International Classification of Diseases (ICD) code. In total, 2,977 unique incident cancers among 2,685 persons were registered. Two hundred eighty‐eight cancers (9.7%) were coded by the RS that were not present in the NCR. These were mostly nonpathology‐confirmed lung and haematological cancers. Furthermore, 116 cancers were coded by the NCR, but not by the RS (3.9%), of which 20.7% were breast cancers. Regarding pathology‐confirmed cancer diagnoses, completeness was >95% in both registries. Eighty per cent of the cancers registered in both registries were coded with the same date of diagnosis and ICD code. Of the remaining cancers, 344 (14.5%) were misclassified with regard to date of diagnosis and 72 (3.0%) with regard to ICD code. Our findings indicate that multiple sources on cancer are complementary and should be combined to ensure reliable data on cancer incidence., What's new? While national cancer registries and population‐based cohort studies are the primary sources of data on cancer risk and incidence, the degree to which these data sets are concordant remains unknown. In this investigation, the authors evaluated concordance between the population‐based Rotterdam Study and the Netherlands Cancer Registry. The two data sets were highly concordant for pathology‐confirmed cancers and cancer site. Non‐pathology‐confirmed cancers, however, were under‐registered in the Netherlands Cancer Registry, potentially resulting in underestimation of cancer incidence. The findings highlight the important role that different sources of cancer diagnosis registration serve in providing reliable estimates of cancer incidence.

Published
2020

13. Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

Author

Andrew D Beswick, Tõnu Esko, Niki Dimou, Xue Zhong, Jette Bork-Jensen, Petra Schubert, Masato Akiyama, Girish N. Nadkarni, Ruth J. F. Loos, Huijun Qian, Michele K. Evans, Stephen S. Rich, Nicole Soranzo, Henry Völzke, Yongmei Liu, Nicholas A. Watkins, Markus M. Lerch, Richard C. Trembath, Adam S. Butterworth, Erwin P. Bottinger, Jennifer E. Huffman, Bruce M. Psaty, Jingzhong Ding, Michael Preuss, Yoav Ben-Shlomo, Bhavi Trivedi, Yoichiro Kamatani, David A. van Heel, Kjell Nikus, Torben Hansen, Adolfo Correa, Mohsen Ghanbari, Paul L. Auer, Véronique Laplante, Ken Sin Lo, Hua Tang, Peter W.F. Wilson, Paul Elliott, David J. Roberts, Hilary C. Martin, Jean-Claude Tardif, Praveen Surendran, Regina Manansala, Terho Lehtimäki, Emanuele Di Angelantonio, Fotis Koskeridis, Alexander P. Reiner, Mélissa Beaudoin, Vijay G. Sankaran, Benjamin Rodriguez, William J. Astle, Parsa Akbari, Frank J. A. van Rooij, Yun Li, Andreas Greinacher, Abdou Mousas, Andrew D. Johnson, Yukinori Okada, Michael H. Guo, Leo-Pekka Lyytikäinen, Traci M. Bartz, Minhui Chen, Alan B. Zonderman, Niels Grarup, Oluf Pedersen, Kumaraswamynaidu Chitrala, Jeffrey Haessler, Ming-Huei Chen, Cassandra N. Spracklen, Karen L. Mohlke, Guillaume Lettre, Erik L. Bao, Bingshan Li, James S. Floyd, Wei Huang, Ani Manichaikul, John Danesh, Uwe Völker, Allan Linneberg, Evangelos Evangelou, Joanna M. M. Howson, Olli T. Raitakari, Tim Kacprowski, Jean-François Gauchat, Hélène Choquet, Arden Moscati, Saori Sakaue, Mika Kähönen, Linda Broer, Caleb A. Lareau, Qin Qin Huang, Matthias Nauck, Yoshinori Murakami, Charleston W. K. Chiang, VA Million Veteran Program, Nina Mononen, Tao Jiang, Laura M. Raffield, Jerome I. Rotter, Leslie A. Lange, Jonathan D. Rosen, Eric Jorgenson, Savita Karthikeyan, Karen A. Hunt, Nathan Pankratz, Kelly Cho, Masahiro Kanai, Willem H. Ouwehand, Jennifer A. Brody, Koichi Matsuda, Dragana Vuckovic, Epidemiology, and Internal Medicine

Subjects
LOCI, Mutation, Missense, Ethnic group, POLYGENIC RISK SCORES, HUMAN HEMATOPOIESIS, Biology, BIOBANK, phenome-wide association study, Polymorphism, Single Nucleotide, DISEASE, White People, General Biochemistry, Genetics and Molecular Biology, Article, Blood cell, 03 medical and health sciences, SINGLE-CELL, selective sweeps, 0302 clinical medicine, Asian People, parasitic diseases, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, AFRICAN-AMERICANS, 0303 health sciences, interleukin-7, Interleukin-7, genetic architecture, Genetic architecture, TRAIT, HEK293 Cells, Phenotype, medicine.anatomical_structure, fine-mapping, polygenic trait score, lipids (amino acids, peptides, and proteins), FREQUENCY CODING VARIANTS, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Published
2020

14. Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time

Author

Frank J. A. van Rooij, Joost Verlouw, Robert Kraaij, Linda Broer, Jeroen van Rooij, André G. Uitterlinden, Pascal P. Arp, Annemieke J.M.H. Verkerk, Internal Medicine, and Epidemiology

Subjects
0301 basic medicine, medicine.medical_specialty, Genomics, Penetrance, 030105 genetics & heredity, Biology, Gene mutation, Article, Cohort Studies, 03 medical and health sciences, Rotterdam Study, medicine, Humans, Gene, pathogenic variants, Genetics (clinical), Exome sequencing, Aged, Genetics, Genetic Variation, clinical interpretation, 030104 developmental biology, Phenotype, ACMG genes, Medical genetics, exome sequencing, Cohort study
Abstract

Purpose We studied the penetrance of pathogenically classified variants in an elderly Dutch population from the Rotterdam Study, for which deep phenotyping is available. We screened the 59 actionable genes for which reporting of known pathogenic variants was recommended by the American College of Medical Genetics and Genomics (ACMG), and demonstrate that determining what constitutes a known pathogenic variant can be quite challenging. Methods We defined “known pathogenic” as classified pathogenic by both ClinVar and the Human Gene Mutation Database (HGMD). In 2628 individuals, we performed exome sequencing and identified known pathogenic variants. We investigated the clinical records of carriers and evaluated clinical events during 25 years of follow-up for evidence of variant pathogenicity. Results Of 3815 variants detected in the 59 ACMG genes, 17 variants were considered known pathogenic. For 14/17 variants the ClinVar classification had changed over time. Of 24 confirmed carriers of these variants, we observed at least one clinical event possibly caused by the variant in only three participants (13%). Conclusion We show that the definition of “known pathogenic” is often unclear and should be approached carefully. Additionally variants marked as known pathogenic do not always have clinical impact on their carriers. Definition and classification of true (individual) expected pathogenic impact should be defined carefully.

Published
2020

15. Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium

Author

Panos Deloukas, Christina-Alexandra Schulz, Caren E. Smith, Lu Qi, Mary F. Feitosa, Melissa E. Garcia, Natalia Pervjakova, Denise K. Houston, Michael A. Province, Stavroula Kanoni, Torben Hansen, Jean Shin, Lynda M. Rose, Oscar H. Franco, Yongmei Liu, Trudy Voortman, Marie-Claude Vohl, Luigi Ferrucci, Chloé Sarnowski, Paul S. de Vries, Jose C. Florez, John C. Lieske, Louis Pérusse, Misa Graff, Jian'an Luan, Nicola M. McKeown, Felix R. Day, L. Adrienne Cupples, Qibin Qi, Frank J. A. van Rooij, Robert A. Scott, Josée Dupuis, Stephen S. Rich, Jorma Viikari, Tarunveer S. Ahluwalia, Leo-Pekka Lyytikäinen, Paul M. Ridker, Tomáš Paus, Stephen Turner, Harri Rissanen, Audrey Y. Chu, Albert Hofman, Olli T. Raitakari, Paul Knekt, Daniel I. Chasman, Nita G. Forouhi, Vera Mikkilä, Toshiko Tanaka, Mika Kähönen, George Dedoussis, Minjung Kho, Yun J. Sung, Anne E. Justice, Julius S. Ngwa, Ani Manichaikul, M. Carola Zillikens, Jordi Merino, Dena G. Hernandez, Rozenn N. Lemaitre, Tao Huang, Sharon L.R. Kardia, Jing Hua Zhao, Stefania Bandinelli, Veikko Salomaa, Arne Astrup, Wei Zhao, David S. Siscovick, John Blangero, Zdenka Pausova, Dabeeru C. Rao, Oluf Pedersen, Craig E. Pennell, Wendy H. Oddy, Jose M. Ordovas, Jessica C. Kiefte-de Jong, Marju Orho-Melander, Hassan S. Dashti, Satu Männistö, Tuomo Rankinen, Constantina Papoutsakis, Sherly X. Li, Antti Jula, Kari E. North, Thorkild I. A. Sørensen, André G. Uitterlinden, Alexis C. Frazier-Wood, Nicholas J. Wareham, Ulrika Ericson, Markus Perola, Ioanna P. Kalafati, Renée de Mutsert, Jinyan Huang, Ruifang Li-Gao, Claudia Langenberg, Mike A. Nalls, Olivia Li, Joanne E. Curran, Dennis O. Mook-Kanamori, Niina Eklund, Jerome I. Rotter, Angelo Tremblay, Claude Bouchard, Jennifer A. Smith, Terho Lehtimäki, Mary K. Wojczynski, Carol A. Wang, Epidemiology, Internal Medicine, Zhao, Jing Hua [0000-0003-4930-3582], Luan, Jian'an [0000-0003-3137-6337], Day, Felix [0000-0003-3789-7651], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Forouhi, Nita [0000-0002-5041-248X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Aging, Calorie, Genotype, Heart Diseases, Receptors, Retinoic Acid, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Obesity, Molecular Biology, Aged, 2. Zero hunger, Genetics, Family aggregation, Membrane Proteins, Genomics, Nutrients, Middle Aged, medicine.disease, 3. Good health, Fibroblast Growth Factors, Psychiatry and Mental health, 030104 developmental biology, Genetic Loci, Meta-analysis, Medical genetics, Female, Energy Intake, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10(−6)) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

Published
2019

16. Genome-wide association study identifies 48 common genetic variants associated with handedness

Author

Inês Barroso, Gail Davies, H.-Erich Wichmann, Bjarke Feenstra, Peter Vollenweider, Nicholas J. Timpson, Alan F. Wright, Frank Geller, Gérard Waeber, John M. Starr, Benjamin M. Neale, George Davey Smith, Tõnu Esko, Ruth J. F. Loos, Andrew A. Hicks, Pedro Marques-Vidal, Dorret I. Boomsma, Harry Campbell, Zoltán Kutalik, David M. Evans, Scott D. Gordon, Eva Albrecht, Peter P. Pramstaller, Leena Peltonen, Jing Hua Zhao, Lavinia Paternoster, Thomas Hansen, Massimo Mangino, Fazil Aliev, Beate St Pourcain, Panos Deloukas, Heather A. Boyd, Guillaume Paré, Marco P. Boks, Monique M.B. Breteler, Jouke-Jan Hottenga, Xin Li, Kari Stefansson, Ian J. Deary, Jari Lahti, Inga Prokopenko, Nicholas Eriksson, Lili Milani, Nicholas J. Wareham, Jordan W. Smoller, Norman Klopp, Lynn Cherkas, Reedik Mägi, Margaret J. Wright, Peter Kraft, Jacques S. Beckmann, Brenda W.J.H. Penninx, Gabriel Cuellar-Partida, André G. Uitterlinden, Fernando Rivadeneira, Wendy L. McArdle, Johan G. Eriksson, Jiali Han, Jennifer E. Huffman, Andres Metspalu, J.M. Vink, Frank J. A. van Rooij, Christian Gieger, M. Arfan Ikram, Cecilia M. Lindgren, Aarno Palotie, Daniel I. Chasman, Joyce Y. Tung, Liang-Dar Hwang, David A. Hinds, Elisabeth Widen, Caroline Hayward, Michelle Luciano, Johannes H. Smit, Gonneke Willemsen, Dale R. Nyholt, Carolina Medina-Gomez, Nicole M. Warrington, Teemu Palviainen, Stacy Steinberg, Kay-Tee Khaw, Kevin S. O’Connell, Bettina Konte, Gudmar Thorleifsson, Eco J. C. de Geus, John P. Kemp, Mads Melbye, Mark I. McCarthy, Sarah E. Medland, Jaakko Kaprio, Cameron D. Palmer, Joel N. Hirschhorn, Ina Giegling, Scott Melville, Thomas Werge, Nicole Soranzo, Sigurdur H. Magnusson, Maris Teder-Laving, Hreinn Stefansson, Kauko Heikkilä, Cornelia M. van Duijn, David L. Duffy, Samuli Ripatti, Igor Rudan, Annette M. Hartmann, Ole A. Andreassen, Mari Nelis, Ozren Polasek, Vincent Mooser, Mousheng Xu, Eero Vuoksimaa, Katri Räikkönen, Nicholas G. Martin, Dan Rujescu, Tim D. Spector, Dawn M. Waterworth, Danielle M. Dick, Roel A. Ophoff, Epidemiology, Internal Medicine, Psychiatry, Biological Psychology, APH - Mental Health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Epidemiology and Data Science, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Pediatric surgery, and APH - Digital Health

Subjects
Male, Netherlands Twin Register (NTR), Linkage disequilibrium, Genome-wide association study, LANGUAGE DOMINANCE, Functional Laterality, Linkage Disequilibrium, Behavioral Neuroscience, 0302 clinical medicine, ddc:150, Gene Frequency, SCHIZOPHRENIA, Genetics, 0303 health sciences, Middle Aged, genetics [Genetic Variation], genetics [Functional Laterality], Schizophrenia, ASYMMETRY, genetics [Polymorphism, Single Nucleotide], Female, Adult, Social Psychology, LATERALIZATION, Experimental and Cognitive Psychology, genetics [Genetic Loci], Biology, Quantitative trait locus, Genetic correlation, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, LINKAGE ANALYSIS, METAANALYSIS, MICROTUBULE, AUTISM, ORIGINS, SCREEN, Quantitative Trait, Heritable, Sex Factors, Genetic linkage, medicine, Humans, Bipolar disorder, 030304 developmental biology, Genetic association study, Aged, Genetic Variation, medicine.disease, Genetic Loci, Autism, genetics [Gene Frequency], Developmental Psychopathology, 030217 neurology & neurosurgery, Neuroscience, Genome-Wide Association Study
Abstract

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

Published
2021

17. Genomic analysis of diet composition finds novel loci and associations with health and lifestyle

Author

Fumiaki Imamura, George Davey Smith, Chanwook Lee, Nicholas J. Wareham, M. Arfan Ikram, George McMahon, Aysu Okbay, Frank J. A. van Rooij, Peter Bowers, Carson C. Chow, Patrick Turley, Ronald de Vlaming, Jian'an Luan, Oscar H. Franco, Trudy Voortman, Daniel J. Benjamin, André G. Uitterlinden, Casper A.P. Burik, Nita G. Forouhi, K. Paige Harden, Pauline M Emmett, Cornelius A. Rietveld, Juan R. González, Bruce H. R. Wolffenbuttel, Philipp Koellinger, Mark Alan Fontana, James J. Lee, David Cesarini, Harold Snieder, Kim Valeska Emilie Braun, Emma L Anderson, Jana V. van Vliet-Ostaptchouk, Peter J. van der Most, Richard Karlsson Linnér, Susan M. Ring, Claudia Langenberg, Tonũ Esko, Fernando Rivadeneira, Kaitlin H Wade, Jessica C. Kiefte-de Jong, Taulant Muka, Mohsen Ghanbari, S. Fleur W. Meddens, Linnér, Richard Karlsson [0000-0001-7839-2858], Okbay, Aysu [0000-0002-5170-7781], Rietveld, Cornelius A [0000-0003-4053-1861], Ghanbari, Mohsen [0000-0002-9476-7143], Imamura, Fumiaki [0000-0002-6841-8396], van der Most, Peter J [0000-0001-8450-3518], Voortman, Trudy [0000-0003-2830-6813], Wade, Kaitlin H [0000-0003-3362-6280], Braun, Kim VE [0000-0001-8738-4139], Gonzalez, Juan R [0000-0003-3267-2146], Kiefte-de Jong, Jessica C [0000-0002-8136-0918], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Ring, Susan [0000-0003-3103-9330], Rivadeneira, Fernando [0000-0001-9435-9441], Snieder, Harold [0000-0003-1949-2298], van Rooij, Frank JA [0000-0002-8600-9852], Smith, George Davey [0000-0002-1407-8314], Forouhi, Nita G [0000-0002-5041-248X], Ikram, M Arfan [0000-0003-0372-8585], Uitterlinden, Andre G [0000-0002-7276-3387], van Vliet-Ostaptchouk, Jana V [0000-0002-7943-3153], Lee, James J [0000-0001-6547-5128], Benjamin, Daniel J [0000-0002-2642-5416], Apollo - University of Cambridge Repository, Rietveld, Cornelius A. [0000-0003-4053-1861], van der Most, Peter J. [0000-0001-8450-3518], Wade, Kaitlin H. [0000-0003-3362-6280], Braun, Kim V. E. [0000-0001-8738-4139], Gonzalez, Juan R. [0000-0003-3267-2146], Kiefte-de Jong, Jessica C. [0000-0002-8136-0918], Luan, Jian’an [0000-0003-3137-6337], van Rooij, Frank J. A. [0000-0002-8600-9852], Forouhi, Nita G. [0000-0002-5041-248X], Ikram, M. Arfan [0000-0003-0372-8585], Uitterlinden, Andre G. [0000-0002-7276-3387], van Vliet-Ostaptchouk, Jana V. [0000-0002-7943-3153], Lee, James J. [0000-0001-6547-5128], Benjamin, Daniel J. [0000-0002-2642-5416], Applied Economics, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Economics, and Amsterdam Neuroscience - Complex Trait Genetics

Subjects
0301 basic medicine, BETA-KLOTHO, PROTEIN-INTAKE, LD SCORE REGRESSION, Diseases, Genome-wide association study, Type 2 diabetes, METABOLIC-ACTIVITY, OBESITY RISK, Cardiovascular, Medical and Health Sciences, CHAIN AMINO-ACIDS, Body Mass Index, 631/208, 0302 clinical medicine, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, SOCIOECONOMIC-STATUS, 030212 general & internal medicine, Aetiology, Psychiatry, 2. Zero hunger, Genetics, 692/699, Diabetes, article, Genomics, Biological Sciences, SDG 11 - Sustainable Cities and Communities, 3. Good health, Psychiatry and Mental health, SDG 1 - No Poverty, Type 2, WEIGHT-LOSS, Single-nucleotide polymorphism, Biology, 23andMe Research Team, Genetic correlation, 03 medical and health sciences, Cellular and Molecular Neuroscience, Lifelines Cohort Study, Behavioral and Social Science, Diabetes Mellitus, medicine, Humans, Obesity, Molecular Biology, Life Style, Metabolic and endocrine, Nutrition, Genetic association, EPIC- InterAct Consortium, Prevention, Human Genome, Psychology and Cognitive Sciences, medicine.disease, Genetic architecture, Diet, BODY-MASS INDEX, 030104 developmental biology, Diabetes Mellitus, Type 2, Body mass index, Genome-Wide Association Study
Abstract

We conducted genome-wide association studies (GWAS) of relative intake from the macronutrients fat, protein, carbohydrates, and sugar in over 235,000 individuals of European ancestries. We identified 21 unique, approximately independent lead SNPs. Fourteen lead SNPs are uniquely associated with one macronutrient at genome-wide significance (P < 5 × 10-8), while five of the 21 lead SNPs reach suggestive significance (P < 1 × 10-5) for at least one other macronutrient. While the phenotypes are genetically correlated, each phenotype carries a partially unique genetic architecture. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease (rg ≈ 0.15-0.5). In contrast, relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood deprivation (|rg| ≈ 0.1-0.3) and positive genetic correlations with physical activity (rg ≈ 0.1 and 0.2). Relative fat intake has no consistent pattern of genetic correlations with poor health but has a negative genetic correlation with educational attainment (rg ≈-0.1). Although our analyses do not allow us to draw causal conclusions, we find no evidence of negative health consequences associated with relative carbohydrate, sugar, or fat intake. However, our results are consistent with the hypothesis that relative protein intake plays a role in the etiology of metabolic dysfunction. This research was carried out under the auspices of the Social Science Genetic Association Consortium (SSGAC, https://www.thessgac.org/). The research has also been conducted using the UK Biobank Resource under Application Number 11425. The study was supported by funding from the Ragnar Söderberg Foundation (E9/11 and E42/15), the Swedish Research Council (421-2013-1061), The Jan Wallander and Tom Hedelius Foundation, an ERC Consolidator Grant to Philipp Koellinger (647648 EdGe), the Pershing Square Fund of the Foundations of Human Behavior, The Open Philanthropy Project (2016-152872, 010623-00001), and the NIA/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23 to NBER, and R01-AG042568-02 and R56-AG042568-04 to the University of Southern California. CCC was supported by the Intramural Research Program of the NIH/NIDDK and thanks Kevin Hall for informative discussions. PME was funded by Nestlé Nutrition. We thank the DietGen and CHARGE consortia for sharing diet-composition GWAS summary statistics, and we thank 23andMe, Inc., for sharing physical activity GWAS summary statistics. A full list of acknowledgements is provided in Supplementary Information 13.

Published
2020

18. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author

Jean-Claude Tardif, Kelly Cho, Adolfo Correa, Na Cai, Koichi Matsuda, Paul L. Auer, Ken Sin Lo, Jennifer A. Brody, Dragana Vuckovic, Oluf Pedersen, Eric Jorgenson, Cassandra N. Spracklen, Jennifer E. Huffman, Stefan Weiss, Tim Kacprowski, Nicholas A. Watkins, Yoichiro Kamatani, Michele K. Evans, John Danesh, Masahiro Kanai, Karyn Megy, Kumaraswamy Naidu Chitrala, Michael H. Guo, James S. Floyd, Savita Karthikeyan, Ani Manichaikul, Petra Schubert, Vijay G. Sankaran, Torben Hansen, Traci M. Bartz, Laura M. Raffield, Regina Manansala, Parsa Akbari, Scott C. Ritchie, Ruth J. F. Loos, Manuel Tardaguila, Willem H. Ouwehand, Peter W.F. Wilson, Emanuele Di Angelantonio, Abdou Mousas, Jeffrey Haessler, Yoav Ben-Shlomo, Benjamin Rodriguez, Karen L. Mohlke, Girish N. Nadkarni, Oliver Stegle, Paul Elliott, Erwin P. Bottinger, Nathan Pankratz, Hélène Choquet, Julian C. Knight, Niels Grarup, Niki Dimou, Leslie A. Lange, Stephan B. Felix, William J. Astle, Jerome I. Rotter, Frank J. A. van Rooij, Andreas Greinacher, Yongmei Liu, Tao Jiang, Michael Inouye, Ming-Huei Chen, Jingzhong Ding, Uwe Völker, Huijun Qian, Henry Völzke, Alan B. Zonderman, Evangelos Evangelou, Wei Huang, Jonathan D. Rosen, Christopher J. Penkett, Michel Georges, Kousik Kundu, Mohsen Ghanbari, Hannes Ponstingl, Adam S. Butterworth, Joanna M. M. Howson, Praveen Surendran, Terho Lehtimäki, Allan Linneberg, Emilie M. Wigdor, Michael Preuss, Olli T. Raitakari, Arden Moscati, Yukinori Okada, Yoshinori Murakami, Guillaume Lettre, Leo-Pekka Lyytikäinen, Hua Tang, Caleb A. Lareau, David J. Roberts, Saori Sakaue, Mika Kähönen, Alexander P. Reiner, VA Million Veteran Program, Fotis Koskeridis, Nina Mononen, Linda Broer, Kjell Nikus, Andrew D. Johnson, Patrick K. Albers, Stephen B. Watt, Erik L. Bao, Yun Li, Klaudia Walter, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Andrew D Beswick, Tõnu Esko, Jette Bork-Jensen, and Masato Akiyama

Subjects
Genetics, Gene regulatory network, Oxygen transport, Genome-wide association study, Biology, Genetic architecture, Blood cell, symbols.namesake, medicine.anatomical_structure, medicine, Mendelian inheritance, symbols, Allele, Allele frequency
Abstract

SummaryBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.

Published
2020
Full Text
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19. Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood

Author

George Dedoussis, Frédéric Fumeron, Zhonghan Sun, E-Shyong Tai, Bruce M. Psaty, Paul M. Ridker, Kim Overvad, Marcus E. Kleber, Wolfgang Lieb, Marju Orho-Melander, Xueling Sim, Philippe Froguel, Mark I. McCarthy, Tiange Wang, Diana van Heemst, Emily Sonestedt, Veit Grote, Karen L. Mohlke, Inke R. König, Tibor V. Varga, Chris Power, Matthias Munz, Ulrika Ericson, Luc Djoussé, Dariush Mozaffarian, Tuomas O. Kilpeläinen, Jorma Viikari, Ralph Burkhardt, Chao-Qiang Lai, Klaus Bønnelykke, Mariaelisa Graff, Woon-Puay Koh, Jin-Fang Chai, Nanette R. Lee, Harri Niinikoski, Torben Hansen, Christina-Alexandra Schulz, Caizheng Yu, Renée de Mutsert, Colin Boreham, Jean Dallongeville, Anne Tjønneland, Philippe Amouyel, Tao Zhang, Markus Scholz, Elina Hyppönen, Tarunveer S. Ahluwalia, Niina Pitkänen, Fernando Rivadeneira, Rebecca K. Vinding, Donna K. Arnett, Craig E. Pennell, Joachim Thiery, Jose M. Ordovas, Thorkild I. A. Sørensen, Lu Qi, Oscar Coltell, Daniel I. Chasman, Olli T. Raitakari, Preeti Gupta, Dariusz Gruszfeld, Rajkumar Dorajoo, Berthold Koletzko, Seang-Mei Saw, Tangchun Wu, Charumathi Sabanayagam, Rozenn N. Lemaitre, Meian He, Tao Huang, Carol A. Wang, Graciela E. Delgado, Rob M. van Dam, Luis A. Moreno, Peter Rossing, Mika Kähönen, Aline Meirhaeghe, Christina Ellervik, Frédéric Gottrand, Yan Zheng, Katherine L. Tucker, Ying Wu, Lavinia Paternoster, Lingyao Zeng, Joaquin Escribano, David A. Mackey, Raymond Noordam, Masato Akiyama, Dolores Corella, Thorsten Kessler, Frank J. A. van Rooij, Terho Lehtimäki, Jeanette Erdmann, Ang Zhou, Michiaki Kubo, Winfried März, Frits R. Rosendaal, Kari E. North, Cécile Lecoeur, Cornelia Enzenbach, Albert Hofman, Elvira Verduci, Tien Yin Wong, Hans Bisgaard, Zhendong Mei, Trudy Voortman, Yujie Wang, Heribert Schunkert, Beverley Balkau, Annette Peters, Dennis O. Mook-Kanamori, Vincent W. V. Jaddoe, Peter Rzehak, Christina Willenborg, Katja Pahkala, Jean-Paul Langhendries, Janine F. Felix, Angela C. Estampador, Ramon Estruch, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 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), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning National Basic Research Program of China (973 Program): 2016YFC1304801 2017SHZDZX01, This work was supported by Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01) and the National Key Research and Development Program of China (Grant No. 2016YFC1304801). YZ was supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning. For the funding information of each study within CHARGE-BIG consortium, please see Supplemental Table 8., CHU Lille, CNRS, Inserm, Université de Lille, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID) - UMR 8199, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)], Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167, Lille Inflammation Research International Center (LIRIC) - U995, Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Zheng, Yan, Huang, Tao, Wang, Tiange, Mei, Zhendong, Zhou, A, Hypponen, E, and Qi, L

Subjects
Adult, Male, medicine.medical_specialty, Epidemiology, Birth weight, [SDV]Life Sciences [q-bio], Birthweight, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Mendelian randomization, medicine, Birth Weight, Humans, Hypertension, Blood pressure, Causal association, Genetic Predisposition to Disease, 030212 general & internal medicine, business.industry, Infant, Newborn, Mendelian Randomization Analysis, Odds ratio, Infant, Low Birth Weight, 3. Good health, Pulse pressure, Cohort, Female, business, Genome-Wide Association Study
Abstract

International audience; Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = − 0.76, 95% CI − 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = − 0.06, 95% CI − 0.93 to 0.87 mmHg), or pulse pressure (β = − 0.65, 95% CI − 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

Published
2020

20. Objectives, design and main findings until 2020 from the Rotterdam Study

Author

Bruno H. Stricker, Meike W. Vernooij, Frank J. A. van Rooij, André G. Uitterlinden, Mohsen Ghanbari, Robin P. Peeters, M. Arfan Ikram, Guy Brusselle, M. Kamran Ikram, Tamar Nijsten, Robert J. de Knegt, André Goedegebure, Caroline C W Klaver, Brenda C.T. Kieboom, Maryam Kavousi, Annemarie I. Luik, Trudy Voortman, Epidemiology, Otorhinolaryngology and Head and Neck Surgery, Ophthalmology, Gastroenterology & Hepatology, Dermatology, Internal Medicine, and Radiology & Nuclear Medicine

Subjects
Gerontology, Male, Respiratory diseases, Epidemiology, SEROTONIN REUPTAKE INHIBITORS, Epidemiologic methods, Renal diseases, 030204 cardiovascular system & hematology, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Endocrine diseases, Cohort Studies, Rotterdam Study, 0302 clinical medicine, Risk Factors, Dermatological diseases, Medicine and Health Sciences, PULMONARY-DISEASE, Cancer and related diseases, HORMONE-BINDING GLOBULIN, Nutrition and lifestyle, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Netherlands, Cohort, Nutrition and lifestyle epidemiology, Middle Aged, 3. Good health, Natural history, Cardiovascular diseases, Oncology, CARDIAC DEATH, Population Surveillance, Respiratory, Female, epidemiology, Study Update, Cohort study, Adult, medicine.medical_specialty, Population imaging, Otolaryngological diseases, OBSTRUCTIVE, methods, diseases, 03 medical and health sciences, Life Expectancy, SUDDEN, medicine, Humans, CORONARY-HEART-DISEASE, study, GENOME-WIDE ASSOCIATION, Genetic and molecular epidemiology, Liver diseases, Epidemiologic, CAUSE-SPECIFIC, business.industry, Public health, MORTALITY, Pharmacoepidemiology, INDIVIDUAL-PARTICIPANT-DATA, BODY-MASS INDEX, WHITE-MATTER MICROSTRUCTURE, Epidemiologic Research Design, Ophthalmic diseases, Chronic Disease, Etiology, Psychiatric diseases, business, Biomarkers, Neurological diseases
Abstract

Contains fulltext : 220949.pdf (Publisher’s version ) (Open Access) The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the city of Rotterdam, The Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. The study focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1700 research articles and reports. This article provides an update on the rationale and design of the study. It also presents a summary of the major findings from the preceding 3 years and outlines developments for the coming period.

Published
2020

21. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author

Nicholas A. Watkins, Julian C. Knight, William J. Astle, Stephan B. Felix, Petra Schubert, Andreas Greinacher, Laura M. Raffield, Guillaume Lettre, Leslie A. Lange, Erwin P. Bottinger, Jonathan D. Rosen, Frank J. A. van Rooij, Tim Kacprowski, Hua Tang, Regina Manansala, Manuel Tardaguila, Mohsen Ghanbari, Tao Jiang, Torben Hansen, Abdou Mousas, Adam S. Butterworth, Yoav Ben-Shlomo, Praveen Surendran, Terho Lehtimäki, Peter W.F. Wilson, Parsa Akbari, Hélène Choquet, Niels Grarup, Girish N. Nadkarni, Jean-Claude Tardif, Jennifer E. Huffman, Dragana Vuckovic, Ruth J. F. Loos, Karyn Megy, Emilie M. Wigdor, Michael Preuss, Alan B. Zonderman, Yukinori Okada, Oluf Pedersen, Arden Moscati, Leo-Pekka Lyytikäinen, Masahiro Kanai, Wei Huang, Andrew D Beswick, Stephen B. Watt, Erik L. Bao, Allan Linneberg, Paul Elliott, Eric Jorgenson, Tõnu Esko, Michael H. Guo, VA Million Veteran Program, Saori Sakaue, Mika Kähönen, Olli T. Raitakari, Stefan Weiss, Traci M. Bartz, Nina Mononen, Jette Bork-Jensen, Willem H. Ouwehand, Linda Broer, John Danesh, Masato Akiyama, James S. Floyd, Scott C. Ritchie, Kjell Nikus, Paul L. Auer, Emanuele Di Angelantonio, Ken Sin Lo, Kelly Cho, Uwe Völker, Ming-Huei Chen, Evangelos Evangelou, David J. Roberts, Na Cai, Benjamin Rodriguez, Savita Karthikeyan, Yoichiro Kamatani, Michael Inouye, Yoshinori Murakami, Yongmei Liu, Alexander P. Reiner, Koichi Matsuda, Jingzhong Ding, Kumaraswamy Naidu Chitrala, Niki Dimou, Andrew D. Johnson, Nathan Pankratz, Jeffrey Haessler, Vijay G. Sankaran, Oliver Stegle, Qi Guo, Karen L. Mohlke, Jennifer A. Brody, Michele K. Evans, Fotios Koskeridis, Cassandra N. Spracklen, Jerome I. Rotter, Ani Manichaikul, Patrick K. Albers, Caleb A. Lareau, Michel Georges, Hannes Ponstingl, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Yun Li, Klaudia Walter, Huijun Qian, Henry Völzke, Christopher J. Penkett, J. M. M. Howson, Kousik Kundu, Epidemiology, and Internal Medicine

Subjects
Gene regulatory network, LOCI, EFFICIENT, Genome-wide association study, VARIANTS, Blood cell, 0302 clinical medicine, RARE, genetics, 11 Medical and Health Sciences, 0303 health sciences, rare diseases, Biobank, ddc, medicine.anatomical_structure, fine-mapping, VA Million Veteran Program, symbols, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, UK Biobank, polygenic risk, rare disease, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, GENETIC ARCHITECTURE, 03 medical and health sciences, symbols.namesake, splicing, blood, medicine, CELL, Allele, GENOME-WIDE ASSOCIATION, COMMON, 030304 developmental biology, Science & Technology, COMPLEX, Oxygen transport, Cell Biology, 06 Biological Sciences, Genetic architecture, hematopoiesis, INTERROGATION, Mendelian inheritance, chromatin, omnigenic, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Summary Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation., Graphical Abstract, Highlights • Largest genome-wide association study of blood cell traits to date • Empiric assessments of omnigenic and infinitesimal models of polygenic variation • Functional insights into how genetic variants impact human hematopoiesis • Assessment of the effect of polygenic trait scores upon blood diseases, Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases.

Published
2020
Full Text
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22. Macronutrient intake and frailty: the Rotterdam Study

Author

Josje D. Schoufour, Jessica C. Kiefte-de Jong, Eline Verspoor, Fernando Rivadeneira, Oscar H. Franco, Trudy Voortman, Frank J. A. van Rooij, Epidemiology, Public Health, Internal Medicine, Kenniscentrum ACHIEVE, and Urban Vitality

Subjects
Frailty Index, Medicine (miscellaneous), 610 Medicine & health, Frailty Index score, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Eating, Rotterdam Study, Macronutrient intake, 360 Social problems & social services, Dietary Carbohydrates, Humans, Medicine, Macronutrient composition, Aged, Frailty index, Nutrition and Dietetics, Frailty, Multivariable linear regression, business.industry, Healthy population, Confounding, Nutrients, Original Contribution, Middle Aged, Dietary Fats, Diet, Animal protein, Older adults, Dietary Proteins, Energy Intake, business, Demography
Abstract

Purpose To investigate the longitudinal association between the macronutrient composition of the diet and frailty. Methods Data were obtained from 5205 Dutch middle-aged and older adults participating in the Rotterdam Study. Frailty was measured using a frailty index based on the accumulation of 38 health-related deficits, score between 0 and 100, and a higher score indicating more frailty. Frailty was assessed at baseline and 11 years later (range of 23 years). Macronutrient intake was assessed using food-frequency questionnaires. The association between macronutrients and frailty over time was evaluated using multivariable linear regression, adjusted for the frailty index at baseline, energy intake, and other relevant confounders. All analyses were performed in strata of BMI. Results Median frailty index score was 13.8 points (IQR 9.6; 19.1) at baseline and increased by a median of 2.3 points (IQR − 2.0; 7.6) after 11 years. Overall, we found no significant associations between intake of carbohydrates or fat and frailty over time. We did observe a significant positive association between an iso-energetic intake of 10 g protein and frailty over time (β 0.31 (95% CI 0.06; 0.55)) which was mainly driven by animal protein (β 0.31 (95% CI 0.07; 0.56)). It did not depend on whether it was substituted fat or carbohydrates. Conclusions Our findings suggest that a reduction in the intake of animal protein may improve the overall health status over time in a relatively healthy population. More research is needed on the optimal macronutrient composition of the diet and frailty in more vulnerable populations.

Published
2020

23. Physical activity types and atrial fibrillation risk in the middle-aged and elderly: The Rotterdam Study

Author

M. Arfan Ikram, Frank J. A. van Rooij, Josje D. Schoufour, Oscar H. Franco, Chantal M. Koolhaas, Marijn Albrecht, and Maryam Kavousi

Subjects
medicine.medical_specialty, Rotterdam Study, Population, Walking, 030204 cardiovascular system & hematology, Lower risk, elderly, Full Research Paper, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Atrial Fibrillation, medicine, Humans, 030212 general & internal medicine, education, Prospective cohort study, Exercise, Netherlands, Aged, education.field_of_study, Proportional hazards model, business.industry, Hazard ratio, Anticoagulants, Atrial fibrillation, Physical Activity, Middle Aged, medicine.disease, Stroke, Cohort, epidemiology, Morbidity, Cardiology and Cardiovascular Medicine, business
Abstract

Background The association between physical activity and atrial fibrillation remains controversial. Physical activity has been associated with a higher and lower atrial fibrillation risk. These inconsistent results might be related to the type of physical activity. We aimed to investigate the association of total and types of physical activity, including walking, cycling, domestic work, gardening and sports, with atrial fibrillation. Design Prospective cohort study. Methods Our study was performed in the Rotterdam Study, a prospective population-based cohort. We included 7018 participants aged 55 years and older with information on physical activity between 1997–2001. Cox proportional hazards models were used to examine the association of physical activity with atrial fibrillation risk. Models were adjusted for biological and behavioural risk factors and the remaining physical activity types. Physical activity was categorised in tertiles and the low group was used as reference. Results During 16.8 years of follow-up (median: 12.3 years, interquartile range: 8.7–15.9 years), 800 atrial fibrillation events occurred (11.4% of the study population). We observed no association between total physical activity and atrial fibrillation risk in any model. After adjustment for confounders, the hazard ratio and 95% confidence interval for the high physical activity category compared to the low physical activity category was: 0.71 (0.80–1.14) for total physical activity. We did not observe a significant association between any of the physical activity types with atrial fibrillation risk. Conclusion Our results suggest that physical activity is not associated with higher or lower risk of atrial fibrillation in older adults. Neither total physical activity nor any of the included physical activity types was associated with atrial fibrillation risk.

Published
2018

24. Physical activity derived from questionnaires and wrist-worn accelerometers: comparability and the role of demographic, lifestyle, and health factors among a population-based sample of older adults

Author

Henning Tiemeier, Josje D. Schoufour, Frank J. A. van Rooij, Chantal M. Koolhaas, Magda Cepeda, Oscar H. Franco, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Psychiatry

Subjects
medicine.medical_specialty, Epidemiology, Population, Physical activity, physical activity, Wrist, Accelerometer, elderly, Spearman's rank correlation coefficient, 03 medical and health sciences, Rotterdam Study, 0302 clinical medicine, Linear regression, medicine, Clinical Epidemiology, 030212 general & internal medicine, education, Original Research, education.field_of_study, business.industry, questionnaire, 030229 sport sciences, medicine.disease, Obesity, disagreement, accelerometer, medicine.anatomical_structure, Physical therapy, business
Abstract

Chantal M Koolhaas,1 Frank JA van Rooij,1 Magda Cepeda,1 Henning Tiemeier,1–3 Oscar H Franco,1 Josje D Schoufour1 1Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; 2Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands; 3Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands Background: Agreement between questionnaires and accelerometers to measure physical activity (PA) differs between studies and might be related to demographic, lifestyle, and health characteristics, including disability and depressive symptoms.Methods: We included 1,410 individuals aged 51–94 years from the population-based Rotterdam Study. Participants completed the LASA Physical Activity Questionnaire and wore a wrist-worn accelerometer on the nondominant wrist for 1 week thereafter. We compared the Spearman correlation and disagreement (level and direction) for total PA across levels of demographic, lifestyle, and health variables. The level of disagreement was defined as the absolute difference between questionnaire- and accelerometer-derived PA, whereas the direction of disagreement was defined as questionnaire PA minus accelerometer PA. We used linear regression analyses with the level and direction of disagreement as outcome, including all demographic, lifestyle, and health variables in the model.Results: We observed a Spearman correlation of 0.30 between questionnaire- and accelerometer-derived PA in the total population. The level of disagreement (ie, absolute difference) was 941.9 (standard deviation [SD] 747.0) minutes/week, and the PA reported by questionnaire was on average 529.4 (SD 1,079.5) minutes/week lower than PA obtained by the accelerometer. The level of disagreement decreased with higher educational levels. Additionally, participants with obesity, higher disability scores, and more depressive symptoms underestimated their self-reported PA more than their healthier counterparts.Conclusion: We observed large differences in PA time derived from the LASA Physical Activity Questionnaire and the wrist-worn accelerometer. Differences between the methods were related to body-mass index, level of disability, and presence of depressive symptoms. Future studies using questionnaires and/or accelerometers should account for these differences. Keywords: physical activity, questionnaire, accelerometer, disagreement, elderly

Published
2018

25. Osteoporotic Vertebral Fracture Prevalence Varies Widely Between Qualitative and Quantitative Radiological Assessment Methods: The Rotterdam Study

Author

Frank J. A. van Rooij, Fjorda Koromani, Emma Clark, Fernando Rivadeneira, Edwin H. G. Oei, M. Arfan Ikram, Ling Oei, M. C. Zillikens, Joyce B. J. van Meurs, John T. Schousboe, Stephan J Breda, Jan H. Waarsing, and Gabriel P. Krestin

Subjects
0301 basic medicine, medicine.medical_specialty, education.field_of_study, business.industry, Endocrinology, Diabetes and Metabolism, Radiography, Osteoporosis, Gold standard, Population, Dentistry, 030209 endocrinology & metabolism, medicine.disease, 03 medical and health sciences, Rotterdam Study, 030104 developmental biology, 0302 clinical medicine, Epidemiology, medicine, Orthopedics and Sports Medicine, business, education, Depression (differential diagnoses), Kappa
Abstract

Accurate diagnosis of vertebral osteoporotic fractures is crucial for the identification of individuals at high risk of future fractures. Different methods for radiological assessment of vertebral fractures exist, but a gold standard is lacking. The aim of our study was to estimate statistical measures of agreement and prevalence of osteoporotic vertebral fractures in the population-based Rotterdam Study, across two assessment methods. The quantitative morphometry assisted by SpineAnalyzer® (QM SA) method evaluates vertebral height loss that affects vertebral shape whereas the algorithm-based qualitative (ABQ) method judges endplate integrity and includes guidelines for the differentiation of vertebral fracture and nonfracture deformities. Cross-sectional radiographs were assessed for 7582 participants aged 45 to 95 years. With QM SA, the prevalence was 14.2% (95% CI, 13.4% to 15.0%), compared to 4.0% (95% CI, 3.6% to 4.5%) with ABQ. Inter-method agreement according to kappa (κ) was 0.24. The highest agreement between methods was among females (κ = 0.31), participants age >80 years (κ = 0.40), and at the L1 level (κ = 0.40). With ABQ, most fractures were found at the thoracolumbar junction (T12–L1) followed by the T7–T8 level, whereas with QM SA, most deformities were in the mid thoracic (T7–T8) and lower thoracic spine (T11–T12), with similar number of fractures in both peaks. Excluding mild QM SA deformities (grade 1 with QM) from the analysis increased, the agreement between the methods from κ = 0.24 to 0.40, whereas reexamining mild deformities based on endplate depression increased agreement from κ = 0.24 to 0.50 (p

Published
2017

26. Adherence to the 2015 Dutch dietary guidelines and risk of non-communicable diseases and mortality in the Rotterdam Study

Author

Bruno H. Stricker, Henning Tiemeier, Josje D. Schoufour, Lies Lahousse, Oscar H. Franco, Trudy Voortman, Frank J. A. van Rooij, Jessica C. Kiefte-de Jong, M. Arfan Ikram, Guy Brusselle, Epidemiology, Internal Medicine, Child and Adolescent Psychiatry / Psychology, Psychiatry, and Pulmonary Medicine

Subjects
0301 basic medicine, Male, Epidemiology, Type 2 diabetes, RECOMMENDATIONS, Nutrition Policy, Rotterdam Study, 0302 clinical medicine, Risk Factors, Cause of Death, Validation, Medicine and Health Sciences, Medicine, Nutritional Epidemiology, Health Status Indicators, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Cancer, Netherlands, Aged, 80 and over, education.field_of_study, DEMENTIA, Incidence (epidemiology), Middle Aged, Cardiovascular disease, CANCER, CARDIOVASCULAR-DISEASE, Population Surveillance, Neurological, EATING INDEX, Female, Guideline Adherence, Cohort study, RESEARCH FUND/AMERICAN INSTITUTE, Diet quality, medicine.medical_specialty, Population, QUESTIONNAIRE, Guidelines as Topic, Lower risk, OBSTRUCTIVE PULMONARY-DISEASE, Diet Surveys, diseases, 03 medical and health sciences, SDG 3 - Good Health and Well-being, FOOD, Internal medicine, Humans, Mortality, HEALTHY, education, Noncommunicable Diseases, Aged, Proportional Hazards Models, 030109 nutrition & dietetics, business.industry, medicine.disease, PREVENTION, Surgery, PROSPECTIVE COHORT, Chronic Disease, business, Neurological diseases
Abstract

We aimed to evaluate the criterion validity of the 2015 food-based Dutch dietary guidelines, which were formulated based on evidence on the relation between diet and major chronic diseases. We studied 9701 participants of the Rotterdam Study, a population-based prospective cohort in individuals aged 45 years and over [median 64.1 years (95%-range 49.0–82.8)]. Dietary intake was assessed at baseline with a food-frequency questionnaire. For all participants, we examined adherence (yes/no) to fourteen items of the guidelines: vegetables (≥200 g/day), fruit (≥200 g/day), whole-grains (≥90 g/day), legumes (≥135 g/week), nuts (≥15 g/day), dairy (≥350 g/day), fish (≥100 g/week), tea (≥450 mL/day), ratio whole-grains:total grains (≥50%), ratio unsaturated fats and oils:total fats (≥50%), red and processed meat (

Published
2017

27. Standard process-oriented workflow introduces pre-analytical error when used in large study sample batches

Author

Robert Zietse, Frank J. A. van Rooij, Jan Heeringa, Ewout J. Hoorn, Brenda C.T. Kieboom, Robin P. Peeters, M. Arfan Ikram, Bruno H. Stricker, Albert Hofman, Cornelia M. van Duijn, Yolanda B. de Rijke, Christian Ramakers, Epidemiology, Internal Medicine, and Clinical Chemistry

Subjects
Quality Control, 030213 general clinical medicine, Medical Errors, Pre analytical, Computer science, Biochemistry (medical), Clinical Biochemistry, Sample (statistics), General Medicine, 030204 cardiovascular system & hematology, computer.software_genre, Workflow, 03 medical and health sciences, 0302 clinical medicine, Process oriented, Large study, Humans, Data mining, computer, Blood Chemical Analysis
Published
2018

28. Associations of Activity and Sleep With Quality of Life: A Compositional Data Analysis

Author

Sanne Verhoog, Arjola Bano, Chantal M. Koolhaas, Kim V.E. Braun, Frank J. A. van Rooij, Oscar H. Franco, Trudy Voortman, and Epidemiology

Subjects
Gerontology, Data Analysis, Male, 2019-20 coronavirus outbreak, Time Factors, Epidemiology, Psychological intervention, Physical activity, 01 natural sciences, 03 medical and health sciences, Rotterdam Study, 0302 clinical medicine, Quality of life, Accelerometry, Medicine, Humans, 030212 general & internal medicine, 0101 mathematics, 610 Medicine & health, Exercise, Aged, Aged, 80 and over, business.industry, 010102 general mathematics, Public Health, Environmental and Occupational Health, food and beverages, Sedentary behavior, Middle Aged, Sleep in non-human animals, Cross-Sectional Studies, Quality of Life, Sleep diary, Female, business, Sleep, 360 Social problems & social services
Abstract

Introduction: Associations between time spent on physical activity, sedentary behavior, and sleep and quality of life are usually studied without considering that their combined time is fixed. This study investigates the reallocation of time spent on physical activity, sedentary behavior, and sleep during the 24-hour day and their associations with quality of life. Methods: Data from the 2011–2016 Rotterdam Study were used to perform this cross-sectional analysis among 1,934 participants aged 51–94 years. Time spent in activity levels (sedentary, light-intensity physical activity, moderate-to-vigorous physical activity, and sleep) were objectively measured with a wrist-worn accelerometer combined with a sleep diary. Quality of life was measured using the EuroQoL 5D-3L questionnaire. The compositional isotemporal substitution method was used in 2018 to examine the association between the distribution of time spent in different activity behaviors and quality of life. Results: Reallocation of 30 minutes from sedentary behavior, light-intensity physical activity, or sleep to moderate-to-vigorous physical activity was associated with a higher quality of life, whereas reallocation from moderate-to-vigorous physical activity to sedentary behavior, light-intensity physical activity, or sleep was associated with lower quality of life. To illustrate this, a reallocation of 30 minutes from sedentary behavior to moderate-to-vigorous physical activity was associated with a 3% (95% CI=2, 4) higher quality of life score. By contrast, a reallocation of 30 minutes from moderate-to-vigorous physical activity to sedentary behavior was associated with a 4% (95% CI=2, 6) lower quality of life score. Conclusions: Moderate-to-vigorous physical activity is important with regard to the quality of life of middle-aged and elderly individuals. The benefits of preventing less time spent in moderate-to-vigorous physical activity were greater than the benefits of more time spent in moderate-to-vigorous physical activity. These results could shift the attention to interventions focused on preventing reductions in moderate-to-vigorous physical activity levels. Further longitudinal studies are needed to confirm these findings and explore causality.

Published
2019

29. Genome-wide association study identifies 48 common genetic variants associated with handedness

Author

Christian Gieger, Teemu Palviainen, Bettina Konte, Peter P. Pramstaller, Aarno Palotie, Elisabeth Widen, Monique M.B. Breteler, Caroline Hayward, Xin Li, Tim D. Spector, Jing Hua Zhao, John M. Starr, David M. Evans, Nicholas G. Martin, Wendy L. McArdle, Nicole Soranzo, Mads Melbye, Peter Kraft, André G. Uitterlinden, Beate St Pourcain, Massimo Mangino, Daniel I. Chasman, Jacques S. Beckmann, Gabriel Cuellar Partida, George Davey Smith, Cecilia M. Lindgren, Johan G. Eriksson, Alan F. Wright, Kauko Heikkilä, Eva Albrecht, Gudmar Thorleifsson, Mari Nelis, Nicholas Eriksson, Dawn M. Waterworth, Leena Peltonen, Frank J. A. van Rooij, Jari Lahti, Maris Teder-Laving, Igor Rudan, Annette M. Hartmann, Guillaume Paré, Ole A. Andreassen, Mohammad Arfan Ikram, Stacy Steinberg, Bjarke Feenstra, Peter Vollenweider, Sarah E. Medland, Brenda W.J.H. Penninx, Mark I. McCarthy, Jordan W. Smoller, Fazil Aliev, Joel N. Hirschhorn, Dan Rujescu, J.M. Vink, Dorret I. Boomsma, Harry Campbell, Pedro Marques-Vidal, David A. Hinds, Tõnu Esko, Ruth J. F. Loos, Zoltán Kutalik, Jouke-Jan Hottenga, Reedik Mägi, Dale R. Nyholt, Kari Stefansson, Kevin S. O’Connell, Hreinn Stefansson, Scott Melville, Andres Metspalu, Inês Barroso, Marco P. Boks, Gail Davies, Lavinia Paternoster, Thomas Hansen, Norman Klopp, H.-Erich Wichmann, David L. Duffy, Lili Milani, Heather A. Boyd, Michelle Luciano, Benjamin M. Neale, Margaret J. Wright, Fernando Rivadeneira, Liang-Dar Hwang, Scott D. Gordon, Jiali Han, Jennifer E. Huffman, Danielle M. Dick, Roel A. Ophoff, Ozren Polasek, Nicholas J. Wareham, Vincent Mooser, Mousheng Xu, Johannes H. Smit, Gonneke Willemsen, Ian J. Deary, Panos Deloukas, John P. Kemp, Cornelia M. van Duijn, Samuli Ripatti, Joyce Y. Tung, Eco J. C. de Geus, Cameron D. Palmer, Ina Giegling, Katri Räikkönen, Thomas Werge, Eero Vuoksimaa, Andrew A. Hicks, Inga Prokopenko, Lynn Cherkas, Sigurdur H. Magnusson, Gérard Waeber, Nicholas J. Timpson, Frank Geller, Carolina Medina-Gomez, Nicole M. Warrington, Kay-Tee Khaw, and Jaakko Kaprio

Subjects
Genetics, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Genetic variants, Biology, Association (psychology), Biobank, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

Published
2019

30. Associations of autozygosity with a broad range of human phenotypes

Author

Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott D [0000-0001-7623-328X], Harris, Sarah E [0000-0002-4941-5106], Kacprowski, Tim [0000-0002-5393-2413], Karlsson, Torgny [0000-0001-8095-6149], Kleber, Marcus E [0000-0003-0663-7275], Mahajan, Anubha [0000-0001-5585-3420], Matsuda, Koichi [0000-0001-7292-2686], Meng, Weihua [0000-0001-5388-8494], van der Most, Peter J [0000-0001-8450-3518], Munz, Matthias [0000-0002-4728-3357], Palviainen, Teemu [0000-0002-7847-8384], Prasad, Rashmi B [0000-0002-4400-6741], Salvi, Erika [0000-0002-2724-2291], Skotte, Line [0000-0002-7398-1271], van der Spek, Ashley [0000-0001-7136-0159], Spracklen, Cassandra N [0000-0003-3590-7182], Strawbridge, Rona J [0000-0001-8506-3585], Tajuddin, Salman M [0000-0002-7919-8528], Verweij, Niek [0000-0002-4303-7685], Yanek, Lisa R [0000-0001-7117-1075], Zhao, Wei [0000-0001-7388-0692], Albert, Matthew L [0000-0001-7285-6973], Bentley, Amy R [0000-0002-0827-9101], Chanock, Stephen [0000-0002-2324-3393], Chen, Zhengming [0000-0001-6423-105X], Chiu, Yen-Feng [0000-0002-3352-4500], Cocca, Massimiliano [0000-0002-1127-7596], Collins, Francis S [0000-0002-1023-7410], Cugliari, Giovanni [0000-0002-6080-0718], Damulina, Anna [0000-0001-8241-2727], Day, Felix R [0000-0003-3789-7651], Dhana, Klodian [0000-0002-6397-7009], Dzimiri, Nduna [0000-0003-3395-5754], Elliott, Paul [0000-0002-7511-5684], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Girotto, Giorgia [0000-0003-4507-6589], Goel, Anuj [0000-0003-2307-4021], Goodarzi, Mark O [0000-0001-6364-5103], Gudbjartsson, Daniel F [0000-0002-5222-9857], Guity, Kamran [0000-0002-8379-9668], van Heel, David A [0000-0002-0637-2265], Hirata, Makoto [0000-0002-9994-9958], Ikram, M Arfan [0000-0003-0372-8585], Kamatani, Yoichiro [0000-0001-8748-5597], Kanai, Masahiro [0000-0001-5165-4408], Khor, Chiea Chuen [0000-0002-1128-4729], Kolcic, Ivana [0000-0001-7918-6052], Langenberg, Claudia [0000-0002-5017-7344], Lawlor, Deborah A [0000-0002-6793-2262], Liu, Jianjun [0000-0002-3255-3019], London, Stephanie J [0000-0003-4911-5290], Luan, Jian’an [0000-0003-3137-6337], Matoba, Nana [0000-0001-5329-0134], Mei, Xue W [0000-0002-6279-4884], Mezzavilla, Massimo [0000-0002-9000-4595], Milani, Lili [0000-0002-5323-3102], Mori, Trevor A [0000-0002-5264-9229], Murakami, Yoshinori [0000-0002-2826-4396], Murray, Alison D [0000-0003-4915-4847], Mychaleckyj, Josyf C [0000-0003-2595-0005], Neville, Matt J [0000-0002-6004-5433], Nolte, Ilja M [0000-0001-5047-4077], Ong, Ken K [0000-0003-4689-7530], Pálsson, Gunnar [0000-0002-8231-3961], Pankow, James S [0000-0001-7076-483X], Pattaro, Cristian [0000-0002-4119-0109], Quintana-Murci, Lluis [0000-0003-2429-6320], van Rheenen, Wouter [0000-0002-5860-1533], Rich, Stephen S [0000-0003-3872-7793], Rietveld, Cornelius A [0000-0003-4053-1861], Ruggiero, Daniela [0000-0003-3898-7827], Sabanayagam, Charumathi [0000-0002-4042-4719], Sabater-Lleal, Maria [0000-0002-0128-379X], Sala, Cinzia Felicita [0000-0003-2514-2075], Salomaa, Veikko [0000-0001-7563-5324], Scott, Laura J [0000-0002-4886-5084], Sedaghati-Khayat, Bahareh [0000-0002-7665-8648], Sennblad, Bengt [0000-0002-4360-8003], van Setten, Jessica [0000-0002-4934-7510], Smith, Blair H [0000-0002-5362-9430], Stančáková, Alena [0000-0002-1375-0252], Stanton, Alice [0000-0002-4961-165X], Straker, Leon [0000-0002-7786-4128], Sulem, Patrick [0000-0001-7123-6123], Swertz, Morris A [0000-0002-0979-3401], Taylor, Kent D [0000-0002-2756-4370], Tzoulaki, Ioanna [0000-0002-4275-9328], Veldink, Jan H [0000-0001-5572-9657], Vitart, Veronique [0000-0002-4991-3797], Völker, Uwe [0000-0002-5689-3448], Wander, Gurpreet S [0000-0002-4596-4247], Wang, Ya Xing [0000-0003-2749-7793], Wild, Sarah [0000-0001-7824-2569], Yuan, Jian-Min [0000-0002-4620-3108], Asselbergs, Folkert W [0000-0002-1692-8669], Boehnke, Mike [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Brody, Jennifer A [0000-0001-8509-148X], Campbell, Archie [0000-0003-0198-5078], Caulfield, Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics

Subjects
0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract

Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.

Published
2019

31. Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study

Author

Kari E. North, Cécile Lecoeur, Katja Pahkala, Meng Gao, Kim Overvad, Cyrus Cooper, Luis A. Moreno, Keith M. Godfrey, Wanting Zhao, Sing Hui Lim, Emily Sonestedt, Albert Hofman, Karen A. Jameson, Zhe Fang, Frits R. Rosendaal, Yih Chung Tham, Jean-Paul Langhendries, Janine F. Felix, Tao Huang, Frédéric Gottrand, Woon-Puay Koh, Torben Hansen, Lu Qi, Hans Bisgaard, Jorma Viikari, Jianjun Liu, Marju Orho-Melander, Meian He, Beverley Balkau, Xueling Sim, Xiang Li, Peter Rzehak, Oluf Pedersen, Philippe Froguel, Donna K. Arnett, Oscar Coltell, Ulrika Ericson, George Davey Smith, Seang-Mei Saw, Joachim Thiery, Joaquin Escribano, Elvira Verduci, Tien Yin Wong, Nadia R. Fink, Yujie Wang, Eirini Marouli, Tiange Wang, Yan Zheng, Chao-Qiang Lai, Aline Meirhaeghe, Colin Boreham, Daniel I. Chasman, Chiea Chuen Khor, Frédéric Fumeron, Graciela E. Delgado, Katherine L. Tucker, Dennis O. Mook-Kanamori, Dariush Mozaffarian, Tuomas O. Kilpeläinen, Jin-Fang Chai, Thorkild I. A. Sørensen, André G. Uitterlinden, Oscar H. Franco, Trudy Voortman, Jian-Min Yuan, Frank J. A. van Rooij, Vincent W. V. Jaddoe, Fernando Rivadeneira, Rebecca K. Vinding, Astrid Sevelsted, Masato Akiyama, Hazel Inskip, Dolores Corella, Jean Dallongeville, Rajkumar Dorajoo, Jose M. Ordovas, Tao Zhang, Diana van Heemst, Blanche Lim, Nanette R. Lee, Michiaki Kubo, Preeti Gupta, Caizheng Yu, Mariaelisa Graff, Peter Rossing, Carol A. Wang, Tarunveer S. Ahluwalia, Jorge E. Chavarro, Elaine M. Dennison, Yik Ying Teo, Terho Lehtimäki, Alexis C. Frazier-Wood, Christina Ellervik, Chris Power, Marie Standl, Christina-Alexandra Schulz, David A. Mackey, Anne Tjønneland, Panagiotis Deloukas, Ramon Estruch, George Dedoussis, Niina Pitkänen, Paul M. Ridker, Olli T. Raitakari, Charumathi Sabanayagam, Markus Loeffler, Rob M. van Dam, Raymond Noordam, Yoichiro Kamatani, Winfried März, Markus Scholz, Harri Niinikoski, Dariusz Gruszfeld, Tangchun Wu, Elina Hyppönen, Rozenn N. Lemaitre, Marcus E. Kleber, Berthold Koletzko, E-Shyong Tai, Veit Grote, Klaus Bønnelykke, Ching-Yu Cheng, Carla M. T. Tiesler, Karen L. Mohlke, E. Thiering, Renée de Mutsert, Ang Zhou, Mika Kähönen, Luc Djoussé, Philippe Amouyel, Sarah Crozier, Ralph Burkhardt, Yuan Shi, Bruce M. Psaty, Huang, Tao, Wang, Tiange, Zheng, Yan, Ellervik, Christina, Zhou, Ang, Hyppönen, Elina, Qi, Lu, BIRTH-GENE (BIG) Study Working Group, Department of Technology and Operations Management, Epidemiology, Erasmus MC other, and Pediatrics

Subjects
Blood Glucose, Male, Type 2 diabetes, 0302 clinical medicine, Odds Ratio, Birth Weight, Insulin, 030212 general & internal medicine, Original Investigation, 0303 health sciences, Asia, Eastern, Mendelian Randomization Analysis, General Medicine, Middle Aged, 16. Peace & justice, 3. Good health, Online Only, Diabetes and Endocrinology, Female, type 2 diabetes, Adult, medicine.medical_specialty, Diabetes risk, Adolescent, Birth weight, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Young Adult, SDG 3 - Good Health and Well-being, Asian People, Diabetes mellitus, Internal medicine, Mendelian randomization, medicine, Humans, 030304 developmental biology, Glycemic, Aged, Glycated Hemoglobin, business.industry, Research, Infant, Newborn, birth weight, Genetic Variation, Odds ratio, medicine.disease, Diabetes Mellitus, Type 2, mendelian randomization study, business
Abstract

Key Points Question Is birth weight associated with type 2 diabetes and glycemic traits? Findings This mendelian randomization study found that a 1-SD decrease in birth weight due to the genetic risk score was associated with a higher risk of type 2 diabetes among European and East Asian populations. In addition, a 1-SD decrease in birth weight was associated with a 0.189-SD increase in fasting glucose concentration, but not with fasting insulin, 2-hour glucose, or hemoglobin A1c level. Meaning A genetic predisposition to lower birth weight was associated with an increased risk of type 2 diabetes and increased fasting glucose, suggesting potential mechanisms through which perturbation of the antenatal and early-life environment affect predisposition to diabetes in later life., This mendelian randomization study examines the association of birth weight with type 2 diabetes and glycemic traits., Importance Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures Type 2 diabetes and glycemic traits. Results This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10−5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (β = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

Published
2019

32. 10-Year Survival After FFR-Guided Strategy in Isolated Proximal Left Anterior Descending Coronary Stenosis

Author

Frank J. A. van Rooij, Maryam Kavousi, Oscar H. Franco, Bernard De Bruyne, Emanuele Barbato, Anastasios Milkas, Oscar L. Rueda-Ochoa, Carlos Collet, Stephane Fournier, Olivier Muller, Graduate School, ACS - Heart failure & arrhythmias, Milkas, A., Rueda-Ochoa, O. L., Fournier, S., Muller, O., Van Rooij, F., Franco, O. H., Collet, C., Barbato, E., Kavousi, M., and De Bruyne, B.

Subjects
Male, Coronary angiography, medicine.medical_specialty, Poor prognosis, Kaplan-Meier Estimate, Fractional flow reserve, Coronary stenosis, 030204 cardiovascular system & hematology, Anterior Descending Coronary Artery, Coronary Angiography, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Myocardial Revascularization, medicine, Humans, 030212 general & internal medicine, medicine.diagnostic_test, business.industry, Patient Selection, Coronary Stenosis, Middle Aged, medicine.disease, Coronary Vessels, Fractional Flow Reserve, Myocardial, Stenosis, Angiography, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract

The presence at coronary angiography of a stenosis in the proximal left anterior descending coronary artery (LAD) bears a poor prognosis [(1)][1]. Given the known limitations of angiography to define severity of stenosis, fractional flow reserve (FFR) is now considered the standard of reference to

Published
2019

33. Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits

Author

Mary Cushman, John M. Starr, Min-Lee Yang, Wei Zhou, Ursula M. Schick, Vinna Clavo, Bella Hu, Oluf Pedersen, Tarunveer S. Ahluwalia, John D. Eicher, Santhi K. Ganesh, Albert V. Smith, Abbas Dehghan, Rebecca D. Jackson, Ian J. Deary, Mika Kähönen, Megan L. Grove, Jennifer A. Brody, Judy Wang, Amanda M Rosa Di Sant, Lenore J. Launer, Stephen S. Rich, Jiansong Wang, David C. Liewald, Paul I.W. de Bakker, Jerome I. Rotter, Leo-Pekka Lyytikäinen, Ruth J. F. Loos, Leonard I. Zon, Bruce M. Psaty, Nora Franceschini, Erwin P. Bottinger, Ming-Huei Chen, Paul L. Auer, James G. Wilson, Raha Pazoki, Nathan Pankratz, Russell P. Tracy, Vilmundur Gudnason, André G. Uitterlinden, Mike A. Nalls, Kristina L. Hunker, Frank J. A. van Rooij, Eric Boerwinkle, Kent D. Taylor, Albert Hofman, Yan Zhang, Mattijs E. Numans, Yong Huo, Yi Zhou, Folkert W. Asselbergs, James S. Floyd, Richard L. Proia, Yingchang Lu, Terho Lehtimäki, Liguang Dong, Riccardo E. Marioni, Jette Bork-Jensen, Jia Jia, Tamara B. Harris, Vy M. Nguyen, Fernando Rivadeneira, Oscar H. Franco, Yongmei Liu, Niels Grarup, Andrew D. Johnson, L. Adrienne Cupples, Ani Manichaikul, Elliott J. Hagedorn, Xiaoling Zhang, Maarten Leusink, Torben Hansen, Ingrid B. Borecki, Maria L. Allende, Betina Heinsbek Thuesen, Allan Linneberg, Olli T. Raitakari, Christopher J. O'Donnell, Mary F. Feitosa, Melissa E. Garcia, Alexander P. Reiner, Epidemiology, and Internal Medicine

Subjects
Male, 0301 basic medicine, Erythrocytes, Quantitative Trait Loci, Population, Genome-wide association study, Quantitative trait locus, Hematocrit, Biology, Article, Mice, 03 medical and health sciences, White blood cell, Genotype, Ethnicity, Journal Article, Genetics, medicine, Animals, Humans, Exome, education, Zebrafish, Medicine(all), education.field_of_study, medicine.diagnostic_test, ta1184, ta3121, 3. Good health, Receptors, Lysosphingolipid, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, Immunology, Erythrocyte Count, Absolute neutrophil count, Female, Genome-Wide Association Study
Abstract

Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.

Published
2016

34. Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

Author

Anne-Claire Vergnaud, Nauder Faraday, Tim Kacprowski, Lisa R. Yanek, Oscar H. Franco, Yongmei Liu, Andreas Greinacher, Gina M. Peloso, Cristen J. Willer, Leslie A. Lange, Eric S. Torstenson, Reedik Mägi, Jeanette Erdmann, Ethan M. Lange, Deborah A. Nickerson, Henry Völzke, David R. Crosslin, Gunnar Engström, Albert V. Smith, André G. Uitterlinden, Salman M. Tajuddin, W. David Hill, Diane M. Becker, Paul Elliot, Caterina Vacchi-Suzzi, Linda M. Polfus, Traci M. Bartz, Nathalie Chami, Abbas Dehghan, Mike A. Nalls, John D. Eicher, Leo-Pekka Lyytikäinen, Evelin Mihailov, Uwe Völker, Caroline Hayward, Ioanna Tzoulaki, Myriam Fornage, Marju Orho-Melander, Mary Cushman, Lars Wallentin, Terho Lehtimäki, Ayush Giri, Laura M. Raffield, Lewis C. Becker, Yingchang Lu, Emma Raitoharju, Sekar Kathiresan, Simon de Denus, Ruth J. F. Loos, James S. Floyd, Dawn M. Waterworth, James G. Wilson, Nathan Pankratz, Lenore J. Launer, Andrew D. Johnson, Andrew J. Slater, Jean-Claude Tardif, Raha Pazoki, Evangelos Evangelou, Kenneth Rice, Harvey D. White, Marie-Pierre Dubé, Frank J. A. van Rooij, Akihiro Nomura, Tamara B. Harris, Vilmundur Gudnason, Gonçalo R. Abecasis, Alan B. Zonderman, Guillaume Lettre, Todd L. Edwards, Amber A. Burt, Ani Manichaikul, Heribert Schunkert, Ming-Huei Chen, Ian J. Deary, Michelle L. O'Donoghue, Jennifer A. Brody, Russell P. Tracy, Tõnu Esko, Mika Kähönen, Panos Deloukas, Eric Boerwinkle, Rasika A. Mathias, Dajiang J. Liu, Jin Li, Santhi K. Ganesh, David C. Liewald, Paul L. Auer, Digna R. Velez Edwards, Erwin P. Bottinger, Nina Mononen, Claudia Schurmann, Michele K. Evans, John M. Starr, Thomas Thiele, Jussi Hernesniemi, Jerome I. Rotter, Rakale C. Quarells, He Gao, Kjell Nikus, Stephen S. Rich, Heather M. Highland, Bruce M. Psaty, Ursula M. Schick, Andres Metspalu, Melissa A. Richard, Neil A. Zakai, Olle Melander, John D. Rioux, Olli T. Raitakari, Alexander P. Reiner, Joel N. Hirschhorn, Nilesh J. Samani, Epidemiology, Internal Medicine, Home Office, National Institute for Health Research, and Medical Research Council (MRC)

Subjects
0301 basic medicine, Blood Platelets, Male, CARDIoGRAM Exome Consortium, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Myocardial Infarction Genetics Consortium, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Platelet, Exome, Genetics(clinical), Mean platelet volume, Allele frequency, Genotyping, Genetics (clinical), Genetics & Heredity, Platelet Count, ta1184, Genetic Variation, Global Lipids Genetics Consortium, 11 Medical And Health Sciences, 06 Biological Sciences, FCER1A, Genetic architecture, 030104 developmental biology, Hemostasis, Immunology, Female, Mean Platelet Volume, Genome-Wide Association Study
Abstract

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

Published
2016

35. Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis

Author

Raha Pazoki, Nora Franceschini, James S. Floyd, Guillaume Lettre, Fernando Rivadeneira, Abbas Dehghan, Leo-Pekka Lyytikäinen, Albert Hofman, Ming-Huei Chen, Eric Boerwinkle, Jill M. Johnsen, Mart Kals, Xiaoling Zhang, Lewis C. Becker, Jennifer A. Brody, Dennis O. Mook-Kanamori, Lu Chen, James G. Wilson, Rajiv K. Khajuria, Vijay G. Sankaran, Nathan Pankratz, Lisa R. Yanek, Leslie A. Lange, Mika Kähönen, Linda M. Polfus, Traci M. Bartz, Nena Matijevic, Oscar H. Franco, Donna M. Muzny, Keolu Fox, Richard A. Gibbs, Narayanan Veeraraghavan, Tõnu Esko, Aoi Wakabayashi, Gina M. Peloso, André G. Uitterlinden, Paul L. Auer, Frank J. A. van Rooij, Kenneth Rice, Santhi K. Ganesh, Terho Lehtimäki, Klaudia Walter, Ruifang Li-Gao, Ginger A. Metcalf, Jie Huang, Stephen S. Rich, Cornelia M. van Duijn, Nicole Soranzo, Bruce M. Psaty, Robert B. Wallace, Ursula M. Schick, Andres Metspalu, Olli T. Raitakari, Christopher J. O'Donnell, Alexander P. Reiner, Andrew D. Johnson, Epidemiology, and Internal Medicine

Subjects
0301 basic medicine, Blood Platelets, Megakaryocyte differentiation, DNA Mutational Analysis, 030204 cardiovascular system & hematology, Biology, Blood cell, 03 medical and health sciences, 0302 clinical medicine, Proto-Oncogene Proteins, Report, medicine, Genetics, CRISPR, Humans, splice, Exome, Genetics(clinical), Progenitor cell, Genetics (clinical), Exome sequencing, Gene Editing, Platelet Count, Alternative splicing, Correction, ta3121, Hematopoietic Stem Cells, Human genetics, 3. Good health, Hematopoiesis, Repressor Proteins, Haematopoiesis, Alternative Splicing, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, CRISPR-Cas Systems, Megakaryocytes
Abstract

Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0.33, discovery + replication p = 6.38 × 10(-10)) and a rare synonymous variant in GFI1B (rs150813342, MAF = 0.009, discovery + replication p = 1.79 × 10(-27)). By performing CRISPR/Cas9 genome editing in hematopoietic cell lines and follow-up targeted knockdown experiments in primary human hematopoietic stem and progenitor cells, we demonstrate an alternative splicing mechanism by which the GFI1B rs150813342 variant suppresses formation of a GFI1B isoform that preferentially promotes megakaryocyte differentiation and platelet production. These results demonstrate how unbiased studies of natural variation in blood cell traits can provide insight into the regulation of human hematopoiesis.

Published
2016

36. Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

Author

Yingchang Lu, Lisa R. Yanek, Evangelos Evangelou, Andreas Greinacher, Leslie A. Lange, Albert Hofman, Rakale C. Quarells, Christopher J. O'Donnell, Simon de Denus, Marcus Dörr, Tamara B. Harris, Mary Cushman, Lars Wallentin, Digna R. Velez Edwards, Michelle L. O'Donoghue, Deborah A. Nickerson, Lisa Bastarache, Caterina Vacchi-Suzzi, Harvey D. White, Rasika A. Mathias, Jin Li, Santhi K. Ganesh, Leo-Pekka Lyytikäinen, Kjell Nikus, Ayush Giri, Paul Elliott, John M. Starr, Ruth J. F. Loos, Vilmundur Gudnason, Ioanna Tzoulaki, Myriam Fornage, Joshua C. Denny, Alan B. Zonderman, Caroline Hayward, Lewis C. Becker, Raha Pazoki, Guillaume Lettre, Lenore J. Launer, Ursula M. Schick, Michele K. Evans, Andrew J. Slater, Diane M. Becker, Jean-Claude Tardif, Ethan M. Lange, John D. Eicher, He Gao, James S. Floyd, Eric Boerwinkle, Paul L. Auer, Nathalie Chami, Frank J. A. van Rooij, Claudia Schurmann, Nele Friedrich, Kent D. Taylor, Andres Metspalu, Todd L. Edwards, Anne-Claire Vergnaud, Yongmei Liu, W. David Hill, Nauder Faraday, Terho Lehtimäki, Amber A. Burt, Jerome I. Rotter, Albert V. Smith, Tõnu Esko, Traci M. Bartz, Tim Kacprowski, Mike A. Nalls, Alexander P. Reiner, Ani Manichaikul, Ian J. Deary, Eric S. Torstenson, Laura M. Raffield, David C. Liewald, Ming-Huei Chen, Erwin P. Bottinger, Reedik Mägi, Andrew D. Johnson, Melissa A. Richard, Neil A. Zakai, John D. Rioux, Mika Kähönen, Stephen S. Rich, Heather M. Highland, Bruce M. Psaty, Joel N. Hirschhorn, Salman M. Tajuddin, Linda M. Polfus, Dawn M. Waterworth, James G. Wilson, Nathan Pankratz, Abbas Dehghan, Evelin Mihailov, David R. Crosslin, André G. Uitterlinden, Georg Homuth, Jennifer A. Brody, Gastroenterology & Hepatology, Epidemiology, and Internal Medicine

Subjects
0301 basic medicine, Quality Control, Myeloid, 1.1 Normal biological development and functioning, Genome-wide association study, Biology, Autoimmune Disease, Medical and Health Sciences, Article, 03 medical and health sciences, Underpinning research, White blood cell, medicine, Leukocytes, Genetics, Humans, 2.1 Biological and endogenous factors, Genetics(clinical), Exome, Aetiology, Genetics (clinical), Genetic association, Genetics & Heredity, Medical And Health Sciences, Neutrophil clearance, Hematopoietic stem cell differentiation, Inflammatory and immune system, Human Genome, Genetic Pleiotropy, Hematology, Biological Sciences, Acquired immune system, Stem Cell Research, 3. Good health, Blood Cell Count, 030104 developmental biology, medicine.anatomical_structure, Immune System Diseases, Genetic Loci, Immunology, Stem Cell Research - Nonembryonic - Non-Human, Genome-Wide Association Study
Abstract

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

Published
2016

37. Genomic analysis of diet composition finds novel loci and associations with health and lifestyle

Author

Tõnu Esko, Bruce H. R. Wolffenbuttel, Jana V. van Vliet-Ostaptchouk, Peter J. van der Most, Richard Karlsson Linnér, Juan R. González, Emma L Anderson, Harold Snieder, Josje D. Schoufour, Taulant Muka, Chanwook Lee, Philipp Koellinger, Daniel J. Benjamin, K. Paige Harden, George Davey Smith, George McMahon, Kim Valeska Emilie Braun, Kaitlin H Wade, Nita G. Forouhi, James J. Lee, André G. Uitterlinden, Fumiaki Imamuri, Nicholas J. Wareham, Oscar H. Franco, Trudy Voortman, Peter Bowers, Cornelius A. Rietveld, Frank J. A. van Rooij, David Cesarini, Susan M. Ring, Ronald de Vlaming, Jian'an Luan, Aysu Okbay, Jessica C. Kiefte-de Jong, Claudia Langenberg, Mark Alan Fontana, Patrick Turley, Fernando Rivadeneira, M. Arfan Ikram, Mohsen Ghanbari, Pauline M Emmett, S. Fleur W. Meddens, Casper A.P. Burik, and Carson C. Chow

Subjects
2. Zero hunger, Genetics, 0303 health sciences, Waist, Heart disease, 1. No poverty, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Genome-wide association study, Type 2 diabetes, Biology, medicine.disease, Obesity, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, medicine, Sugar, 030304 developmental biology
Abstract

We conducted genome-wide association study (GWAS) meta-analyses of relative caloric intake from fat, protein, carbohydrates and sugar in over 235,000 individuals. We identified 21 approximately independent lead SNPs. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease (rg ≈ 0.15 – 0.5). Relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood poverty (|rg| ≈ 0.1 – 0.3). Overall, our results show that the relative intake of each macronutrient has a distinct genetic architecture and pattern of genetic correlations suggestive of health implications beyond caloric content.

Published
2018

38. The association between lifestyle and overall health, using the frailty index

Author

Frank J. A. van Rooij, Oscar H. Franco, Trudy Voortman, Josje D. Schoufour, M. Arfan Ikram, Stef Brinkman, Fernando Rivadeneira, Jessica C. Kiefte-de Jong, Epidemiology, and Internal Medicine

Subjects
Gerontology, Male, Aging, Health (social science), Population, Health Behavior, Frailty Index, 030204 cardiovascular system & hematology, Healthy Aging, 03 medical and health sciences, Rotterdam Study, 0302 clinical medicine, Quality of life, Risk Factors, Health care, Medicine, Health Status Indicators, Humans, 030212 general & internal medicine, Prospective Studies, education, Association (psychology), Life Style, Aged, Netherlands, Aged, 80 and over, education.field_of_study, Frailty, business.industry, Physical activity, Smoking, Middle Aged, Lifestyle factors, Cross-Sectional Studies, Cohort, Quality of Life, Female, Geriatrics and Gerontology, business, Alcohol use, Diet quality
Abstract

Objective To evaluate the associations of four individual lifestyle factors with frailty. Methods We used cross-sectional data from 11,539 participants of the Rotterdam Study, a population-based cohort, running from 1990 till now. A frailty index was used with a range from 0 to 100 (higher values indicating increasing frailty). We examined physical activity, dietary quality, alcohol intake, and smoking and calculated a sum-score of these, with a range from 0 (lowest) to 8 (highest). The associations between each lifestyle factor and the lifestyle score with frailty were evaluated. Results Each lifestyle factor was independently associated with frailty. Participants with high physical activity levels had lower frailty scores than participants with low physical activity (β = −4.70,95%CI = −5.10,−4.30). High diet quality, compared to low diet quality was associated with less frailty (β=-0.88,95%CI = −1.35,−0.42). Low alcohol intake was associated more frailty (β = 0.84, 95%CI = 0.39, 1.29). Never-smokers or former smokers had on average 1.15 (95%CI = −1.60,−0.69) and 1.28 (95%CI = −1.78,−0.79) better frailty scores than smokers. A one-unit increment of the lifestyle score was associated with lower frailty (β = −0.62;95%CI = −0.84,−0.53). Conclusions The prevention of frailty can lead to lower health care costs and a higher quality of life among the growing group of elderly people. Our results emphasize that there is an urgent need for preventions that combine several lifestyle factors to improve healthy ageing.

Published
2018

39. Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences1

Author

Edward Kong, Pascal Timshel, Danielle Posthuma, Tõnu Esko, Maël Lebreton, Kathleen Mullan Harris, Philipp Koellinger, Murray B. Stein, Abraham A. Palmer, Urs Fischbacher, Robert J. Ursano, Erdogan Taskesen, Peter Eibich, Paul R. H. J. Timmers, Anke R. Hammerschlag, Ann H. Caplin, Jian Yang, Sandra Sanchez-Roige, Peter K. Joshi, Matthias Sutter, Pierre Fontanillas, Chia-Yen Chen, Albert Hofman, Patrick Turley, David A. Hinds, Futao Zhang, David Cesarini, Christina M. Lill, Laura Buzdugan, Ville Karhunen, Abdel Abdellaoui, S. Fleur W. Meddens, Henning Tiemeier, Christian L. Zund, Gert G. Wagner, Richard Karlsson Linnér, Lars Bertram, David W. Clark, Roy Thurik, André G. Uitterlinden, Maciej Trzaskowski, Mohammad Arfan Ikram, David Laibson, Cornelius A. Rietveld, Arcadi Navarro, Ernst Fehr, Yang Wu, Matthew B. McQueen, Ronald C. Kessler, Magnus Johannesson, Patrick J. F. Groenen, Gregor Hasler, James F. Wilson, Daniel Schunk, Stephen P. Tino, Pietro Biroli, Mark Alan Fontana, Juan R. González, Meena Kumari, Gerardus A. Meddens, Jonathan P. Beauchamp, Michelle N. Meyer, Jason D. Boardman, James J. Lee, Carlos Morcillo-Suarez, Aaron Kleinman, Minna Männikkö, Andrew Conlin, Adam Auton, Tune H. Pers, Michel G. Nivard, Ronald de Vlaming, Jon White, Robert Karlsson, Daniel J. Benjamin, Maarten Kooyman, Jacob Gratten, Aysu Okbay, Remy Z. Levin, Melissa C. Smart, Harriet de Wit, Conor C. Dolan, Frank J. A. van Rooij, Patrik K. E. Magnusson, Sonia Jain, Rauli Svento, Klaus M. Schmidt, Dorret I. Boomsma, Gerard Muntané, James MacKillop, Robbee Wedow, and Yanchun Bao

Subjects
Genetics, 0303 health sciences, Gabaergic neurotransmission, Single-nucleotide polymorphism, Genome-wide association study, Biology, Phenotype, 03 medical and health sciences, 0302 clinical medicine, SNP, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

Humans vary substantially in their willingness to take risks. In a combined sample of over one million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. We identified 611 approximately independent genetic loci associated with at least one of our phenotypes, including 124 with general risk tolerance. We report evidence of substantial shared genetic influences across general risk tolerance and risky behaviors: 72 of the 124 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is moderately to strongly genetically correlated (to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near general-risk-tolerance-associated SNPs are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We find no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.

Published
2018
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40. Physical activity and cause-specific mortality: the Rotterdam Study

Author

Henning Tiemeier, Frank J. A. van Rooij, Chantal M. Koolhaas, M. Arfan Ikram, Guy Brusselle, Oscar H. Franco, Lies Lahousse, Josje D. Schoufour, Klodian Dhana, Epidemiology, Neurology, Radiology & Nuclear Medicine, Pulmonary Medicine, and Psychiatry

Subjects
Lung Diseases, Male, medicine.medical_specialty, Time Factors, Epidemiology, Population, Infections, Lower risk, 03 medical and health sciences, Rotterdam Study, 0302 clinical medicine, Risk Factors, Interquartile range, Neoplasms, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, education, Exercise, Aged, Netherlands, Proportional Hazards Models, Cause of death, Aged, 80 and over, education.field_of_study, business.industry, Proportional hazards model, Hazard ratio, 030229 sport sciences, General Medicine, Middle Aged, Cardiovascular Diseases, Multivariate Analysis, Female, business
Abstract

Background: Physical activity (PA) is associated with lower risk for all-cause mortality. However, in elderly people, it remains unknown which types of PA are associated with mortality and whether the association between PA and mortality differs by cause of death. Methods: We assessed the association of total PA, walking, cycling, domestic work, sports and gardening with all-cause mortality, and the association of total PA with cause-specific mortality, using Cox proportional hazard models among 7225 older adults (mean age: 70 years) from the prospective population-based Rotterdam Study. Deaths were classified as due to cardiovascular diseases (CVDs), cancer, infections, external causes, dementia, chronic lung diseases or other causes. Activities were categorized into tertiles (lowest tertile as reference). To account for the possibility of reverse causation, we excluded the first 5 and 10 years of follow-up. Results: Over a median of 13.1 years of follow-up (interquartile range: 8.4-14.6 years), 3261 participants died. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) associated with high total PA compared with low were 0.69 (0.63, 0.75), 0.69 (0.58, 0.81), 0.44 (0.27, 0.71), 0.47 (0.32, 0.71) and 0.56 (0.46, 0.69) for mortality from all causes, CVDs, chronic lung diseases, infections and other causes, respectively. With longer exclusion times, the strength of these associations was attenuated. All PA types were associated with lower all-cause mortality risk. Conclusions: Engagement in higher PA levels was associated with lower risk of mortality from CVDs, chronic lung diseases, infections and other causes. Participating in any PA might reduce mortality risk in older adults.

Published
2018

41. Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE study

Author

Ran Tao, James S. Floyd, Charles Kooperberg, Kari E. North, Alexander P. Reiner, Christy L. Avery, Claudia Schurmann, Chani J. Hodonsky, Jonathan M. Kocarnik, Ursula M. Schick, Danyu Lin, Ruth J. F. Loos, Myriam Fornage, Santhi K. Ganesh, Frank J. A. van Rooij, Steven Buyske, Lucia A. Hindorff, Christina L. Wassel, and Epidemiology

Subjects
0301 basic medicine, Genetics, education.field_of_study, Population, Locus (genetics), Single-nucleotide polymorphism, Hematology, Biology, Heritability, Genetic architecture, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Trait, Population study, education, 030217 neurology & neurosurgery, Genetic association
Abstract

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p

Published
2018

42. Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts

Author

Panos Deloukas, Mia-Maria Perälä, Andres Metspalu, Frank J. A. van Rooij, Lyn M. Steffen, Antti Jula, Aarno Palotie, Julius S. Ngwa, Markus Perola, Paul F. Jacques, K. Harald, Denise K. Houston, Johan G. Eriksson, Daniel I. Chasman, Albert Hofman, Veikko Salomaa, Vera Mikkilä, Jorma Viikari, André G. Uitterlinden, Rozenn N. Lemaitre, Lu Qi, Kati Kristiansson, George Dedoussis, Olli T. Raitakari, Paul Knekt, Loukianos S. Rallidis, Nike A. Nalls, Marcia C de Oliveira Otto, Dariush Mozaffarian, Luigi Ferrucci, Oscar H. Franco, Yongmei Liu, Stephen B. Kritchevsky, Jari Lahti, Terho Lehtimäki, Jennifer A. Nettleton, Paul M. Ridker, Dena G. Hernandez, Audrey Y. Chu, Luc Djoussé, David S. Siscovick, Lynda M. Rose, Mary K. Wojczynski, Mary F. Feitosa, Magi Reedik, Hassan S. Dashti, L. Adrienne Cupples, Stefania Bandinelli, Michael Y. Tsai, Toshiko Tanaka, Ingrid B. Borecki, Julie E. Buring, Jerome I. Rotter, Harri Rissanen, Marilyn C. Cornelis, Fischer Krista, Luting Xue, Jessica C. Kiefte-de Jong, Mika Kähönen, Maria Dimitriou, Evelin Mihailov, Ani Manichaikul, Satu Männistö, Stavroula Kanoni, Bruce M. Psaty, Epidemiology, Virology, Internal Medicine, Helsinki Collegium for Advanced Studies, Medicum, Department of Food and Nutrition, University of Helsinki, Institute for Molecular Medicine Finland, Research Programs Unit, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Developmental Psychology Research Group, Genomics of Neurological and Neuropsychiatric Disorders, and Koellinger, Philipp D

Subjects
0301 basic medicine, Male, Heredity, Physiology, lcsh:Medicine, Genome-wide association study, Cardiovascular, FTO gene, Oral and gastrointestinal, Geographical Locations, Cohort Studies, 0302 clinical medicine, Mathematical and Statistical Techniques, DIETARY-INTAKE, Medicine and Health Sciences, Public and Occupational Health, 030212 general & internal medicine, lcsh:Science, Cancer, RISK, 2. Zero hunger, Multidisciplinary, Genomics, Middle Aged, Eicosapentaenoic acid, Stroke, Europe, Eicosapentaenoic Acid, Docosahexaenoic acid, Physical Sciences, MACRONUTRIENT INTAKE, Female, Behavioral and Social Aspects of Health, Statistics (Mathematics), Research Article, Adult, Docosahexaenoic Acids, General Science & Technology, Fish Biology, Single-nucleotide polymorphism, Population stratification, ta3111, Research and Analysis Methods, White People, EVENTS, 03 medical and health sciences, Fish physiology, Complementary and Integrative Health, Genome-Wide Association Studies, Genetics, Fish Physiology, Animal Physiology, Humans, Statistical Methods, Nutrition, Aged, Prevention, ta1184, Human Genome, lcsh:R, Food Consumption, Biology and Life Sciences, Computational Biology, Human Genetics, Heritability, Genome Analysis, Vertebrate Physiology, United States, 030104 developmental biology, Seafood, People and Places, lcsh:Q, 3111 Biomedicine, Physiological Processes, Zoology, Mathematics, OMEGA-3-FATTY-ACIDS, Demography, Meta-Analysis, Genome-Wide Association Study
Abstract

Background Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences. Objective To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption. Design We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts. Results Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (Freq(A) = 0.015) was associated with 0.029 servings/day (similar to 1 serving/month) lower fish consumption (P = 1.96x10(-8)). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10(-7)). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA. Conclusions These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.

Published
2017

43. Seasonality of physical activity, sedentary behavior, and sleep in a middle-aged and elderly population: The Rotterdam study

Author

Josje D. Schoufour, Mònica Guxens, Oscar H. Franco, Frank J. A. van Rooij, Chantal M. Koolhaas, Magda Cepeda, Henning Tiemeier, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Psychiatry

Subjects
Male, Population, General Biochemistry, Genetics and Molecular Biology, Cohort Studies, 03 medical and health sciences, Rotterdam Study, 0302 clinical medicine, Accelerometry, Medicine, Humans, 030212 general & internal medicine, education, Exercise, Weather, Aged, Netherlands, Sunlight, education.field_of_study, business.industry, Obstetrics and Gynecology, 030229 sport sciences, Sedentary behavior, Seasonality, Middle Aged, medicine.disease, Sleep in non-human animals, Relative risk, Female, Seasons, Sedentary Behavior, business, Sleep, Demography, Cohort study
Abstract

Introduction Physical activity (PA) and sedentary behavior (SB) have seasonal patterns. It remains unclear how these patterns are associated with sleep, meteorological factors, and health. Methods Activity levels were continuously measured with an accelerometer for seven days between July 2011 and May 2016, among middle-aged (50–64 years), young-elderly (65–74 years) and old-elderly (≥75 years) participants of a population-based Dutch cohort study (n = 1116). Meteorological factors (ambient temperature, wind speed, sunlight hours, precipitation, and minimum visibility) were locally recorded. We first examined the seasonality of PA, SB, and nighttime sleep, stratified by age group. Second, we examined the influence of meteorological factors. Third, we modeled the potential seasonality of the all-cause mortality risk due to the seasonality of PA and SB, by using previously published relative risks. Results Levels of light and moderate-to-vigorous PA were higher in summer than in winter among middle-aged (seasonal variation = 18.1 and 14.8 min/day) and young-elderly adults (12.8 and 8.6 min/day). The pattern was explained by ambient temperature and sunlight hours. Nighttime sleep was 31.8 min/day longer in winter among middle-aged adults. SB did not show a seasonal pattern. No seasonality in activity levels was observed among old-elderly adults. The all-cause mortality risk may be higher in winter than in summer due to the accumulation of low levels of moderate to vigorous PA and high levels of SB. Conclusion PA has a larger degree of seasonality than SB and nighttime sleep among middle-aged and young-elderly adults. SB appears strongly ingrained in daily routine. Recommending the interruption of SB with light PA might be a good starting point for public health institutions.

Published
2017

44. Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies

Author

Jorma Viikari, Caren E. Smith, Jose M. Ordovas, Allan Linneberg, Yoriko Heianza, Dariush Mozaffarian, Olli T. Raitakari, Chao-Qiang Lai, Paul M. Ridker, Frida Renström, Marju Orho-Melander, Christina-Alexandra Schulz, Lynda M. Rose, Mary F. Feitosa, Audrey Y. Chu, Ulrika Ericson, Paul W. Franks, Tuomas O. Kilpelainen, Ulla Toft, Craig E. Pennell, Kim Overvad, Anette Varbo, Daniel I. Chasman, M. Carola Zillikens, Lu Qi, Dena G. Hernandez, Luigi Ferrucci, Toshiko Tanaka, Frank B. Hu, David S. Siscovick, Dian-jianyi Sun, Stella Aslibekyan, José V. Sorlí, Frank J. A. van Rooij, Alexis C. Frazier-Wood, Donna K. Arnett, Oscar Coltell, Inês Barroso, Tiange Wang, Børge G. Nordestgaard, Fredric Fumeron, Vera Mikkilä, Christina Ellervik, Tao Huang, Helle K. M. Bergholdt, Ingegerd Johansson, Stefania Bandinelli, Oluf Pedersen, Rozenn N. Lemaitre, Yujie Wang, Anne Tjønneland, Michael A. Province, Katherine L. Tucker, Albert Hofman, Camilla H. Sandholt, Ming Ding, Walter C. Willett, Oscar H. Franco, Trudy Voortman, Jerome I. Rotter, Mariaelisa Graff, M. Ester A. L. de Jonge, Peter R. Eastwood, Thorkild I. A. Sørensen, André G. Uitterlinden, Mary K. Wojczynski, Kari E. North, Carol A. Wang, Terho Lehtimäki, Dolores Corella, Emily Sonestedt, Stephen S. Rich, Bruce M. Psaty, Tzu-An Chen, Torben Hansen, Mika Kähönen, Mathew Allison, Epidemiology, Internal Medicine, Department of Food and Nutrition, and University of Helsinki

Subjects
Adult, medicine.medical_specialty, Milk intake, Genotype, Clinical Biochemistry, 030209 endocrinology & metabolism, Polymorphism, Single Nucleotide, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Environmental health, Epidemiology, Journal Article, medicine, EPIDEMIOLOGY, Humans, HETEROGENEITY, 030212 general & internal medicine, Prospective Studies, Dietary calcium, METAANALYSIS, RISK, 2. Zero hunger, Consumption (economics), Polymorphism, Genetic, DIETARY CALCIUM, business.industry, Biochemistry (medical), Body Weight, Mendelian Randomization Analysis, ASSOCIATION, ta3121, medicine.disease, MILK INTAKE, Obesity, CONTROLLED-TRIALS, WEIGHT-GAIN, Cross-Sectional Studies, OBESITY, Dairy Products, 3143 Nutrition, medicine.symptom, business, Weight gain, Body mass index
Abstract

BACKGROUND Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined. METHODS We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies. RESULTS Higher dairy intake was associated with higher BMI (β = 0.03 kg/m2 per serving/day; 95% CI, 0.00–0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14–0.25) serving/day higher dairy intake (P = 3.15 × 10−12) and 0.12 (95% CI, 0.06–0.17) kg/m2 higher BMI (P = 2.11 × 10−5). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (β = 0.60 kg/m2 per serving/day; 95% CI, 0.27–0.92; P = 3.0 × 10−4). CONCLUSIONS The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults.

Published
2017

45. FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals

Author

Frida Renström, Audrey Y. Chu, Ruth J. F. Loos, Torben Hansen, George Dedoussis, Toshiko Tanaka, W M Monique Verschuren, Denise K. Houston, Albert Hofman, Frank J. A. van Rooij, David J. Hunter, Yu Mi Kim, Ingrid B. Borecki, Majken K. Jensen, M. Carola Zillikens, Lars H. Ängquist, Marju Orho-Melander, David S. Siscovick, Stavroula Kanoni, Denise H. M. Heppe, Panos Deloukas, Dariush Mozaffarian, Nanette R. Lee, Paul M. Ridker, Tuomas O. Kilpeläinen, Nita G. Forouhi, Tarunveer S. Ahluwalia, Vera Mikkilä, Caren E. Smith, Kurt Lohman, Julius S. Ngwa, Yanping Li, Qibin Qi, Kay-Tee Khaw, Pedro Marques-Vidal, Claude Bouchard, Lu Qi, Jacqueline C.M. Witteman, Maarit A. Laaksonen, Muhammad Asif Ali, Robert Luben, Lene Christiansen, Johan G. Eriksson, Yechiel Friedlander, Peter Vollenweider, Shigeru Karasawa, Emily Sonestedt, Louis R. Pasquale, Peng Chen, Jirong Long, Cyrus Cooper, Harri Rissanen, Mi Kyung Kim, Ani Manichaikul, Kari E. North, Yu-Tang Gao, Wanqing Wen, Xu Lin, Terho Lehtimäki, Jaakko Tuomilehto, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Zhonghua Liu, Tao Wang, Nicholas J. Wareham, Ingegerd Johansson, Olli T. Raitakari, John W. Holloway, Oluf Pedersen, Mary K. Wojczynski, L. Adrienne Cupples, Daniel I. Chasman, Huaixing Li, Torben Jørgensen, Satu Männistö, Jingwen Zhu, Tuomo Rankinen, Wei Zheng, Karen L. Mohlke, Jae H. Kang, Frank B. Hu, Louis Pérusse, Gary C. Curhan, Tiina Jääskeläinen, Xiaochen Lin, Keri L. Monda, Kati Kristiansson, Rozenn N. Lemaitre, Ivonne Sluijs, Makoto Daimon, Xiao-Ou Shu, Yvonne T. van der Schouw, M. Perola, Min Xu, Paul W. Franks, Ulla Toft, E. Shyong Tai, Mary K. Downer, Jolanda M. A. Boer, Thorkild I. A. Sørensen, André G. Uitterlinden, Luigi Ferrucci, Jennifer A. Nettleton, Wei Lu, Liming Liang, Yong-Bing Xiang, Jinyan Huang, Qiuyin Cai, Erasmus MC other, Epidemiology, Internal Medicine, and Cardiology

Subjects
Adult, Male, medicine.medical_specialty, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Biology, FTO gene, Polymorphism, Single Nucleotide, White People, Body Mass Index, Asian People, Gene Frequency, SDG 3 - Good Health and Well-being, Internal medicine, Genetics, medicine, Genetic predisposition, Dietary Carbohydrates, Humans, Obesity, Allele, Molecular Biology, Allele frequency, Genetics (clinical), Alleles, Aged, ta1184, Association Studies Articles, Proteins, nutritional and metabolic diseases, General Medicine, ta3121, Middle Aged, medicine.disease, Dietary Fats, Minor allele frequency, Black or African American, Endocrinology, Female, Dietary Proteins, Energy Intake, Body mass index
Abstract

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m2, P = 1.9 × 10-105), and all participants (0.30 [0.30, 0.35] kg/m2, P = 3.6 × 10-107). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10-16), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10-9) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

Published
2017

46. Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

Author

Dennis O. Mook-Kanamori, Rehan Qayyum, Lisa R. Yanek, Luigi Ferrucci, Min-Lee Yang, David J. Stott, P. Eline Slagboom, Jin Li, Santhi K. Ganesh, Vera Grossmann, Myriam Fornage, Edith Hofer, Lewis C. Becker, Lenore J. Launer, Albert V. Smith, Brendan J. Keating, Frank J. A. van Rooij, Albert Hofman, Jun Li, Michiaki Kubo, Christian Mueller, Stella Trompet, Qiong Yang, Andrew D. Johnson, Zhao Chen, Robert J. Klein, Luanne L. Peters, Amy J. Lambert, Reinhold Schmidt, Eirini Trompouki, Kenneth Rice, Josef Coresh, Naoyuki Kamatani, Vilmundur Gudnason, Leslie A. Lange, Brian J. Abraham, Ursula M. Schick, Eric Boerwinkle, Leonard I. Zon, Bruce M. Psaty, Diane M. Becker, David Ginsburg, Gudny Eiriksdottir, Bella Hu, Mohsen Ghanbari, Dan L. Longo, Cornelia M. van Duijn, Oscar H. Franco, Beverly M. Snively, Margaux F. Keller, L. Adrienne Cupples, Yukinori Okada, James E. Hayes, Ian Ford, Jack M. Guralnik, Koichi Matsuda, J. Wouter Jukema, André G. Uitterlinden, Yoichiro Kamatani, Helena Schmidt, James G. Wilson, Michelle K. Evans, Tanja Zeller, Alan B. Zonderman, Fuu Jen Tsai, Yasaman Saba, Daniel Levy, Philipp S. Wild, Paul M. Ridker, Jaden Yang, Jer-Yuarn Wu, Janine F. Felix, Mike A. Nalls, Christopher J. O'Donnell, Karl C. Desch, Caroline S. Fox, Jennifer A. Brody, Alexander P. Reiner, Avik Choudhuri, Ayse Bilge Ozel, Abbas Dehghan, Andrew P. Morris, Ruifang Li-Gao, Daniel I. Chasman, Tamara B. Harris, Audrey Y. Chu, Toshiko Tanaka, Charles Kooperberg, Hua Tang, Song Yang, Yi Zhou, Sun Ha Jee, Kushang V. Patel, James S. Floyd, Atsushi Takahashi, Yuan-Tsong Chen, Ming-Huei Chen, Jerome I. Rotter, Li Ching Chang, Chien-Hsiun Chen, Epidemiology, and Internal Medicine

Subjects
0301 basic medicine, Male, Linkage disequilibrium, Asia, Erythrocytes, Genome-wide association study, Locus (genetics), RBPMS, 030105 genetics & heredity, Biology, Eastern, Genome, Medical and Health Sciences, Article, Linkage Disequilibrium, 03 medical and health sciences, Genetics, Ethnicity, Animals, Humans, Erythropoiesis, Allele, Genetics (clinical), Loss function, Alleles, Zebrafish, Genetic association, Genetics & Heredity, Asia, Eastern, Human Genome, Racial Groups, RNA-Binding Proteins, BioBank Japan Project, Bayes Theorem, Hematology, Biological Sciences, R1, 3. Good health, Europe, 030104 developmental biology, Africa, Female, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong invivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

Published
2017

47. Polygenic scores associated with educational attainment in adults predict educational achievement and ADHD symptoms in children

Author

Sang Hong Lee, Danielle Posthuma, Debbie A Lawlor, Michael B. Miller, Igor Rudan, Jürgen Wellmann, François Bastardot, Lawrence F. Bielak, Anu Realo, William G. Iacono, Lude Franke, Matthew Kowgier, Marika Kaakinen, Helena Schmidt, Jorma Viikari, Jennifer A. Smith, David R. Van Wagoner, Elizabeth G. Holliday, Veronique Vitart, Robert F. Krueger, Pamela A. F. Madden, Jan Emmanuel De, Andrew Heath, David Cesarini, Najaf Amin, Dale R. Nyholt, Juliette Harris, Nicholas J. Timpson, George Dedoussis, Stefania Bandinelli, W. Hoffmann, Albert V. Smith, Beate St Pourcain, Stavroula Kanoni, Martin F. Elderson, Maria Dimitriou, Jouke-Jan Hottenga, Min A. Jhun, Daniel S. Evans, Marjo-Riitta Järvelin, Lei Yu, Krista Fischer, Jae Hoon Sul, Jennifer R. Harris, Brenda W.J.H. Penninx, Antti-Pekka Sarin, Ida Surakka, Arpana Agrawal, Bo Jacobsson, Klaus Berger, Matt McGue, Christopher F. Chabris, Marisa Loitfelder, Veikko Salomaa, David Schlessinger, Mina K. Chung, Erik A. Ehli, Kati Kristiansson, Eva Albrecht, Niina Eklund, Aarno Palotie, Sarah E. Medland, Reinhold E. Schmidt, Kurt Lohman, Luigi Ferrucci, Osorio Meirelles, Ivana Kolcic, Vilmundur Gudnason, Nicholas G. Martin, Tomi E. Mäkinen, Robert M. Kirkpatrick, Thomas Illig, Peter M. Visscher, Håkon K. Gjessing, Sebastian E. Baumeister, Carla A. Ibrahim-Verbaas, Per Hall, Elisabeth Widen, Panos Deloukas, Ronny Myhre, Michelle N. Meyer, Jonathan P. Beauchamp, Caroline Hayward, Eveline L. de Zeeuw, Penelope A. Lind, Erik Ingelsson, Ian J. Deary, George Davey-Smith, Dalton Conley, Peter Lichtner, Cornelia M. van Duijn, Samuli Ripatti, Dena G. Hernandez, Albert Hofman, George McMahon, Thais S. Rizzi, Wei Zhao, Patrick K.E. Magnusson, Jingmei Li, Mariza de Andrade, Ben A. Oostra, Abdel Abdellaoui, Andres Metspalu, Patricia A. Peyser, Jessica D. Faul, David C. Liewald, Christina Holzapfel, Lydia Quaye, John Barnard, Meike Bartels, Christian Gieger, John P. Rice, Christiaan de Leeuw, Patricia A. Boyle, Nicholas D. Hastie, David R. Weir, Adriaan Hofman, Astanand Jugessur, Tamara B. Harris, Catharina E. M. van Beijsterveldt, Gail Davies, H.-Erich Wichmann, Lynn Cherkas, Polasek Ozren Polasek, Harm-Jan Westra, Yongmei Liu, Jari Lahti, Matthijs J. H. M. van der Loos, Rodney J. Scott, Gérard Waeber, Peter Vollenweider, Behrooz Z. Alizadeh, Frank J. A. van Rooij, Susan M. Ring, Judith M. Vonk, Lyle J. Palmer, Alexander Teumer, John M. Starr, Antonio Terracciano, Sara Hägg, Erkki Vartiainen, David Laibson, Eco J. C. de Geus, Mika Kähönen, Marco Masala, Peng Lin, Nicolas W. Martin, André G. Uitterlinden, Dorret I. Boomsma, Harry Campbell, Sutapa Mukherjee, Konstantin Shakhbazov, Henning Tiemeier, Zó Ltan Kutalik, Grant W. Montgomery, Eva Reinmaa, Aldo Rustichini, Wouter J. Peyrot, David M. Evans, Martin Preisig, Cornelius A. Rietveld, T.J. Glasner, J Kaprio, John Attia, Pedro Marques Vidal, Sharon L.R. Kardia, Peter K. Joshi, Toshiko Tanaka, Rauli Svento, Magnus Johannesson, Terho Lethimäki, Jüri Allik, Philip L. De Jager, Antti Latvala, Marja-Liisa Nuotio, Juha Karjalainen, Henry Völzke, Roy Thurik, Rolf Holle, Kelly S. Benke, Christopher Oldmeadow, Esko Toñu Esko, Johan G. Eriksson, Alan F. Wright, Francesco Cucca, Ute Bültmann, Olli T. Raitakari, Melissa E. Garcia, Patrick J. F. Groenen, Maria M. Groen-Blokhuis, Gonneke Willemsen, Jian Yang, Lili Milani, Fernando Rivadeneira, David A. Bennett, Gudny Eiriksdottir, Katri Räikkönen, Harold Snieder, Laura J. Bierut, James J. Hudziak, James F. Wilson, Rudolf S N Fehrmann, Jaime Derringer, Gareth E. Davies, K. Petrovic, Markus Perola, Lenore J. Launer, Daniel J. Benjamin, Paul Lichtenstein, Philipp Koellinger, Andreas Mielck, Jeffrey A. Boatman, Henrik Grönberg, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Public Health Research (PHR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), EMGO+ - Mental Health, Biological Psychology, Methods and Techniques, Child and Adolescent Psychiatry / Psychology, Ophthalmology, and Epidemiology

Subjects
Netherlands Twin Register (NTR), Multifactorial Inheritance, genetic association, genotype, Academic achievement, Educational achievement, single nucleotide polymorphism, genetic variability, Genetics (clinical), Netherlands, child, article, symptom, academic achievement, Psychiatry and Mental health, priority journal, achievement test, Regression Analysis, Psychology, SDG 4 - Quality Education, Clinical psychology, Adult, phenotype, effect size, attention deficit disorder, gene frequency, educational status, Cellular and Molecular Neuroscience, reading, study skills, mental disorders, Genetics, medicine, Humans, ADHD, Attention deficit hyperactivity disorder, Achievement test, controlled study, human, Association (psychology), Genetic association, attention disturbance, language, School performance, medicine.disease, arithmetic, major clinical study, Polygenic scores, Educational attainment, gene linkage disequilibrium, Attention Deficit Disorder with Hyperactivity, Study skills
Abstract

The American Psychiatric Association estimates that 3 to 7 per cent of all school aged children are diagnosed with attention deficit hyperactivity disorder (ADHD). Even after correcting for general cognitive ability, numerous studies report a negative association between ADHD and educational achievement. With polygenic scores we examined whether genetic variants that have a positive influence on educational attainment have a protective effect against ADHD. The effect sizes from a large GWA meta-analysis of educational attainment in adults were used to calculate polygenic scores in an independent sample of 12-year-old children from the Netherlands Twin Register. Linear mixed models showed that the polygenic scores significantly predicted educational achievement, school performance, ADHD symptoms and attention problems in children. These results confirm the genetic overlap between ADHD and educational achievement, indicating that one way to gain insight into genetic variants responsible for variation in ADHD is to include data on educational achievement, which are available at a larger scale. (C) 2014 Wiley Periodicals, Inc.

Published
2014

48. Multiple Nonglycemic Genomic Loci Are Newly Associated With Blood Level of Glycated Hemoglobin in East Asians

Author

Jong-Young Lee, Yasuharu Tabara, Daniel O. Stram, Lu Qi, Rob M. van Dam, Tien Yin Wong, Masato Isono, Yii-Der Ida Chen, Terri L. Young, Jer-Yuarn Wu, Chao A. Hsiung, Ling Lu, Jian-Min Yuan, Norihiro Kato, Min Jin Go, Tao Huang, Young-Jin Kim, Jianjun Liu, Jiemin Liao, Tetsuro Miki, Bong-Jo Kim, Wen-Harn Pan, Huaixing Li, Joo-Yeon Hwang, Jinrui Cui, Jirong Long, Yukinori Okada, Wayne Huey-Herng Sheu, Fumihiko Takeuchi, Mark O. Goodarzi, Chris Hsu, Qibin Qi, Peng Chen, Mark A. Pereira, Xingwang Ye, Yu-Tang Gao, Themistocles L. Assimes, Toshihiro Tanaka, Xiao-Ou Shu, Ken Yamamoto, Yechiel Friedlander, Tin Aung, Jerome I. Rotter, Jun Liang, Ryoichi Takayanagi, Frank J. A. van Rooij, Yiqin Wang, Yik Ying Teo, Atsushi Takahashi, Ching-Yu Cheng, Keizo Ohnaka, Michiaki Kubo, Li-Ching Chang, Jinyan Huang, Chiea Chuen Khor, Jeannette Lee, Xu Lin, Qiuyin Cai, Ah Chuan Thai, Yuan-Tson Chen, Chien-Hsiun Chen, Wei Zheng, Eranga N. Vithana, Myron D. Gross, Chew-Kiat Heng, E-Shyong Tai, Santhi K. Ganesh, Yoshikuni Kita, Woon-Puay Koh, and Hirotsugu Ueshima

Subjects
Adult, Blood Glucose, Male, Diabetes risk, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Cohort Studies, Genetic Heterogeneity, chemistry.chemical_compound, Asian People, Polymorphism (computer science), Diabetes mellitus, Internal Medicine, medicine, Humans, CDKAL1, Aged, Genetic association, Glycated Hemoglobin, Genetics, Asia, Eastern, Genetics/Genomes/Proteomics/Metabolomics, Middle Aged, medicine.disease, 3. Good health, chemistry, Genetic Loci, Female, Glycated hemoglobin, Genome-Wide Association Study
Abstract

Glycated hemoglobin A1c(HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1cin East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [ P value = 1.3 × 10-23], HBS1L/MYB [8.5 × 10-15], MYO9B [9.0 × 10-12], and CYBA [1.1 × 10-8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (

Published
2014

49. Objectively measured sedentary time and mental and cognitive health: Cross-sectional and longitudinal associations in The Rotterdam Study

Author

Henning Tiemeier, Desana Kocevska, M. Arfan Ikram, Chantal M. Koolhaas, Annemarie I. Luik, Oscar H. Franco, Frank J. A. van Rooij, Epidemiology, Child and Adolescent Psychiatry / Psychology, Neurology, and Radiology & Nuclear Medicine

Subjects
education.field_of_study, business.industry, Population, Cognition, 030229 sport sciences, medicine.disease, Mental health, 030227 psychiatry, 03 medical and health sciences, Psychiatry and Mental health, Rotterdam Study, 0302 clinical medicine, Cohort, Medicine, Anxiety, Risk factor, medicine.symptom, education, business, Applied Psychology, Anxiety disorder, Clinical psychology
Abstract

Introduction Based on studies using self-reported sitting time, sedentary behavior has been suggested as a risk factor for poor mental health and cognition. However, it remains unclear whether objectively measured sedentary behavior is longitudinally associated with depression, anxiety disorders or cognition. Methods In the population-based Rotterdam Study, cross-sectional and longitudinal associations of objectively assessed sedentary time with depressive symptoms, anxiety disorders and cognition were assessed among 1841 participants (mean follow-up: 5.7 years). Participants wore a wrist actigraph for seven days between 2004 and 2007 to assess sedentary time (hours/day). Depression, anxiety disorders and cognition were assessed twice between 2004 and 2014. Depressive symptoms were continuously measured with the Centre for Epidemiologic Studies-Depression scale (CES-D) and a diagnoses of anxiety disorder (n = 147) was obtained by interview, using an adapted version of the Munich Composite International Diagnostic Interview (M-CIDI). Cognition was assessed using a test-battery. Linear regression was performed for all continuous outcomes, and logistic regression for all binary outcomes. Results In analyses adjusted for age, sex, cohort and time awake only, 1 h/day more sedentary time was cross-sectionally associated with a 0.25 point (95% confidence interval (95%CI): 0.08, 0.41) higher CES-D score, 1.11 (95%CI: 1.01, 1.21) higher odds of anxiety disorder, and 0.03 (95%CI: 0.05, -0.01) lower global cognition score. After adjustment for confounders, these associations no longer remained. Sedentary time at baseline was not associated longitudinally with changes in depressive symptoms, anxiety disorders and cognition. Conclusions No support was found for an association between actigraphically measured sedentary time and mental health or cognition. All observed associations were explained by confounders, in particular, disability, occupational status and smoking. The previously reported association between sitting time and mental health might reflect residual confounding, bias of subjective measures, or the social context of sedentary behavior.

Published
2019

50. Serum testosterone levels in males are not associated with entrepreneurial behavior in two independent observational studies

Author

Patrick J. F. Groenen, Frank J. A. van Rooij, Fernando Rivadeneira, Robin Haring, Henri Wallaschofski, Albert Hofman, Frank H. de Jong, Thomas Kohlmann, Roy Thurik, Philipp Koellinger, Matthias Nauck, Sebastian E. Baumeister, André G. Uitterlinden, Cornelius A. Rietveld, Matthijs J. H. M. van der Loos, Economics, Amsterdam Neuroscience - Complex Trait Genetics, Management and Organisation, Applied Economics, Erasmus School of Economics, Econometrics, Epidemiology, Internal Medicine, and ABS Other Research (FEB)

Subjects
Male, medicine.medical_specialty, Globulin, Population, Experimental and Cognitive Psychology, Logistic regression, Free testosterone, Behavioral Neuroscience, Rotterdam Study, Sex hormone-binding globulin, Internal medicine, medicine, Humans, Testosterone, Self-employment, education, Aged, Non-sex hormone-binding globulin-bound testosterone, education.field_of_study, biology, Entrepreneurship, Testosterone (patch), Middle Aged, Cross-Sectional Studies, Endocrinology, Study of Health in Pomerania, biology.protein, Serum testosterone, Psychology, hormones, hormone substitutes, and hormone antagonists, Blood sampling
Abstract

Previous research has suggested a positive association between testosterone (T) and entrepreneurial behavior in males. However, this evidence was found in a study with a small sample size and has not been replicated. In the present study, we aimed to verify this association using two large, independent, population-based samples of males. We tested the association of T with entrepreneurial behavior, operationalized as self-employment, using data from the Rotterdam Study (N=587) and the Study of Health in Pomerania (N=1697). Total testosterone (TT) and sex hormone-binding globulin (SHBG) were measured in the serum. Free testosterone (FT), non-SHBG-bound T (non-SHBG-T), and the TT/SHBG ratio were calculated and used as measures of bioactive serum T, in addition to TT adjusted for SHBG. Using logistic regression models, we found no significant associations between any of the serum T measures and self-employment in either of the samples. To our knowledge, this is the first large-scale study on the relationship between serum T and entrepreneurial behavior.

Published
2013

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