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51. Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry

Author: Mariaelisa Graff, Zhaoming Wang, David R. Weir, Ann W. Hsing, Joel N. Hirschhorn, Rebecca S. Fine, Wei Zheng, William Maixner, Adebowale Adeyemo, Rick A. Kittles, Rebecca Rohde, Krista A. Zanetti, Elizabeth K. Speliotes, Keri L. Monda, Ingrid B. Borecki, Yaming Shao, Suhn K. Rhie, Sanjay R. Patel, Richard S. Cooper, Jerome I. Rotter, Michael J. Thun, William J. Blot, Brendan J. Keating, Michèle M. Sale, Scott M. Williams, Yingchang Lu, Margaret A. Tucker, Eric A. Klein, Uma Nayak, Curtis A. Pettaway, Yii-Der Ida Chen, Sailaja Vedantam, Pamela J. Schreiner, Phyllis J. Goodman, Babatunde L. Salako, Christine Neslund-Dudas, Andrew B. Singleton, Michael F. Press, Neil E. Caporaso, Maureen Sanderson, Diane M. Becker, Michele K. Evans, Margaret R. Spitz, Christopher I. Amos, Susan Redline, Kurt Lohman, Ching-Ti Liu, Hampton L. Leonard, Kris Monroe, Sun J. Kang, David Van Den Berg, Janet L. Stanford, Lewis H. Kuller, Traci M. Bartz, J. M. Zmuda, Christopher S. Carlson, Ruth J. F. Loos, Joanne M. Jordan, Guillaume Lettre, Youfang Liu, Lara Sucheston, Mike A. Nalls, Shad B. Smith, Suzanne Kolb, Lisa B. Signorello, Daniel Shriner, Tamara B. Harris, Larry D. Atwood, Wei-Min Chen, Oladosu Ojengbede, Kristin A. Rand, Claudia Schurmann, Guanjie Chen, Sharon L.R. Kardia, Graham Casey, Lawrence F. Bielak, Dena G. Hernandez, Talin Haritunians, Rajiv Nadukuru, Elisa V. Bandera, Matthew A. Allison, Amidou N'Diaye, Donna K. Arnett, Olufunmilayo I. Olopade, Ellen W. Demerath, Babette S. Zemel, Margaret Wrensch, Myriam Fornage, John K. Wiencke, George J. Papanicolaou, Sara S. Strom, Temidayo O. Ogundiran, Gregory L. Burke, Erin B. Ware, Marian L. Neuhouser, James G. Wilson, Dhananjay Vaidya, Nicholette D. Palmer, Marguerite R. Irvin, JoAnn E. Manson, Benjamin A. Rybicki, Laurence N. Kolonel, Chad D. Huff, Jennifer J. Hu, Jennifer A. Brody, L. Keoki Williams, Leslie A. Lange, Qing Duan, David S. Siscovick, Yongmei Liu, Leslie Bernstein, Jennifer A. Smith, Latchezar Dimitrov, Sarah J. Nyante, Sue A. Ingles, Yu Han H. Hsu, Xifeng Wu, Heather M. Ochs-Balcom, Jingzhong Ding, David V. Conti, L. Adrienne Cupples, Gerry A. Coetzee, Thomas H. Mosley, Kristin L. Young, Donald W. Bowden, Edmond K. Kabagambe, Christine B. Ambrosone, Karen C. Johnson, Patricia A. Peyser, Stefan Ambs, Victoria L. Stevens, Minhui Chen, Carl D. Langefeld, Sonja I. Berndt, Andrew F. Olshan, Qiuyin Cai, Jessica D. Faul, Mary F. Feitosa, Brian E. Cade, Esther M. John, Ann G. Schwartz, Yan V. Sun, Xinruo Zhang, Stephen J. Chanock, Jason H. Moore, Alexander P. Reiner, Caroline S. Fox, Charles Kooperberg, Anne E. Justice, Jin Li, Lorna H. McNeill, Alex Stram, Jie Yao, Xiuqing Guo, Mara Z. Vitolins, Edward A. Ruiz-Narváez, Abdullah Kutlar, Charleston W. K. Chiang, Jing Hua Zhao, Lisa R. Yanek, Poorva Mudgal, John D. Carpten, Barbara V. Howard, Anselm Hennis, Charles N. Rotimi, Ulrich Broeckel, Albert M. Levin, Jonathan P. Bradfield, Curtis C. Harris, Regina G. Ziegler, Brian E. Henderson, Bruce M. Psaty, Adeyinka G. Falusi, Katherine L. Nathanson, Barbara McKnight, Melinda C. Aldrich, Herman A. Taylor, Melissa Garcia, Degui Zhi, Dezheng Huo, Barry I. Freedman, D. C. Rao, Sylvia Wassertheil-Smoller, Jie Zhou, Adam B. Murphy, Eric E. Schadt, Sandra L. Deming, John S. Witte, Julie R. Palmer, Neil A. Zakai, Adesola Ogunniyi, Yun Li, Mary Cushman, Victoria L. Buchanan, Jorge L. Rodriguez-Gil, Struan F.A. Grant, Timothy D. Howard, Omri Gottesman, Wei Zhao, Kira C. Taylor, Yan Meng, Hayrettin Okut, Hakon Hakonarson, Xiaofeng Zhu, Elizabeth M. Gillanders, Alan B. Zonderman, Lisa Chu, Badri Padhukasahasram, Vaneet Lotay, W. Ryan Diver, Mary K. Wojczynski, Simin Liu, Erwin P. Bottinger, Cameron D. Palmer, Alessandra Chesi, Elise Lim, Laura J. Rasmussen-Torvik, Eirini Marouli, Kari E. North, Salman M. Tajuddin, Christopher A. Haiman, Barbara Nemesure, Loic Le Marchand, Bamidele O. Tayo, and Maggie C.Y. Ng
Subjects: Male, 0303 health sciences, 030305 genetics & heredity, High density, Black People, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Body Height, Article, Minor allele frequency, Black or African American, Europe, 03 medical and health sciences, Evolutionary biology, Africa, Genetics, Humans, Female, Genotyping, Genetics (clinical), Imputation (genetics), 030304 developmental biology, Genome-Wide Association Study
Abstract: Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
Published: 2020

52. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Author: Yongmei Liu, Tuomas O. Kilpeläinen, Kenneth Rice, Ching-Ti Liu, Jin-Fang Chai, Donna K. Arnett, Dhananjay Vaidya, Nicholette D. Palmer, Lili Milani, Yuri Milaneschi, Leo-Pekka Lyytikäinen, Colleen M. Sitlani, Richard S. Cooper, Gudny Eiriksdottir, Daniel Levy, Jerome I. Rotter, Lihua Wang, Sven Bergmann, Yih Chung Tham, Thomas Meitinger, Lynne E. Wagenknecht, Virginia Fisher, Babatunde L. Salako, Vilmundur Gudnason, Bamidele O. Tayo, Caizheng Yu, Barry I. Freedman, Muhammad Riaz, Kaare Christensen, Ulrich Broeckel, W. James Gauderman, Massimiliano Cocca, Eric Boerwinkle, Meian He, Rob M. van Dam, M. Arfan Ikram, Lisa de las Fuentes, Jiang He, Aldi T. Kraja, Nancy L. Pedersen, Albert V. Smith, Woon-Puay Koh, Bernardo L. Horta, He Gao, Traci M. Bartz, Mike A. Nalls, Federica Laguzzi, Raymond Noordam, Paul M. Ridker, Tien Yin Wong, Patricia B. Munroe, Paul S. de Vries, Adolfo Correa, Maris Alver, Dan E. Arking, Colin A. McKenzie, John M. Starr, Chi Charles Gu, Dongfeng Gu, Stefan Weiss, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Jill M. Norris, Patrik K. E. Magnusson, Tamar Sofer, Ioanna Ntalla, Xiuqing Guo, Paul Elliott, Lawrence F. Bielak, Konstantin Strauch, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Ilja M. Nolte, Steven C. Hunt, Mario Sims, Giorgia Girotto, Chuan Gao, Pamela J. Schreiner, Philippe Froguel, Archie Campbell, Xiao-Ou Shu, Claude Bouchard, Kurt Lohman, David R. Weir, José Eduardo Krieger, Yii-Der Ida Chen, Rainer Rauramaa, Walter Palmas, Cornelia M. van Duijn, James M. Shikany, Michael M. Province, Jennifer A. Smith, Wei Zheng, Xiaofeng Zhu, Jianjun Liu, Ozren Polasek, Alexandre C. Pereira, Diane M. Becker, Kari E. North, Salman M. Tajuddin, Deng Xuan, Leslie J. Raffel, Jie Yao, Astrid Petersmann, Ervin F. Fox, Mark J. Caulfield, Daniel I. Chasman, Jasmin Divers, Claudia P. Cabrera, Rico Rueedi, M. Yldau van der Ende, Carl D. Langefeld, Mika Kähönen, Terrence Forrester, Tangchun Wu, Harold Snieder, Caroline Hayward, Tamara B. Harris, Fang-Chi Hsu, Helen R. Warren, Brenda W.J.H. Penninx, Chiea Chuen Khor, Ruifang Li-Gao, Changwei Li, Sami Heikkinen, Jeffrey R. O'Connell, Christian Gieger, Michele K. Evans, Ching-Yu Cheng, Jingjing Liang, Stephen B. Kritchevsky, Gregory L. Burke, Donald W. Bowden, Alexander Teumer, Marcus Dörr, Alanna C. Morrison, Jian-Min Yuan, Annette Peters, Dennis O. Mook-Kanamori, Pedro Marques-Vidal, Pirjo Komulainen, Lisa R. Yanek, Melanie Waldenberger, Alisa K. Manning, Charles N. Rotimi, Chew-Kiat Heng, Tõnu Esko, Franco Giulianini, Miao Li Chee, Treva Rice, David J. Porteous, Yechiel Friedlander, Bing Yu, Myriam Fornage, Karin Leander, Dina Vojinovic, Sharon L.R. Kardia, Xiaoyin Li, Najaf Amin, Karen Schwander, Thomas T. Perls, Oscar Leonel Rueda-Ochoa, Erin B. Ware, Ya Xing Wang, Sandosh Padmanabhan, H. Janaka de Silva, André G. Uitterlinden, Rajkumar Dorajoo, Bruna Gigante, Jennifer A. Brody, Paolo Gasparini, Maryam Kavousi, Wanqing Wen, Stephen Sidney, Alan B. Zonderman, Michael R. Brown, Tuomo Rankinen, Timo A. Lakka, Yun Ju Sung, Alaitz Poveda, Bruce M. Psaty, Terho Lehtimäki, Tanika N. Kelly, Igor Rudan, Brigitte Kühnel, Christopher P. Nelson, John M. C. Connell, Mickaël Canouil, Niek Verweij, Thomas W. Winkler, Ian J. Deary, Marco Brumat, Yize Li, Fumihiko Takeuchi, Wei Zhao, Andres Metspalu, Marguerite R. Irvin, David C. Liewald, Pim van der Harst, Hugues Aschard, Candace M. Kammerer, Melissa A. Richard, Adesola Ogunniyi, Wen Bin Wei, Morris A. Swertz, Fernando Pires Hartwig, Dabeeru C. Rao, Reedik Mägi, Solomon K. Musani, Mathilde Boissel, Jonathan Marten, Nilesh J. Samani, Amy R. Bentley, Sarah E. Harris, Charumathi Sabanayagam, Mary F. Feitosa, Jost B. Jonas, Andrea R. V. R. Horimoto, Paul W. Franks, E. Shyong Tai, Medical Research Council (MRC), de las Fuentes, L., Sung, Y. J., Noordam, R., Winkler, T., Feitosa, M. F., Schwander, K., Bentley, A. R., Brown, M. R., Guo, X., Manning, A., Chasman, D. I., Aschard, H., Bartz, T. M., Bielak, L. F., Campbell, A., Cheng, C. -Y., Dorajoo, R., Hartwig, F. P., Horimoto, A. R. V. R., Li, C., Li-Gao, R., Liu, Y., Marten, J., Musani, S. K., Ntalla, I., Rankinen, T., Richard, M., Sim, X., Smith, A. V., Tajuddin, S. M., Tayo, B. O., Vojinovic, D., Warren, H. R., Xuan, D., Alver, M., Boissel, M., Chai, J. -F., Chen, X., Christensen, K., Divers, J., Evangelou, E., Gao, C., Girotto, G., Harris, S. E., He, M., Hsu, F. -C., Kuhnel, B., Laguzzi, F., Li, X., Lyytikainen, L. -P., Nolte, I. M., Poveda, A., Rauramaa, R., Riaz, M., Rueedi, R., Shu, X. -O., Snieder, H., Sofer, T., Takeuchi, F., Verweij, N., Ware, E. B., Weiss, S., Yanek, L. R., Amin, N., Arking, D. E., Arnett, D. K., Bergmann, S., Boerwinkle, E., Brody, J. A., Broeckel, U., Brumat, M., Burke, G., Cabrera, C. P., Canouil, M., Chee, M. L., Chen, Y. -D. I., Cocca, M., Connell, J., de Silva, H. J., de Vries, P. S., Eiriksdottir, G., Faul, J. D., Fisher, V., Forrester, T., Fox, E. F., Friedlander, Y., Gao, H., Gigante, B., Giulianini, F., Gu, C. C., Gu, D., Harris, T. B., He, J., Heikkinen, S., Heng, C. -K., Hunt, S., Ikram, M. A., Irvin, M. R., Kahonen, M., Kavousi, M., Khor, C. C., Kilpelainen, T. O., Koh, W. -P., Komulainen, P., Kraja, A. T., Krieger, J. E., Langefeld, C. D., Li, Y., Liang, J., Liewald, D. C. M., Liu, C. -T., Liu, J., Lohman, K. K., Magi, R., Mckenzie, C. A., Meitinger, T., Metspalu, A., Milaneschi, Y., Milani, L., Mook-Kanamori, D. O., Nalls, M. A., Nelson, C. P., Norris, J. M., O'Connell, J., Ogunniyi, A., Padmanabhan, S., Palmer, N. D., Pedersen, N. L., Perls, T., Peters, A., Petersmann, A., Peyser, P. A., Polasek, O., Porteous, D. J., Raffel, L. J., Rice, T. K., Rotter, J. I., Rudan, I., Rueda-Ochoa, O. -L., Sabanayagam, C., Salako, B. L., Schreiner, P. J., Shikany, J. M., Sidney, S. S., Sims, M., Sitlani, C. M., Smith, J. A., Starr, J. M., Strauch, K., Swertz, M. A., Teumer, A., Tham, Y. C., Uitterlinden, A. G., Vaidya, D., van der Ende, M. Y., Waldenberger, M., Wang, L., Wang, Y. -X., Wei, W. -B., Weir, D. R., Wen, W., Yao, J., Yu, B., Yu, C., Yuan, J. -M., Zhao, W., Zonderman, A. B., Becker, D. M., Bowden, D. W., Deary, I. J., Dorr, M., Esko, T., Freedman, B. I., Froguel, P., Gasparini, P., Gieger, C., Jonas, J. B., Kammerer, C. M., Kato, N., Lakka, T. A., Leander, K., Lehtimaki, T., Magnusson, P. K. E., Marques-Vidal, P., Penninx, B. W. J. H., Samani, N. J., van der Harst, P., Wagenknecht, L. E., Wu, T., Zheng, W., Zhu, X., Bouchard, C., Cooper, R. S., Correa, A., Evans, M. K., Gudnason, V., Hayward, C., Horta, B. L., Kelly, T. N., Kritchevsky, S. B., Levy, D., Palmas, W. R., Pereira, A. C., Province, M. M., Psaty, B. M., Ridker, P. M., Rotimi, C. N., Tai, E. S., van Dam, R. M., van Duijn, C. M., Wong, T. Y., Rice, K., Gauderman, W. J., Morrison, A. C., North, K. E., Kardia, S. L. R., Caulfield, M. J., Elliott, P., Munroe, P. B., Franks, P. W., Rao, D. C., Fornage, M., Washington University in Saint Louis (WUSTL), Leiden University Medical Center (LUMC), University of Regensburg, Washington University School of Medicine in St. Louis, National Institutes of Health [Bethesda] (NIH), Harbor UCLA Medical Center [Torrance, Ca.], Massachusetts General Hospital [Boston], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), 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 National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Universiteit Leiden, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Lifelines Cohort Study, Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Cardiovascular Centre (CVC)
Subjects: 0301 basic medicine, CORONARY-HEART-DISEASE, SOCIOECONOMIC-STATUS, RISK-FACTORS, CARDIOVASCULAR-DISEASE, ESSENTIAL-HYPERTENSION, C825T POLYMORPHISM, SOCIAL-CLASS, ASSOCIATION, EXPRESSION, VARIANTS, Blood Pressure, Genome, 0302 clinical medicine, 11 Medical and Health Sciences, Genetics, Psychiatry, [STAT.AP]Statistics [stat]/Applications [stat.AP], 17 Psychology and Cognitive Sciences, Psychiatry and Mental health, Meta-analysis, Hypertension, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, GNB3, Biochemistry & Molecular Biology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Lifelines Cohort Study, SDG 3 - Good Health and Well-being, Humans, Risk factor, Molecular Biology, Gene, Science & Technology, Neurosciences, Epistasis, Genetic, 06 Biological Sciences, Genetic architecture, Educational attainment, 030104 developmental biology, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurosciences & Neurology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Blood Pressure/genetics, Genome-Wide Association Study, Hypertension/genetics, 030217 neurology & neurosurgery
Abstract: Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10 -8 ). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
Published: 2020
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53. Validation of a hybrid approach to standardize immunophenotyping analysis in large population studies: The Health and Retirement Study

Author: Benjamin R. Cole, De Von Hunter-Schlichting, John Lane, Bharat Thyagarajan, Nathan Pankratz, Zachary Flaten, Ramya Ramasubramanian, Erin Cassidy, Hélène Barcelo, Eileen M. Crimmins, and Jessica D. Faul
Subjects: Computer science, Bioinformatics, Population, Large population, lcsh:Medicine, Datasets as Topic, Gating, computer.software_genre, Article, Immunophenotyping, Software, Humans, Longitudinal Studies, education, lcsh:Science, education.field_of_study, Multidisciplinary, business.industry, lcsh:R, High-throughput screening, Computational Biology, Reproducibility of Results, Dendritic Cells, Hybrid approach, Flow Cytometry, Health Surveys, Lymphocyte Subsets, High-Throughput Screening Assays, Feasibility Studies, lcsh:Q, Data mining, business, computer, Algorithms
Abstract: Traditional manual gating strategies are often time-intensive, place a high burden on the analyzer, and are susceptible to bias between analyzers. Several automated gating methods have shown to exceed performance of manual gating for a limited number of cell subsets. However, many of the automated algorithms still require significant manual interventions or have yet to demonstrate their utility in large datasets. Therefore, we developed an approach that utilizes a previously published automated algorithm (OpenCyto framework) with a manually created hierarchically cell gating template implemented, along with a custom developed visualization software (FlowAnnotator) to rapidly and efficiently analyze immunophenotyping data in large population studies. This approach allows pre-defining populations that can be analyzed solely by automated analysis and incorporating manual refinement for smaller downstream populations. We validated this method with traditional manual gating strategies for 24 subsets of T cells, B cells, NK cells, monocytes and dendritic cells in 931 participants from the Health and Retirement Study (HRS). Our results show a high degree of correlation (r ≥ 0.80) for 18 (78%) of the 24 cell subsets. For the remaining subsets, the correlation was low (
Published: 2020

54. Higher Lung Function Is Associated with Younger Subjective Age: The Health and Retirement Study

Author: Eileen M. Crimmins, Ramya Ramasubramanian, Weihua Guan, Jessica D. Faul, David R. Jacobs, and Bharat Thyagarajan
Subjects: Gerontology, business.industry, Medicine, Health and Retirement Study, business, Lung function
Published: 2020
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55. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author: Alexandre C. Pereira, Jie Yao, Makoto Hirata, Ozren Polasek, Dragana Vuckovic, Mariaelisa Graff, Jing Hua Zhao, Michael R. Brown, Xuan Deng, Barbara V. Howard, Vilmundur Gudnason, Tuomo Rankinen, Yuan Shi, Timo A. Lakka, Ulrich Broeckel, Anuradhani Kasturiratne, Eric Boerwinkle, Charles Kooperberg, Hugues Aschard, Stephen S. Rich, Pamela J. Schreiner, Dan E. Arking, Hans J. Grabe, Ilaria Gandin, Mario Sims, Carl D. Langefeld, Yii-Der Ida Chen, Meian He, W. James Gauderman, Bruce M. Psaty, Kent D. Taylor, Tõnu Esko, Olli T. Raitakari, Saima Afaq, Maik Pietzner, Federica Laguzzi, Dennis O. Mook-Kanamori, Gregory P. Wilson, Xiuqing Guo, Jaspal S. Kooner, David R. Jacobs, Yajuan Wang, Raha Pazoki, Wei Zhao, Andres Metspalu, Mary F. Feitosa, Jost B. Jonas, Tin Aung, Tamara B. Harris, Karin Leander, Nancy L. Pedersen, Charles B. Eaton, Sharon L.R. Kardia, Bernardo L. Horta, Candace M. Kammerer, Terrence Forrester, Alexander P. Reiner, Paul W. Franks, Tanika N. Kelly, Igor Rudan, Ruben N. Eppinga, Melissa A. Richard, Colin A. McKenzie, Christine Williams, Christian Gieger, Joseph H. Lee, Brigitte Kühnel, Christopher P. Nelson, Wen Bin Wei, Antonietta Robino, Anne U. Jackson, E. Shyong Tai, Alisa K. Manning, Lisa R. Yanek, Paul Elliott, Lynne E. Wagenknecht, Ananda R. Wickremasinghe, José Eduardo Krieger, Peter S. Sever, Nora Franceschini, André G. Uitterlinden, Paul M. Ridker, Yun J. Sung, Karen L. Mohlke, Thomas H. Mosley, Nilesh J. Samani, Patricia B. Munroe, Jennifer A. Smith, John M. C. Connell, H. Janaka de Silva, Nicholas Y. Q. Tan, Jian'an Luan, Jennifer E. Huffman, Anna F. Dominiczak, Carsten Oliver Schmidt, Christie M. Ballantyne, Peter J. van der Most, Anuj Goel, Jerome I. Rotter, Amy R. Bentley, Lihua Wang, Rajkumar Dorajoo, Lenore J. Launer, Yechiel Friedlander, Mickaël Canouil, Traci M. Bartz, Thomas Meitinger, Robert A. Scott, Mike A. Nalls, Xueling Sim, Sarah E. Harris, Michael A. Province, Chew-Kiat Heng, Zhe Wang, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Virginia Fisher, Leslie J. Raffel, Renée de Mutsert, Michele K. Evans, Brenda W.J.H. Penninx, Yih Chung Tham, Tin Louie, Nana Matoba, Lawrence F. Bielak, Andrea R. V. R. Horimoto, Jingmin Liu, Lynda M. Rose, Nona Sotoodehnia, Daniel I. Chasman, Jasmin Divers, John M. Starr, Patricia A. Peyser, Ervin R. Fox, Barry I. Freedman, Megan L. Grove, Jeffrey R. O'Connell, Rob M. van Dam, Michiaki Kubo, Jessica D. Faul, Fang-Chi Hsu, Yize Li, Ilja M. Nolte, Caroline Hayward, Paolo Gasparini, Chiea Chuen Khor, Changwei Li, Xu Chen, James E. Hixson, Patrik K. E. Magnusson, John C. Chambers, Yoichiro Kamatani, Sami Heikkinen, M. Abdullah Said, Martin Farrall, Alena Stančáková, Konstantin Strauch, Albert V. Smith, Yik Ying Teo, Bamidele O. Tayo, Tamar Sofer, Caizheng Yu, Maris Alver, Oscar H. Franco, Yongmei Liu, Ioanna Ntalla, Myriam Fornage, W. Craig Johnson, Dina Vojinovic, William R. Scott, David R. Weir, Yanick Hagemeijer, Raymond Noordam, Mathilde Boissel, Cornelia M. van Duijn, Karen Schwander, Jingzhong Ding, James Scott, Diana van Heemst, Ching-Yu Cheng, Woon-Puay Koh, Jianjun Liu, Kenneth J. Mukamal, Blair H. Smith, Claude Bouchard, Claudia Langenberg, Jingjing Liang, Wei Zheng, Najaf Amin, Ulf de Faire, Bing Yu, Archie Campbell, Kari E. North, Salman M. Tajuddin, Fernando Pires Hartwig, Steve B. Kritchevsky, Tibor V. Varga, Pirjo Komulainen, Hugh Watkins, Johanna Kuusisto, Kurt Lohman, Rozenn N. Lemaitre, Ani Manichaikul, Dabeeru C. Rao, Kenneth Rice, Weihua Zhang, Franco Giulianini, Reedik Mägi, Solomon K. Musani, Wanqing Wen, Nicholas J. Wareham, Charles N. Rotimi, Marzyeh Amini, Rainer Rauramaa, Nicholette D. Palmer, Annette Peters, Neil R Poulter, Benjamin Lehne, Matthias Nauck, Harold Snieder, Donald W. Bowden, M. Arfan Ikram, Lisa de las Fuentes, C. Charles Gu, Xiaofeng Zhu, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Lili Milani, L. Adrienne Cupples, Yuri Milaneschi, Kiang Liu, Stephen Sidney, Alan B. Zonderman, Thomas W. Winkler, Ian J. Deary, Fumihiko Takeuchi, Mary K. Wojczynski, Pim van der Harst, Leo-Pekka Lyytikäinen, Jennifer G. Robinson, Chuan Gao, Xiao-Ou Shu, Diane M. Becker, Mohsen Ghanbari, Alanna C. Morrison, Jian-Min Yuan, Tomohiro Katsuya, Ivana Kolcic, Melanie Waldenberger, Terho Lehtimäki, Heikki A. Koistinen, Erin B. Ware, Ya Xing Wang, Marie Loh, Treva Rice, Qing Duan, Aldi T. Kraja, Sabanayagam Charumathi, Tien Yin Wong, Paul S. de Vries, Yujie Wang, Muhammad Riaz, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Luan, Jian'an [0000-0003-3137-6337], Pietzner, Maik [0000-0003-3437-9963], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Mental Health, Psychiatry, APH - Digital Health, The University of Texas Health Science Center at Houston (UTHealth), National Institutes of Health [Bethesda] (NIH), Washington University in Saint Louis (WUSTL), University of Regensburg, Queen Mary University of London (QMUL), Washington University School of Medicine in St. Louis, Harbor UCLA Medical Center [Torrance, Ca.], University of North Carolina at Chapel Hill (UNC), Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National University of Singapore (NUS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University Management, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Abdominal Center, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugue, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelo, Graff, Mariaelisa, Alver, Mari, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stancáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, Giulianini, Franco, Grabe, Hans J, Grove, Megan L, Gu, C Charle, Harris, Tamara B, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hixson, James E, Howard, Barbara V, Ikram, M Arfan, Jacobs, David R, Johnson, Craig, Jonas, Jost Bruno, Kammerer, Candace M, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Koistinen, Heikki A, Kolcic, Ivana, Kooperberg, Charle, Krieger, Jose E, Kritchevsky, Steve B, Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lehne, Benjamin, Lemaitre, Rozenn N, Li, Yize, Liang, Jingjing, Liu, Jianjun, Liu, Kiang, Loh, Marie, Louie, Tin, Mägi, Reedik, Manichaikul, Ani W, Mckenzie, Colin A, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L, Mosley, Thomas H, Mukamal, Kenneth J, Nalls, Mike A, Nauck, Matthia, Nelson, Christopher P, Sotoodehnia, Nona, O'Connell, Jeff R, Palmer, Nicholette D, Pazoki, Raha, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Poulter, Neil, Raffel, Leslie J, Raitakari, Olli T, Reiner, Alex P, Rice, Treva K, Rich, Stephen S, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Shi, Yuan, Sidney, Stephen, Sims, Mario, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tan, Nichola, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, van Heemst, Diana, Vuckovic, Dragana, Waldenberger, Melanie, Wang, Lihua, Wang, Yujie, Wang, Zhe, Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Franks, Paul W, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo L, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K E, Penninx, Brenda, Pereira, Alexandre C, Rauramaa, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wang, Ya Xing, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wickremasinghe, Ananda R, Zheng, Wei, Elliott, Paul, North, Kari E, Bouchard, Claude, Evans, Michele K, Gudnason, Vilmundur, Liu, Ching-Ti, Liu, Yongmei, Psaty, Bruce M, Ridker, Paul M, van Dam, Rob M, Kardia, Sharon L R, Zhu, Xiaofeng, Rotimi, Charles N, Mook-Kanamori, Dennis O, Fornage, Myriam, Kelly, Tanika N, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Liu, Jingmin, Rotter, Jerome I, Gauderman, W Jame, Province, Michael A, Munroe, Patricia B, Rice, Kenneth, Chasman, Daniel I, Cupples, L Adrienne, Rao, Dabeeru C, Morrison, Alanna C, and Academic Medical Center
Subjects: Male, Epidemiology, Genome-wide association study, Cardiovascular, MESH: Genotype, Substance Misuse, Alcohol Use and Health, 0302 clinical medicine, Aetiology, triglycerides, 11 Medical and Health Sciences, Public, Environmental & Occupational Health, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Life Style, genome wide, gene-alcohol interaction, lipid levels, Lipid Measurement, Lifelines Cohort, DENSITY-LIPOPROTEIN CHOLESTEROL, MESH: Young Adult, 030220 oncology & carcinogenesis, Kexin, LOW-FREQUENCY, MESH: Cholesterol, HDL, MESH: Cholesterol, LDL, MESH: Triglycerides, HDL, Alcohol Drinking, Genotype, alcohol consumption, MESH: Phenotype, LDL, lipids, 03 medical and health sciences, Genetics, Humans, Life Style, METAANALYSIS, 01 Mathematical Sciences, Aged, MESH: Adolescent, HDL CHOLESTEROL, MESH: Humans, Science & Technology, Cholesterol, APOBEC1, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), MESH: Vascular Endothelial Growth Factor B, Racial Groups, cholesterol, The Netherlands, MESH: Adult, CONSUMPTION, chemistry, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Lipid profile, MESH: Female, MESH: Alcohol Drinking, MESH: Continental Population Groups, Vascular Endothelial Growth Factor B, Original Contributions, Blood lipids, VEGF-B, Medical and Health Sciences, Mathematical Sciences, BLOOD-LIPIDS, chemistry.chemical_compound, 2.1 Biological and endogenous factors, 030212 general & internal medicine, MESH: Aged, medicine.diagnostic_test, PLASMA, gene-environment interactions, Middle Aged, 3142 Public health care science, environmental and occupational health, Alcoholism, Phenotype, Female, gene-lifestyle interactions, genome-wide association studies, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, Groningen, Adult, Adolescent, Biology, Young Adult, medicine, CORONARY-HEART-DISEASE, Human Genome, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, InterAct Consortium, MESH: Lipids, MESH: Male, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract: © The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant
Published: 2019
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56. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Gail Davies, Max Lam, Sarah E. Harris, Joey W. Trampush, Michelle Luciano, W. David Hill, Saskia P. Hagenaars, Stuart J. Ritchie, Riccardo E. Marioni, Chloe Fawns-Ritchie, David C. M. Liewald, Judith A. Okely, Ari V. Ahola-Olli, Catriona L. K. Barnes, Lars Bertram, Joshua C. Bis, Katherine E. Burdick, Andrea Christoforou, Pamela DeRosse, Srdjan Djurovic, Thomas Espeseth, Stella Giakoumaki, Sudheer Giddaluru, Daniel E. Gustavson, Caroline Hayward, Edith Hofer, M. Arfan Ikram, Robert Karlsson, Emma Knowles, Jari Lahti, Markus Leber, Shuo Li, Karen A. Mather, Ingrid Melle, Derek Morris, Christopher Oldmeadow, Teemu Palviainen, Antony Payton, Raha Pazoki, Katja Petrovic, Chandra A. Reynolds, Muralidharan Sargurupremraj, Markus Scholz, Jennifer A. Smith, Albert V. Smith, Natalie Terzikhan, Anbupalam Thalamuthu, Stella Trompet, Sven J. van der Lee, Erin B. Ware, B. Gwen Windham, Margaret J. Wright, Jingyun Yang, Jin Yu, David Ames, Najaf Amin, Philippe Amouyel, Ole A. Andreassen, Nicola J. Armstrong, Amelia A. Assareh, John R. Attia, Deborah Attix, Dimitrios Avramopoulos, David A. Bennett, Anne C. Böhmer, Patricia A. Boyle, Henry Brodaty, Harry Campbell, Tyrone D. Cannon, Elizabeth T. Cirulli, Eliza Congdon, Emily Drabant Conley, Janie Corley, Simon R. Cox, Anders M. Dale, Abbas Dehghan, Danielle Dick, Dwight Dickinson, Johan G. Eriksson, Evangelos Evangelou, Jessica D. Faul, Ian Ford, Nelson A. Freimer, He Gao, Ina Giegling, Nathan A. Gillespie, Scott D. Gordon, Rebecca F. Gottesman, Michael E. Griswold, Vilmundur Gudnason, Tamara B. Harris, Annette M. Hartmann, Alex Hatzimanolis, Gerardo Heiss, Elizabeth G. Holliday, Peter K. Joshi, Mika Kähönen, Sharon L. R. Kardia, Ida Karlsson, Luca Kleineidam, David S. Knopman, Nicole A. Kochan, Bettina Konte, John B. Kwok, Stephanie Le Hellard, Teresa Lee, Terho Lehtimäki, Shu-Chen Li, Christina M. Lill, Tian Liu, Marisa Koini, Edythe London, Will T. Longstreth, Oscar L. Lopez, Anu Loukola, Tobias Luck, Astri J. Lundervold, Anders Lundquist, Leo-Pekka Lyytikäinen, Nicholas G. Martin, Grant W. Montgomery, Alison D. Murray, Anna C. Need, Raymond Noordam, Lars Nyberg, William Ollier, Goran Papenberg, Alison Pattie, Ozren Polasek, Russell A. Poldrack, Bruce M. Psaty, Simone Reppermund, Steffi G. Riedel-Heller, Richard J. Rose, Jerome I. Rotter, Panos Roussos, Suvi P. Rovio, Yasaman Saba, Fred W. Sabb, Perminder S. Sachdev, Claudia L. Satizabal, Matthias Schmid, Rodney J. Scott, Matthew A. Scult, Jeannette Simino, P. Eline Slagboom, Nikolaos Smyrnis, Aïcha Soumaré, Nikos C. Stefanis, David J. Stott, Richard E. Straub, Kjetil Sundet, Adele M. Taylor, Kent D. Taylor, Ioanna Tzoulaki, Christophe Tzourio, André Uitterlinden, Veronique Vitart, Aristotle N. Voineskos, Jaakko Kaprio, Michael Wagner, Holger Wagner, Leonie Weinhold, K. Hoyan Wen, Elisabeth Widen, Qiong Yang, Wei Zhao, Hieab H. H. Adams, Dan E. Arking, Robert M. Bilder, Panos Bitsios, Eric Boerwinkle, Ornit Chiba-Falek, Aiden Corvin, Philip L. De Jager, Stéphanie Debette, Gary Donohoe, Paul Elliott, Annette L. Fitzpatrick, Michael Gill, David C. Glahn, Sara Hägg, Narelle K. Hansell, Ahmad R. Hariri, M. Kamran Ikram, J. Wouter Jukema, Eero Vuoksimaa, Matthew C. Keller, William S. Kremen, Lenore Launer, Ulman Lindenberger, Aarno Palotie, Nancy L. Pedersen, Neil Pendleton, David J. Porteous, Katri Räikkönen, Olli T. Raitakari, Alfredo Ramirez, Ivar Reinvang, Igor Rudan, Dan Rujescu, Reinhold Schmidt, Helena Schmidt, Peter W. Schofield, Peter R. Schofield, John M. Starr, Vidar M. Steen, Julian N. Trollor, Steven T. Turner, Cornelia M. Van Duijn, Arno Villringer, Daniel R. Weinberger, David R. Weir, James F. Wilson, Anil Malhotra, Andrew M. McIntosh, Catharine R. Gale, Sudha Seshadri, Thomas H. Mosley, Jan Bressler, Todd Lencz, Ian J. Deary, 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), Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands (HÍ), University of Iceland (UI), Apollo - University of Cambridge Repository, Epidemiology, Neurology, and Radiology & Nuclear Medicine
Subjects: Genetics of the nervous system, Multifactorial Inheritance, Quantitative trait, genetics [Mental Disorders], Genome-wide association studies, cognitive neuroscience, OLD-AGE, Cognition, PARKINSONS-DISEASE, HUMAN INTELLIGENCE, lcsh:Science, genetics [Multifactorial Inheritance], GENOME-WIDE ASSOCIATION, REACTION-TIME, INTELLIGENCE DIFFERENCES, PROCESSING SPEED, COMMON VARIANTS, METAANALYSIS, SCHIZOPHRENIA, DISCOVERY, REVEALS, DCDC2, Aged, 80 and over, genetics [Neurodevelopmental Disorders], Mental Disorders, physiology [Cognition], Neurodegenerative Diseases, Middle Aged, Taugavísindi, Multidisciplinary Sciences, genetics [Reaction Time], genetics [Polymorphism, Single Nucleotide], Science & Technology - Other Topics, ddc:500, Medical Genetics, Adult, Adolescent, Science, genetics [Genetic Loci], Polymorphism, Single Nucleotide, Article, quantitative trait, Young Adult, genetics of the nervous system, MD Multidisciplinary, Journal Article, Reaction Time, Erfðafræði, Humans, Genetic Predisposition to Disease, Medicinsk genetik, Aged, EDUCATIONAL-ATTAINMENT, Science & Technology, Heilinn, Cognitive neuroscience, Rannsóknir, Genetic Loci, Neurodevelopmental Disorders, genetics [Neurodegenerative Diseases], genome-wide association studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, lcsh:Q, HUMAN LONGEVITY
Abstract: Publisher's version (útgefin grein), General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P, This research was conducted in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, funded by the Biotechnology and Biological Sciences Research Council and Medical Research Council (MR/K026992/1). This research was conducted using the UK Biobank Resource (Application Nos. 10279 and 4844). The Neurology Working Group within the Cohorts for Heart and Aging Research in Genomic Epidemiology is partly supported by grants from the National Institute on Aging (R01 AG033193, U01 AG049505 and U01 AG052409). Cohort-specific acknowledgements are in Supplementary Note 3.
Published: 2018
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57. Muscle weakness is a prognostic indicator of disability and chronic disease multimorbidity

Author: Halimah Hassan, Kimberly Casten, Mark D. Peterson, Stacey D. Collins, Antonio García-Hermoso, and Jessica D. Faul
Subjects: Male, Aging, medicine.medical_specialty, Weakness, Activities of daily living, Biochemistry, Article, Odds, Grip strength, Endocrinology, Internal medicine, Activities of Daily Living, Genetics, Humans, Medicine, Dementia, Molecular Biology, Aged, Muscle Weakness, Hand Strength, business.industry, Multimorbidity, Muscle weakness, Cell Biology, Health and Retirement Study, Prognosis, medicine.disease, United States, Middle age, Chronic Disease, Female, medicine.symptom, business
Abstract: Background The objective of this study was to use nationally-representative data on Americans greater than 50 years of age to determine the association between grip strength and inflammation as independent predictors of incident disability, chronic multimorbidity and dementia. Methods Middle age and older adults (n = 12,618) from the 2006–2008 waves of the Health and Retirement Study with 8-years of follow-up were included. Longitudinal modeling was performed to examine the association between baseline grip strength (normalized to body mass: NGS) and high sensitivity C-reactive protein (hs-CRP) (≥3.0 mg/L) with incident physical disabilities (i.e., ≥2 limitations to activities of daily living), chronic multimorbidity (≥2 of chronic conditions), and dementia. Results The odds of incident disability were 1.25 (95% CI: 1.20–1.30) and 1.31 (95% CI: 1.26–1.36) for men and women respectively, for each 0.05-unit lower NGS. The odds of incident chronic multimorbidity were 1.14 (95% CI: 1.08–1.20) and 1.14 (95% CI: 1.07–1.21) for men and women respectively for each 0.05-unit lower NGS. The odds of incident dementia were 1.10 for men (95% CI: 1.02–1.20) for each 0.05-unit lower NGS, but there was no significant association for women. Elevated hs-CRP was only associated with chronic multimorbidity among men (OR = 1.29; 95% CI: 1.00–1.73) and women (OR = 1.60; 95% CI: 1.26–2.02). Conclusions Our findings indicate a robust inverse association between NGS and disability and chronic, multimorbidity in older men and women, and dementia in men. Elevated hs-CRP was only associated with chronic multimorbidity in men and women. Healthcare providers should implement measures of grip strength in routine health assessments and discuss the potential dangers of weakness as well as interventions to improve strength with their patients.
Published: 2021
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58. Predicting Receipt of Social Security Administration Disability Benefits Using Biomarkers and Other Physiological Measures: Evidence From the Health and Retirement Study

Author: Kevin Bradway, Lakhpreet Gill, David C. Stapleton, Laura Blue, and Jessica D. Faul
Subjects: Male, Gerontology, United States Social Security Administration, Social Security, Article, Body Mass Index, 03 medical and health sciences, Apolipoproteins E, 0302 clinical medicine, Disability benefits, Humans, Medicine, Disabled Persons, 030212 general & internal medicine, Cystatin C, Postural Balance, Alleles, Aged, Community and Home Care, Receipt, 030505 public health, Actuarial science, Hand Strength, Interleukin-6, business.industry, Middle Aged, Health and Retirement Study, Health Surveys, United States, Respiratory Function Tests, Social security, Insurance, Disability, Exercise Test, Regression Analysis, Female, Geriatrics and Gerontology, 0305 other medical science, business, Administration (government), Biomarkers
Abstract: Objectives: The objective of this study was to assess how well physiological measures, including biomarkers and genetic indicators, predict receipt of Social Security Administration (SSA) disability benefits among U.S. adults aged 51 to 65 years. Method: We used data from the 2006 to 2012 waves of the Health and Retirement Study (HRS), linked to SSA administrative data. Using logistic regression, we predicted benefit receipt (either Social Security Disability Insurance or Supplemental Security Income) using 19 distinct physiological markers, adjusting for age, sex, race, and select medication use. We then calculated the propensity (i.e., predicted probability) that each HRS respondent received benefits and assessed how well propensity score–based classifications could identify beneficiaries and nonbeneficiaries. Results: Thirteen percent of respondents received benefits. Using the propensity score cut point that maximized the sum of sensitivity and specificity, the model correctly predicted 75.9% of beneficiaries and 73.5% of nonbeneficiaries. Discussion: Physiological measures have moderate power to predict SSA disability benefit receipt.
Published: 2017
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59. A non-APOE polygenic score for Alzheimers disease and APOE-ε4 have independent associations with dementia in the Health and Retirement Study

Author: Jennifer J. Manly, Jessica D. Faul, Kelly M. Bakulski, Kenneth M. Langa, Kelly S. Benke, Harita S. Vadari, Sharon L.R. Kardia, Erin B. Ware, Steven G. Heeringa, Jennifer A. Smith, and Colter Mitchell
Subjects: 0303 health sciences, education.field_of_study, business.industry, Population, Disease, Odds ratio, Logistic regression, medicine.disease, Confidence interval, 3. Good health, Odds, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Medicine, Dementia, Allele, 10. No inequality, business, education, 030217 neurology & neurosurgery, 030304 developmental biology, Demography
Abstract: INTRODUCTIONAlzheimer’s disease (AD) is a common and costly neurodegenerative disorder. A large proportion of risk is heritable and many genetic risk factors for AD have been identified. The cumulative genetic risk of known markers has not been benchmarked for dementia in a population-based sample.METHODSIn the United States population-based Health and Retirement Study (HRS) (waves 1995-2014), we evaluated the role of cumulative genetic risk for AD, with and without the APOE-ε4 alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry.RESULTSIn the European ancestry sample (n=8399), both AD polygenic score excluding the APOE genetic region (odds ratio (OR)=1.10; 95% confidence interval (CI): 1.00, 1.20) and the presence of any APOE-ε4 alleles (OR=2.42; 95% CI: 1.99, 2.95) were associated with the odds of dementia relative to normal cognition in a mutually-adjusted model. In the African ancestry sample (n=1605), the presence of any APOE-ε4 alleles was associated with 1.77 (95% CI: 1.20, 2.61) times higher odds of dementia, while the AD polygenic score excluding the APOE genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97, 1.30).DISCUSSIONCumulative genetic risk for AD and APOE-ε4 are both independent predictors of dementia. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.
Published: 2020
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60. Dried blood spots: Effects of less than optimal collection, shipping time, heat, and humidity

Author: Yuan S Zhang, Jake Cofferen, Stephen Frochen, Alan J. Potter, Hyunju Shim, Jessica D. Faul, Jung Ki Kim, Hyewon Kang, Eileen M. Crimmins, and Jennifer A. Ailshire
Subjects: Hot Temperature, Transport time, 030209 endocrinology & metabolism, Zip code, Specimen Handling, Climatic data, 03 medical and health sciences, 0302 clinical medicine, Animal science, Genetics, Humans, 0601 history and archaeology, Dried blood, Ecology, Evolution, Behavior and Systematics, 060101 anthropology, Spots, Venous blood sample, Humidity, 06 humanities and the arts, United States, Dried blood spot, Anthropology, Regression Analysis, Environmental science, Dried Blood Spot Testing, Anatomy
Abstract: Objectives This study investigates how factors related to collection, storage, transport time, and environmental conditions affect the quality and accuracy of analyses of dried blood spot (DBS) samples. Methods Data come from the 2016 Health and Retirement Study (HRS) DBS laboratory reports and the HRS merged with the National Climatic Data Center (NCDC) Global Historical Climate Network Daily (NCDC GHCN-Daily) and the NCDC Local Climatological Data, by zip code. We ran regression models to examine the associations between assay values based on DBS for five analytes (total cholesterol, high-density lipoprotein (HDL) cholesterol, glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), and cystatin C) and the characteristics of DBS cards and drops, shipping time, and temperature, and humidity at the time of collection. Results We found cholesterol measures to be sensitive to many factors including small spots, shipping time, high temperature and humidity. Small spots in DBS cards are related to lower values across all analytes. Longer DBS transit time before freezing is associated with lower values of total and HDL cholesterol and cystatin C. Results were similar whether or not venous blood sample values were included in equations. Conclusions Small spots, long shipping time, and exposure to high temperature and humidity need to be avoided if possible. Quality of spots and cards and information on shipping time and conditions should be coded with the data to make adjustments in values when necessary. The different results across analytes indicate that results cannot be generalized to all DBS assays.
Published: 2020
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61. Racial and Ethnic Differences in Knowledge About One's Dementia Status

Author: Karen M. Freund, Jessica D. Faul, Allan T. Daly, Joshua T. Cohen, Joanna Emerson, Peter J. Neumann, Howard Fillit, Nikoletta M. Margaretos, and Pei-Jung Lin
Subjects: Male, Health Knowledge, Attitudes, Practice, Activities of daily living, Ethnic group, White People, Article, 03 medical and health sciences, Diagnostic Self Evaluation, 0302 clinical medicine, Surveys and Questionnaires, mental disorders, medicine, Ethnicity, Odds Ratio, Dementia, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Aged, Aged, 80 and over, business.industry, Racial Groups, Odds ratio, Hispanic or Latino, Health and Retirement Study, medicine.disease, Comorbidity, Health equity, United States, Black or African American, Logistic Models, Female, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Demography
Abstract: Objectives To examine racial and ethnic differences in knowledge about one's dementia status. Design Prospective cohort study. Setting The 2000 to 2014 Health and Retirement Study. Participants Our sample included 8,686 person-wave observations representing 4,065 unique survey participants, aged 70 years or older, with dementia, as identified by a well-validated statistical prediction model based on individual demographic and clinical characteristics. Measurements Primary outcome measure was knowledge of one's dementia status, as reported in the survey. Patient characteristics included race/ethnicity, age, sex, survey year, cognition, function, comorbidity, and whether living in a nursing home. Results Among subjects identified as having dementia by the prediction model, 43.5% to 50.2%, depending on the survey year, reported that they were informed of the dementia status by their physician. This proportion was lower among Hispanics (25.9%-42.2%) and non-Hispanic blacks (31.4%-50.5%) than among non-Hispanic whites (47.7%-52.9%). Our fully adjusted regression model indicated lower dementia awareness among non-Hispanic blacks (odds ratio [OR] = 0.74; 95% confidence interval [CI] = 0.58-0.94) and Hispanics (OR = 0.60; 95% CI = 0.43-0.85), compared to non-Hispanic whites. Having more instrumental activity of daily living limitations (OR = 1.65; 95% CI = 1.56-1.75) and living in a nursing home (OR = 2.78; 95% CI = 2.32-3.32) were associated with increased odds of subjects reporting being told about dementia by a physician. Conclusion Less than half of individuals with dementia reported being told by a physician about the condition. A higher proportion of non-Hispanic blacks and Hispanics with dementia may be unaware of their condition, despite higher dementia prevalence in these groups, compared to non-Hispanic whites. Dementia outreach programs should target diverse communities with disproportionately high disease prevalence and low awareness. J Am Geriatr Soc 68:1763-1770, 2020.
Published: 2019

62. Mendelian randomization of smoking behavior on cognitive status among older Americans

Author: Yuan Jin, Kelly M. Bakulski, Jessica D. Faul, Mingzhou Fu, and Erin B. Ware
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Public health, medicine.medical_treatment, Instrumental variable, Health and Retirement Study, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, Medicine, Dementia, Smoking cessation, Risk factor, business, Association (psychology), 030217 neurology & neurosurgery, 030304 developmental biology, Clinical psychology
Abstract: BackgroundSmoking is a likely risk factor for dementia, and smoking behavior has a strong genetic component. In this study, we jointly test the associations between cumulative genetic risk for smoking, smoking behavior, and cognitive status using a Mendelian randomization framework.MethodsWe conducted a cross-sectional study using the 2010 wave of the Health and Retirement Study database. Individuals aged between 50 and 90 were included. Smoking status was self-reported. Polygenic scores (PGSs) were calculated by weighting participant genotype by published smoking genome-wide association estimates. Cognitive status (normal, impaired, dementia) was measured using multiple assessments. A Mendelian randomization framework was used to infer causal relationships between smoking behavior and cognitive status via genetic instruments.ResultsAmong European ancestry participants (N = 8,735), current smoking behavior was positively associated with cognitive impairment (OR = 1.62, 95% CI: 1.29, 2.01) relative to normal cognition. Using smoking PGS as an instrumental variable, a causal relationship was observed between current smoking and cognitive impairment (OR = 1.53, 95% CI: 1.07, 2.18). There were no associations between smoking PGS, smoking behaviors and cognitive status in the African ancestry study sample (N = 2,511).ConclusionsCurrent smoking is a modifiable risk factor which causes cognitive impairment. Promotion of smoking cessation is important for public health. Further studies on dose and duration of smoking behaviors on cognitive impairment are critically needed, as well as in research other ancestries.
Published: 2019
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63. Considering the APOE locus in polygenic scores for Alzheimer’s disease

Author: Colter Mitchell, Jessica D. Faul, Kelly M. Bakulski, and Erin B. Ware
Subjects: Apolipoprotein E, Genetics, 0303 health sciences, Single-nucleotide polymorphism, Locus (genetics), Disease, Biology, medicine.disease, Phenotype, 03 medical and health sciences, 0302 clinical medicine, Covariate, medicine, Dementia, 030217 neurology & neurosurgery, Cumulative effect, 030304 developmental biology
Abstract: Polygenic scores are a strategy to aggregate the small, additive effects of single nucleotide polymorphisms across the genome. With phenotypes like Alzheimer’s disease, which have a strong and well established genomic locus (APOE), the cumulative effect of genetic variants outside of this area has not been well established in a population-representative sample. Here we examine the association between polygenic scores both with and without the APOE region at different P value thresholds. We also investigate the addition of APOE-ε4 carrier status and its effect on the polygenic score – dementia association. We found that including the APOE region through weighted variants in a polygenic score was insufficient to capture the large amount of risk attributed to this region. We recommend removing this region from polygenic score calculation and treating the APOE locus as an independent covariate.
Published: 2019
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64. A meta-analysis of genome-wide association studies identifies multiple longevity genes

Author: Jerome I. Rotter, Rachel Duncan, Lenore J. Launer, Iris E. Jansen, Sarah Cubaynes, Nir Barzilai, Elizabeth J. Becker, Wiesje M. van der Flier, Joris Deelen, Sharon L.R. Kardia, Birgit Debrabant, Wanlin Zheng, Michael A. Province, Janina Dose, Anne B. Newman, Vilmundur Gudnason, Carol Jagger, Kenny Ye, Gil Atzmon, Carmen Martin-Ruiz, Kathryn L. Lunetta, Claudio Franceschi, Marianne Nygaard, Diana van Heemst, Najaf Amin, P. Eline Slagboom, Thomas B. L. Kirkwood, Ilkka Seppälä, Chloé Sarnowski, Heather J. Cordell, Terho Lehtimäki, Jennifer A. Smith, Cornelia M. van Duijn, Marja Jylhä, Dan E. Arking, Hélène Blanché, Jessica D. Faul, Yi Zeng, Henne Holstege, Kent D. Taylor, Junxia Min, Alice M. Arnold, Kristin L. Ayers, Mika Kähönen, Olli T. Raitakari, Pilar Galan, Mary K. Wojczynski, Jean-Marie Robine, Lene Christiansen, David R. Weir, Karen Davies, J. Collerton, Kaare Christensen, Douglas P. Kiel, Niccolò Tesi, Andrew Kingston, Bruce M. Psaty, Joanne M. Murabito, Marcel J. T. Reinders, Albert V. Smith, Xiaomin Liu, Leo-Pekka Lyytikäinen, Mary L. Biggs, Almut Nebel, Sven J. van der Lee, Mikko Hurme, David Karasik, Jean-François Deleuze, Thomas T. Perls, Erin B. Ware, Martijn Huisman, Marian Beekman, Chao Nie, Tamara B. Harris, Ellen A. Nohr, Eric S. Orwoll, Steven R. Cummings, Paola Sebastiani, James W. Vaupel, Wolfgang Lieb, Daniel S. Evans, Thorkild I. A. Sørensen, André G. Uitterlinden, Ashley van der Spek, Max planck Institute for Biology of Ageing [Cologne], Leiden University Medical Center (LUMC), California Pacific Medical Center Research Institute, Johns Hopkins University School of Medicine [Baltimore], McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Delft Bioinformatics Lab [Delft], Delft University of Technology (TU Delft), University of Southern Denmark (SDU), Beijing Genomics Institute [Shenzhen] (BGI), China National GeneBank, Division of Statistical Genomics, Washington University School of Medicine, Department of Biostatistics, University of Washington [Seattle], Department of Medicine, Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Medicine [Bronx, NY, USA], Albert Einstein College of Medicine [New York], Department of Biology, Faculty of Sciences and Science Education, Haifa University, University of Haifa [Haifa], Institute for Social Research, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Biostatistics [Boston, MA, USA], Harvard T.H. Chan School of Public Health, Icelandic Heart Association [Kopavogur, Iceland] (IHA), Department of Clinical Chemistry, Tempere University, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Institute of Clinical Molecular Biology, Kiel University, SEMA4, Department of Biostatistics, University of Washington, Boston University [Boston] (BU), Fondation Jean Dausset CEPH, Odense University Hospital, Odense, Copenhagen University Hospital, Institute of Health and Society, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), 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)-Université de Montpellier (UM), Institute of Neuroscience [Newcastle] (ION), Institute of Clinical Research, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute of Ageing and Health, Newcastle University, Newcastle Upon Tyne, Department of Applied Mathematics and Centre of Bioinformatics, Lobachevsky State University [Nizhni Novgorod], Institute of Neurological Sciences of Bologna IRCCS, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Department of Clinical Epidemiology and Biostatistics, VU Medical Centre, Amsterdam, Amsterdam Public Health Research Institute [The Netherlands], Department of Microbiology and Immunology, University of Tampere [Finland], Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, Institute of Health & Society, Department of Complex Trait Genetics, Vrije Universiteit Amsterdam [Amsterdam] (VU), Tampere University Hospital, School of Public Health, University of Michigan [Dearborn], Faculty of Medicine and Life Sciences [Tampere], Institute of Epidemiology and Biobank PopGen, Faculty of Medicine and Health Technology [Tampere, Finland], Zhejiang University School of Medicine [China], University of Pittsburgh Graduate School of Public Health, Oregon Health & Sciences University, Oregon Health and Science University [Portland] (OHSU), Boston University School of Medicine (BUSM), Department of Medicine, University of Washington, Department of Epidemiology, University of Washington, Kaiser Permanente Washington Health Research Institute [Seattle] (KPWHRI), Turku University Hospital (TYKS), University of Turku, School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), UCLA Medical Center, University of Michigan System, University of Copenhage, Faculty of Health and Medical Sciences, MRC Integrative Epidemiology Unit [Bristol, Royaume-Uni] (MRC IEU), University of Bristol [Bristol], Los Angeles Biomedical Research Institute (LA BioMed), Harbor UCLA Medical Center [Torrance, Ca.], Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine (ROTTERDAM - Med Int), Maasstad Ziekenhuis = Maasstad Hospital, Alzheimercentre, department of Neurology, VU University Medical Center, Nuffield Department of Population Health [Oxford], University of Oxford, Max Planck Institute for Demographic Research (MPIDR), Max-Planck-Gesellschaft, Beijing Forestry University, Medical School of Duke University, Hinda and Arthur Marcus Institute for Aging Research,Hebrew SeniorLife, Harvard Medical School [Boston] (HMS), Broad Institute of MIT & Harvard, AUDOUX, Michèle, Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-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), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), University of California-University of California, Maasstad Hospital, University of Oxford [Oxford], Epidemiology and Data Science, APH - Aging & Later Life, APH - Societal Participation & Health, Neurology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, APH - Personalized Medicine, APH - Methodology, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Epidemiology, Internal Medicine, Universiteit Leiden, and École Pratique des Hautes Études (EPHE)
Subjects: 0301 basic medicine, Percentile, Aging, Apolipoprotein E2, media_common.quotation_subject, Science, [SDV]Life Sciences [q-bio], Longevity, Apolipoprotein E4, Áhættuþættir, General Physics and Astronomy, Genome-wide association study, Diseases, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Genetic correlation, Genome-wide association studies, Article, General Biochemistry, Genetics and Molecular Biology, Odds, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, lcsh:Science, Endoplasmic Reticulum Chaperone BiP, Heat-Shock Proteins, media_common, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Öldrun, Sjúkdómar, Human Genome, General Chemistry, Genetic architecture, [SDV] Life Sciences [q-bio], Ageing, 030104 developmental biology, Risk factors, Meta-analysis, lcsh:Q, Erfðarannsóknir, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein)., Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity., Alexander von Humboldt-Stiftung
Published: 2019
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65. The burden of health conditions across race and ethnicity for aging Americans: Disability-adjusted life years

Author: Mark D. Peterson, Jessica D. Faul, Brenda M. Vincent, Soham Al Snih, Ryan McGrath, Orman T. Hall, and Kyriakos S. Markides
Subjects: Male, Aging, Health Status, Psychological intervention, Ethnic group, Observational Study, Disease, 03 medical and health sciences, Race (biology), 0302 clinical medicine, Sex Factors, Health care, Ethnicity, Medicine, Humans, 030212 general & internal medicine, 10. No inequality, Aged, Aged, 80 and over, DALY, geriatrics, business.industry, Racial Groups, Age Factors, General Medicine, Health and Retirement Study, Middle Aged, mortality, United States, 3. Good health, Quality-adjusted life year, Socioeconomic Factors, 030220 oncology & carcinogenesis, Chronic Disease, Observational study, Female, epidemiology, Quality-Adjusted Life Years, business, Demography, Research Article
Abstract: Despite evidence suggesting race and ethnicity are important factors in responses to environmental exposures, drug therapies, and disease risk, few studies focus on the health needs of racially- and ethnically-diverse aging adults. The objective of this study was to determine the burden of 10 health conditions across race and ethnicity for a nationally-representative sample of aging Americans. Data from the 1998 to 2014 waves of the Health and Retirement Study, an ongoing longitudinal-panel study, were analyzed. Those aged over 50 years who identified as Black, Hispanic, or White were included. There were 5510 Blacks, 3423 Hispanics, and 21,168 Whites in the study. At each wave, participants reported if they had cancer, chronic obstructive pulmonary disease, congestive heart failure, diabetes, back pain, hypertension, a fractured hip, myocardial infarction, rheumatism or arthritis, and a stroke. Disability-adjusted life years (DALYs) were calculated for each health condition by race and ethnicity. Ranked DALYs determined how race and ethnicity was differentially impacted by the burden of each health condition. Sample weights were utilized to make DALY estimates nationally-representative. Weighted DALY estimates (in thousands) ranged from 1405 to 55,631 for Blacks, 931 to 28,442 for Hispanics, and 15,313 to 295,623 for Whites. Although the health conditions affected each race and ethnicity differently, hypertension had the largest number of DALYs, and hip fractures had the fewest across race and ethnicity. In total, there were an estimated 198,621, 101,462, and 1,187,725 DALYs for older Black, Hispanic, and White aging adults. Our findings indicate that race and ethnicity may be influential on health and disease for aging adults in the United States. Monitoring DALYs may help guide the flow of health-related expenditures, improve the impact of health interventions, advance inclusive health care for diverse aging adult populations, and prepare healthcare providers for serving the health needs of aging adults.
Published: 2019

66. 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
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67. How Does Subjective Age Get 'Under the Skin'? The Association Between Biomarkers and Feeling Older or Younger Than One’s Age: The Health and Retirement Study

Author: Helen Parsons, Bharat Thyagarajan, Tetyana P Shippee, Nathan D. Shippee, Jessica D. Faul, Eileen M. Crimmins, and Sithara Vivek
Subjects: Research design, medicine.medical_specialty, Health (social science), Age discrepancy score, Health Professions (miscellaneous), 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, 0501 psychology and cognitive sciences, Original Research Article, Biological domains, Risk factor, Life-span and Life-course Studies, 2. Zero hunger, business.industry, 05 social sciences, Health and Retirement Study, 3. Good health, Marital status, Biomarker (medicine), Liver function, Physiological aging, business, Body mass index, Psychosocial, 030217 neurology & neurosurgery
Abstract: Background and Objectives Though subjective age is a well-recognized risk factor for several chronic diseases, the biological basis for these associations remains poorly understood. Research Design and Methods We used new comprehensive biomarker data from the 2016 wave of the nationally representative Health and Retirement Study (HRS) to evaluate the association between biomarker levels and self-reported subjective age in a subset of 3,740 HRS participants who provided a blood sample. We measured biomarkers in seven biological domains associated with aging: inflammation, glycemia, lipids, liver function, endocrine function, renal function, and cardiac function. The primary outcome was the age discrepancy score (subjective age − chronological age) categorized as those who felt younger, older, or the same as their chronological age (reference group). Analyses adjusted for comprehensive psychosocial factors (chronic stress index, depression score), demographic factors (race, sex, body mass index, marital status, physical activity), and prevalence of chronic health conditions (comorbidity index). Results The prevalence of clinically relevant reduced levels of albumin concentrations was lower in those who felt younger (8.8% vs. 16.0%; p = .006) and higher in those who felt older (20.4% vs. 16.0%; p = .03) when compared with the reference category. The prevalence of clinically significant elevation in liver enzymes such as alanine aminotransferase was also significantly lower among those who felt younger (7.1% vs. 8.6%; p = .04) when compared with the reference category. Prevalence of clinically elevated levels in cystatin C was also lower among those who felt younger when compared with the reference category (50.0% vs. 59.1%; p = .04). There was no association between lipids, glucose, or C-reactive protein (inflammatory marker) and subjective age categories. Discussion and Implications These results suggest that people who feel younger may have favorable biomarker profiles and as a result may have lower prevalence of age-related diseases when compared with those who feel older or those who feel the same as their chronological age.
Published: 2019
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68. O5‐08‐01: TRENDS IN RACIAL AND ETHNIC DIFFERENCES IN DEMENTIA PREVALENCE RATES AND DISEASE AWARENESS

Author: Pei-Jung Lin, Jessica D. Faul, Karen M. Freund, Joshua T. Cohen, Joanna Emerson, Peter J. Neumann, Nikoletta M. Margaretos, and Howard Fillit
Subjects: Epidemiology, business.industry, Health Policy, Prevalence, Ethnic group, Disease, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, business, Demography
Published: 2019
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69. Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

Author: Michael Boehnke, Anke R. Hammerschlag, Stavroula Kanoni, Nilesh J. Samani, Stefan Blankenberg, Arpana Agrawal, Ersin Yavas, Chris Hsu, Dominique Arveiler, Giovanni Veronesi, Sarah E. Harris, Guillaume Lettre, Leah Wetherill, Helen R. Warren, M Samuel, Manav Kapoor, Praveen Surendran, Mengzhen Liu, Massimo Mangino, Abdulla Al Shafi Majumder, Chiara Batini, Jeff Haessler, Anton J. M. De Craen, Matt McGue, Laura J. Bierut, Yi Ling Chou, Markku Laakso, Ian J. Deary, Rebecca Rohde, Nhung Le, David Schlessinger, J. Dylan Weissenkampen, Claudia Langenberg, Tim D. Spector, Paul W. Franks, John P. Rice, Philippe M. Frossard, Hanieh Yaghootkar, Janie Corley, Frank Kee, J. Wouter Jukema, Pim van der Harst, Dermot F. Reily, Jenny Chang-Claude, Nicholas G. Martin, Tatiana Foroud, Sune F. Nielsen, Charles Kooperberg, Rudolf A. de Boer, Francesco Cucca, Paul D.P. Pharoah, Alex P. Reiner, Daniel R. Barnes, Anders Mälarstig, Jonathan Marten, Henry Völzke, Yu Jiang, Jukka Kontto, J Danesh, Antonis C. Antoniou, Andrew C. Heath, Nicholas J. Wareham, Joanna M. M. Howson, Alison Goate, Olov Rolandsson, Frida Renström, Chu Chen, Vinicius Tragante, Matt J. Neville, Kathleen Stirrups, Clemens Baumbach, Colin N. A. Palmer, Adam S. Butterworth, William G. Iacono, Naveed Sattar, Ian P. Hall, Daniel O. Stram, Giorgio Pistis, Jan-Håkan Jansson, Jaakko Kaprio, David R. Weir, David P. Strachan, Martin D. Tobin, Folkert W. Asselbergs, John M. Starr, Stefan Weiss, Thomas F. Vogt, Riccardo E. Marioni, Maarten Hoek, Jessica Tyrrell, Hilary A. Tindle, Alison M. Dunning, Anu Loukola, Joe Dennis, Victoria E. Jackson, Louise V. Wain, Eleftheria Zeggini, Weihua Zhang, Yaming Shao, Kari Kuulasmaa, Elisabeth Altmaier, Jean-Claude Tardif, Jian Gong, A. Mesut Erzurumluoglu, Andries R. van der Leij, Kari E. North, Anna F. Dominiczak, Martina Müller-Nurasyid, Scott I. Vrieze, Sarah Bertelsen, Markus Perola, Evangelos Evangelou, Chris J. Packard, Gonçalo R. Abecasis, Robert A. Scott, S. Trompet, Jennifer A. Smith, H. Steven Scholte, Timothy M. Frayling, Danielle Posthuma, Ian Ford, Douglas F. Easton, Børge Grønne Nordestgaard, Michiel L. Bots, Charles B. Eaton, Sharon L.R. Kardia, Dewan S. Alam, Xiaowei Zhan, Sean P. David, Maria Uria-Nickelsen, Dongbing Lai, Ilonca Vaartjes, Mark J. Caulfield, Valérie Turcot, Jean Ferrières, Emanuele Di Angelantonio, Robin Young, Pamela A. F. Madden, Tibor V. Varga, Asif Rasheed, Peter van der Meer, Dajiang J. Liu, Ioanna Tachmazidou, Panos Deloukas, Danish Saleheen, Evelin Mihailov, Caroline Hayward, Patricia B. Munroe, Beenish Qaiser, Jessica D. Faul, John C. Chambers, Matthias Nauck, Niek Verweij, Jordan M. Hughey, Christopher A. Haiman, Hans J. Grabe, Muriel Caslake, Saima Afaq, Jaspal S. Kooner, Tinca J. C. Polderman, Philippe Amouyel, Wei Zhao, Göran Hallmans, Andres Metspalu, Jarmo Virtamo, Carl A. Melbourne, Kaixin Zhou, Christiaan de Leeuw, Peter S. Sever, Eirini Marouli, Neil Poulter, Rajiv Chowdhury, Jian'an Luan, Deborah J. Thompson, F Karpe, Kyriaki Michailidou, David M. Brazel, Heather M. Stringham, Brein en Cognitie (Psychologie, FMG), Psychology Other Research (FMG), Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Graduate School, Experimental Vascular Medicine, ACS - Diabetes & metabolism, Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, Laboratory Genetic Metabolic Diseases, Gastroenterology and Hepatology, Experimental Immunology, Radiotherapy, Cardiology, HUSLAB, Institute for Molecular Medicine Finland, Department of Public Health, Genetic Epidemiology, Barnes, Daniel [0000-0002-3781-7570], Erzurumluoglu, Mesut [0000-0003-1322-8138], Apollo - University of Cambridge Repository, Biological Psychology, and Complex Trait Genetics
Subjects: 0301 basic medicine, Nonsynonymous substitution, Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, DEPENDENCE, Genotype, Databases, Genetic, SEQUENCE VARIANTS, GWAS, Exome, Non-U.S. Gov't, Oligonucleotide Array Sequence Analysis, Genetics, RISK, HERITABILITY, Research Support, Non-U.S. Gov't, Smoking, ASSOCIATION, 3. Good health, ADH1B, Phenotype, Behavioral genetics, LOW-FREQUENCY, Alcohol, Heritability, Nicotine, Tobacco, Alcohol Drinking, Non-P.H.S, Single-nucleotide polymorphism, Biology, Research Support, Polymorphism, Single Nucleotide, N.I.H, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Genetic variation, Journal Article, Humans, Genetic Predisposition to Disease, COMMON, Biological Psychiatry, 3112 Neurosciences, Genetic Variation, Extramural, MISSENSE VARIANTS, R1, Genetic architecture, 030104 developmental biology, U.S. Gov't, 030217 neurology & neurosurgery, Research Support, U.S. Gov't, Non-P.H.S, Genome-Wide Association Study
Abstract: BackgroundSmoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.MethodsWe analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.ResultsMeta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals.ConclusionsRare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.
Published: 2019
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70. A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Author: Bamidele O. Tayo, RJ Waken, Mario Sims, Diane M. Becker, Tõnu Esko, Yingchang Lu, Pamela J. Schreiner, Antonietta Robino, Anne U. Jackson, H. Janaka de Silva, Peter J. van der Most, Archie Campbell, Ozren Polasek, Salman M. Tajuddin, Jing Hua Zhao, Barbara V. Howard, Saima Afaq, Vilmundur Gudnason, Lynda M. Rose, Francis S. Collins, Massimiliano Cocca, Ruth J. F. Loos, Yii-Der Ida Chen, W. James Gauderman, Jaspal S. Kooner, Lawrence F. Bielak, Ulrich Broeckel, Anuradhani Kasturiratne, Melissa A. Richard, Tomohiro Katsuya, Nicola D. Kerrison, Tin Aung, Lisa de las Fuentes, Lynne E. Wagenknecht, Oscar H. Franco, Yongmei Liu, Eric Boerwinkle, Nana Matoba, Saskia P. Hagenaars, Rob M. van Dam, Tibor V. Varga, Nilesh J. Samani, Tangchun Wu, Thomas H. Mosley, Caroline Hayward, Joseph H. Lee, Frida Renström, Tamara B. Harris, Alena Stančáková, Adesola Ogunniyi, Wen Bin Wei, Lenore J. Launer, Marcus Dörr, Xiuqing Guo, Jennifer A. Smith, Terho Lehtimäki, Dan E. Arking, Fang-Chi Hsu, Karin Leander, Martin Farrall, Konstantin Strauch, Albert V. Smith, Richard S. Cooper, Chiea Chuen Khor, Changwei Li, James E. Hixson, Sami Heikkinen, David R. Weir, Pirjo Komulainen, Renée de Mutsert, Raymond Noordam, Ubaydah Nasri, Paul M. Ridker, C. Charles Gu, Tamuno Alfred, Jerome I. Rotter, Nora Franceschini, Nita G. Forouhi, Lihua Wang, Alanna C. Morrison, Jian-Min Yuan, Ching-Yu Cheng, Peter S. Braund, Paul Elliott, Gregory P. Wilson, Jianjun Liu, Xiaofeng Zhu, Markku Laakso, Christian Gieger, Yukihide Momozawa, Rainer Rettig, Carsten Oliver Schmidt, Amy R. Bentley, Wei Zhao, Ioanna Ntalla, Kenneth Rice, Yoichiro Kamatani, Andres Metspalu, Helen R. Warren, Yechiel Friedlander, Susan Redline, Kurt Lohman, Cornelia M. van Duijn, Aravinda Chakravarti, Traci M. Bartz, Sarah E. Harris, Yih Chung Tham, He Gao, Mike A. Nalls, Mathilde Boissel, Donna K. Arnett, Harold Snieder, James S. Pankow, Babatunde L. Salako, Laura J. Bierut, Tin Louie, Albertine J. Oldehinkel, Xueling Sim, Thomas Meitinger, Maris Alver, Claudia Langenberg, Stephen B. Kritchevsky, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Alexandre C. Pereira, Michael R. Brown, Karen Schwander, Charles Kooperberg, Blair H. Smith, Annette Peters, Fernando Pires Hartwig, Yanhua Zhou, Jie Yao, Alisa K. Manning, Keng-Hung Lin, Dennis O. Mook-Kanamori, Ervin R. Fox, Tuomo Rankinen, Timo A. Lakka, Charles N. Rotimi, Nicholette D. Palmer, Jiang He, Nicholas J. Wareham, Jingmin Liu, Yun Ju Sung, Cathy C. Laurie, Donald W. Bowden, Yong-Bing Xiang, Lisa R. Yanek, B. Kuhnel, Nancy L. Pedersen, Yajuan Wang, Ananda R. Wickremasinghe, Jonathan Marten, Yi-Jen Hung, Dabeeru C. Rao, Bernardo L. Horta, Joel D. Kaufman, Barry I. Freedman, Chuan Gao, Olli T. Raitakari, Reedik Mägi, Solomon K. Musani, Albert Hofman, Wanqing Wen, Heming Wang, Xiao-Ou Shu, Y Liu, Mark J. Caulfield, Meian He, Daniel I. Chasman, Carl D. Langefeld, Charumathi Sabanayagam, Bruce M. Psaty, Jasmin Divers, R. Graham Barr, Chew-Kiat Heng, Stella Aslibekyan, John M. Starr, Stefan Weiss, Anuj Goel, Tuomas O. Kilpeläinen, Terrence Forrester, Mary F. Feitosa, Jost B. Jonas, Kae-Woei Liang, Colleen M. Sitlani, Daniel Levy, Marie Loh, Qing Duan, Aldi T. Kraja, Tien Yin Wong, Myriam Fornage, Andrea R. V. R. Horimoto, Michele K. Evans, David J. Porteous, Dina Vojinovic, Hua Tang, Michael A. Province, Ching-Ti Liu, Rainer Rauramaa, William R. Scott, Cora E. Lewis, Charles B. Eaton, Sharon L.R. Kardia, Michael Boehnke, James Scott, Colin A McKenzie, Jin-Fang Chai, Woon-Puay Koh, Yucheng Jia, Claude Bouchard, Peter S. Sever, Koichi Matsuda, Najaf Amin, Ulf de Faire, Walter Palmas, André G. Uitterlinden, Thomas T. Perls, Erin B. Ware, Wayne Huey-Herng Sheu, Michiaki Kubo, Ya Xing Wang, Hugh Watkins, Steven C. Hunt, Weihua Zhang, Johanna Kuusisto, Lili Milani, Rajkumar Dorajoo, Georg Ehret, L. Adrienne Cupples, Franco Giulianini, Zoltán Kutalik, Jose E Krieger, Kevin Sandow, Bruna Gigante, Alexander P. Reiner, Preeti Gupta, Heikki A. Koistinen, Treva Rice, Patricia B. Munroe, Wen-Jane Lee, Jennifer A. Brody, Paolo Gasparini, Paul W. Franks, Yik Ying Teo, Leo-Pekka Lyytikäinen, Thomas W. Winkler, Patricia A. Peyser, Ian J. Deary, Jessica D. Faul, Sing Hui Lim, Fumihiko Takeuchi, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, E. Shyong Tai, Candace M Kammerer, Mary K. Wojczynski, Pim van der Harst, Marzyeh Amini, Jennifer G. Robinson, Erwin P. Bottinger, Alan B. Zonderman, Benjamin Lehne, M. Waldenberger, Jeffrey R. O'Connell, Hugues Aschard, Ilaria Gandin, Kent D. Taylor, Igor Rudan, Christopher P. Nelson, John M. C. Connell, Jian'an Luan, Mickaël Canouil, Robert A. Scott, Yize Li, Marguerite R. Irvin, Sung, Yun Ju, de Las Fuentes, Lisa, Winkler, Thomas W, Chasman, Daniel I, Bentley, Amy R, Kraja, Aldi T, Ntalla, Ioanna, Warren, Helen R, Guo, Xiuqing, Schwander, Karen, Manning, Alisa K, Brown, Michael R, Aschard, Hugue, Feitosa, Mary F, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K, Kilpeläinen, Tuomas O, Richard, Melissa A, Aslibekyan, Stella, Bartz, Traci M, Dorajoo, Rajkumar, Li, Changwei, Liu, Yongmei, Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M, Tayo, Bamidele O, Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kammerer, Candace M, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Leander, Karin, Lee, Wen-Jane, Lin, Keng-Hung, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Mckenzie, Colin A, Nelson, Christopher P, Noordam, Raymond, Scott, Robert A, Sheu, Wayne H H, Stančáková, Alena, Takeuchi, Fumihiko, van der Most, Peter J, Varga, Tibor V, Waken, Robert J, Wang, Heming, Wang, Yajuan, Ware, Erin B, Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Alfred, Tamuno, Amin, Najaf, Arking, Dan E, Aung, Tin, Barr, R Graham, Bielak, Lawrence F, Boerwinkle, Eric, Bottinger, Erwin P, Braund, Peter S, Brody, Jennifer A, Broeckel, Ulrich, Cade, Brian, Campbell, Archie, Canouil, Mickaël, Chakravarti, Aravinda, Cocca, Massimiliano, Collins, Francis S, Connell, John M, de Mutsert, Renée, de Silva, H Janaka, Dörr, Marcu, Duan, Qing, Eaton, Charles B, Ehret, Georg, Evangelou, Evangelo, Faul, Jessica D, Forouhi, Nita G, Franco, Oscar H, Friedlander, Yechiel, Gao, He, Gigante, Bruna, Gu, C Charle, Gupta, Preeti, Hagenaars, Saskia P, Harris, Tamara B, He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hofman, Albert, Howard, Barbara V, Hunt, Steven C, Irvin, Marguerite R, Jia, Yucheng, Katsuya, Tomohiro, Kaufman, Joel, Kerrison, Nicola D, Khor, Chiea Chuen, Koh, Woon-Puay, Koistinen, Heikki A, Kooperberg, Charles B, Krieger, Jose E, Kubo, Michiaki, Kutalik, Zoltan, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Joseph H, Lehne, Benjamin, Levy, Daniel, Lewis, Cora E, Li, Yize, Lim, Sing Hui, Liu, Ching-Ti, Liu, Jianjun, Liu, Jingmin, Liu, Yeheng, Loh, Marie, Lohman, Kurt K, Louie, Tin, Mägi, Reedik, Matsuda, Koichi, Meitinger, Thoma, Metspalu, Andre, Milani, Lili, Momozawa, Yukihide, Mosley, Thomas H, Nalls, Mike A, Nasri, Ubaydah, O'Connell, Jeff R, Ogunniyi, Adesola, Palmas, Walter R, Palmer, Nicholette D, Pankow, James S, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Porteous, David, Raitakari, Olli T, Renström, Frida, Rice, Treva K, Ridker, Paul M, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Sabanayagam, Charumathi, Salako, Babatunde L, Sandow, Kevin, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Sims, Mario, Sitlani, Colleen M, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tang, Hua, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, Waldenberger, Melanie, Wang, Lihua, Wang, Ya Xing, Wei, Wen Bin, Wilson, Gregory, Wojczynski, Mary K, Xiang, Yong-Bing, Yao, Jie, Yuan, Jian-Min, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Chen, Yii-Der Ida, Weir, David R, de Faire, Ulf, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Forrester, Terrence, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo Lessa, Hung, Yi-Jen, Jonas, Jost Bruno, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Lehtimäki, Terho, Liang, Kae-Woei, Magnusson, Patrik K E, Oldehinkel, Albertine J, Pereira, Alexandre C, Perls, Thoma, Rauramaa, Rainer, Redline, Susan, Rettig, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wareham, Nicholas J, Watkins, Hugh, Wickremasinghe, Ananda R, Wu, Tangchun, Kamatani, Yoichiro, Laurie, Cathy C, Bouchard, Claude, Cooper, Richard S, Evans, Michele K, Gudnason, Vilmundur, Hixson, Jame, Kardia, Sharon L R, Kritchevsky, Stephen B, Psaty, Bruce M, van Dam, Rob M, Arnett, Donna K, Mook-Kanamori, Dennis O, Fornage, Myriam, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Loos, Ruth J F, Reiner, Alex P, Rotimi, Charles N, Bierut, Laura J, Zhu, Xiaofeng, Cupples, L Adrienne, Province, Michael A, Rotter, Jerome I, Franks, Paul W, Rice, Kenneth, Elliott, Paul, Caulfield, Mark J, Gauderman, W Jame, Munroe, Patricia B, Rao, Dabeeru C, Morrison, Alanna C, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham and Women's Hospital [Boston], Queen Mary University of London (QMUL), Harbor UCLA Medical Center [Torrance, Ca.], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), U.S. National Heart, Lung, and Blood Institute (NHLBI) (K25HL121091 to Y.J.S.), National Institutes of Health (R01HL118305), We thank anonymous reviewers for critical reading and providing constructive and insightful comments, which substantially improved the article. This project, like several other projects, was carried out as part of the CHARGE Gene–Lifestyle Interactions Working Group., Conflict of Interest statement. The authors declare no competing financial interests except for the following: B.M.P. serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson, O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health), L.J.B. is listed as an inventor on Issued U.S. Patent 8,080,371,‘Markers for Addiction’ covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction, P.S. has received research awards from Pfizer Inc, J.B.J. is a consultant for Mundipharma Co. (Cambridge, UK), Patent holder with Biocompatibles UK Ltd (Franham, Surrey, UK) (title: treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor, Patent number: 20120263794) and Patent application with University of Heidelberg (Heidelberg, Germany) (title: agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia, Europäische Patentanmeldung 15000771.4), P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative project, M.A.N.'s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, M.A.N. also consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare among others, and M.J. C. is chief scientist for Genomics England, a UK government company., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), 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 National de la Recherche Scientifique (CNRS), Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), University Management, Department of Medicine, University of Helsinki, HUS Abdominal Center, Endokrinologian yksikkö, Marten, Jonathan [0000-0001-6916-2014], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, and Medical Research Council (MRC)
Subjects: Male, Receptors, Vasopressin, multi-ancestry, Genome-wide association study, Blood Pressure, HYDROCARBON RECEPTOR AHR, 030204 cardiovascular system & hematology, Antiporters, gene-smoking interaction, 0302 clinical medicine, Polymorphism (computer science), genome-wide study, Ethnicity, OXIDATIVE STRESS, Association Studies Article, 11 Medical and Health Sciences, Genetics (clinical), Genetics & Heredity, Genetics, ddc:616, Aged, 80 and over, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], DEPENDENT HYPERTENSION, CARDIOVASCULAR RISK, Smoking, 1184 Genetics, developmental biology, physiology, General Medicine, ASSOCIATION, Middle Aged, Caspase 9, 3. Good health, Pulse pressure, ENVIRONMENT INTERACTION, Sulfate Transporters, T-CADHERIN, Hypertension, Female, Life Sciences & Biomedicine, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, Biochemistry & Molecular Biology, Mean arterial pressure, Adolescent, Diastole, Biology, elevated blood pressure, gene-smoking interactions, 03 medical and health sciences, Young Adult, Insulin resistance, Lifelines Cohort Study, medicine, Humans, Arterial Pressure, Molecular Biology, METAANALYSIS, 030304 developmental biology, Aged, Science & Technology, Polymorphism, Genetic, Tumor Suppressor Proteins, Racial Groups, Membrane Proteins, 06 Biological Sciences, SYSTOLIC BLOOD-PRESSURE, BODY-MASS INDEX, medicine.disease, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Heart failure, 1182 Biochemistry, cell and molecular biology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Gene-Environment Interaction, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Genome-Wide Association Study
Abstract: Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P
Published: 2019
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71. The complex genetics of gait speed: genome-wide meta-analysis approach

Author: Steven R. Cummings, Dan Mellström, Ian J. Deary, Jennifer A. Smith, David Karasik, Dena G. Hernandez, Beverly G Windham, David C. Liewald, Maria Nethander, D. S. Knopman, Sharon L.R. Kardia, Velandai Srikanth, Rotem Vered, Albert V. Smith, Joanne M. Murabito, Magnus Karlsson, Alice M. Arnold, Tamara B. Harris, Joris Deelen, Philip L. De Jager, Janie Corley, Andrew D. Johnson, Hieab H.H. Adams, Jos N. van der Geest, Neeta Parimi, A.B. Newman, Gail Davies, David R. Weir, Yongmei Liu, Russell Thomson, John M. Starr, David A. Bennett, Joe Verghese, Lei Yu, Aron S. Buchman, Jessica D. Faul, Gil Atzmon, Gregory J. Tranah, Myriam Fornage, Douglas P. Kiel, Marian Beekman, Alison Pattie, Vilmundur Gudnason, Claes Ohlsson, Toshiko Tanaka, Lenore J. Launer, Daniel S. Evans, Vincent J. A. Verlinden, Michele L. Callisaya, Jeanine J. Houwing-Duistermaat, Stephen Turner, Luigi Ferrucci, Albert Hofman, Simon P. Mooijaart, Danielle Gutman, Rebekah McWhirter, M. Arfan Ikram, André G. Uitterlinden, Wei Zhao, Jeremy D. Walston, Amy M. Matteini, Denis A. Evans, Matthijs Moed, Stefania Bandinelli, Danny Ben-Avraham, John D. Eicher, Thomas H. Mosley, Eline Slagboom, Kathryn L. Lunetta, Lital Sharvit, Epidemiology, Radiology & Nuclear Medicine, Neurosciences, and Internal Medicine
Subjects: 0301 basic medicine, Genetics, Aging, medicine.medical_specialty, aging, Genome-wide association study, Single-nucleotide polymorphism, Cell Biology, Quantitative trait locus, Genome, meta-analysis, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Geography, meta‐analysis, Meta-analysis, Genetic variation, Expression quantitative trait loci, medicine, GWAS, Medical genetics, gait speed, 030217 neurology & neurosurgery
Abstract: Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.
Published: 2017
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72. GENOME-WIDE ASSOCIATION STUDY (GWAS) AND GENOME-WIDE BY ENVIRONMENT INTERACTION STUDY (GWEIS) OF DEPRESSIVE SYMPTOMS IN AFRICAN AMERICAN AND HISPANIC/LATINA WOMEN

Author: Beverly M. Snively, Thomas W. Soare, Gloria E. Sarto, Farid Radmanesh, Jessica D. Faul, Tamar Sofer, Karin Hek, Peter Kraft, Marilyn C. Cornelis, Jordan W. Smoller, David R. Weir, Wei Zhao, Kerry J. Ressler, Jennifer A. Smith, Sylvia Wassertheil-Smoller, Jonathan Rosand, Joseph S. Goveas, Shaun Purcell, Anna Wiste, Henning Tiemeier, Saira Saeed Mirza, Erin C. Dunn, Lynn M. Almli, Sharon L.R. Kardia, Karestan C. Koenen, and Stephanie M. Gogarten
Subjects: 0301 basic medicine, Gerontology, business.industry, Poison control, Single-nucleotide polymorphism, Genome-wide association study, Heritability, 03 medical and health sciences, Psychiatry and Mental health, Clinical Psychology, Social support, 030104 developmental biology, 0302 clinical medicine, Cohort, Medicine, Gene–environment interaction, business, 030217 neurology & neurosurgery, Demography, Genetic association
Abstract: Background Genome-wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene–environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide by environment interaction study (GWEIS) of depressive symptoms. Methods Using data from the SHARe cohort of the Women's Health Initiative, comprising African Americans (n = 7,179) and Hispanics/Latinas (n = 3,138), we examined genetic main effects and GxE with stressful life events and social support. We also conducted a heritability analysis using genome-wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts. Results No SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20 kb from GPR139, P = 5.75 × 10−8) and rs75407252 (intronic to CACNA2D3, P = 6.99 × 10−7). In Hispanics/Latinas, the top signals were rs2532087 (located 27 kb from CD38, P = 2.44 × 10−7) and rs4542757 (intronic to DCC, P = 7.31 × 10−7). In the GEWIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; P = 4.10 × 10−10; located 14 kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG = 0.95), suggesting that common variation underlying self-reported depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample. Conclusions Our results underscore the need for larger samples, more GEWIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities.
Published: 2016
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73. Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies

Author: Johan G. Eriksson, Ayse Demirkan, Francesco Cucca, Hanna Ollila, Klaus Berger, A.G. Uitterlinden, Sharon L.R. Kardia, Yongmei Liu, Veikko Salomaa, W. V. Zhuang, Antonio Terracciano, Nese Direk, Osorio Meirelles, K. L. Lunetta, Myriam Fornage, Jennifer A. Smith, Lei Yu, Karin Hek, Aarno Palotie, Elisabeth Widen, Karestan C. Koenen, Thomas H. Mosley, Jürgen Wellmann, Markus Perola, Wei Zhao, Luigi Ferrucci, Kristine Yaffe, C M van Duijn, A. Hofman, Angelina R. Sutin, Aaron Isaacs, Jessica D. Faul, Paul Lichtenstein, Mike A. Nalls, Patrik K. E. Magnusson, Ben A. Oostra, Alexander Viktorin, Anna Murray, Jari Lahti, Mikael Landén, Joanne M. Murabito, David R. Weir, Toshiko Tanaka, Nancy L. Pedersen, Jun Ding, Luke C. Pilling, David A. Bennett, Tiina Paunio, Alan B. Zonderman, Marilyn C. Cornelis, Fernando Rivadeneira, David J. Llewellyn, Henning Tiemeier, Katri Räikkönen, Annemarie I. Luik, Antonella Mulas, Tamara B. Harris, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Epidemiology, Psychiatry, Internal Medicine, and Clinical Genetics
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Population, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, SNP, Somatoform Disorders, education, Applied Psychology, Genetic association, Genetics, Depressive Disorder, Major, education.field_of_study, major depressive disorder, Depression, Receptor, Melatonin, MT1, Heritability, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, meta-analyses, Meta-analysis, Major depressive disorder, Psychology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: BackgroundMajor depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.MethodWe performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).ResultsOne single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (pdiscovery = 3.82 × 10−8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (pdiscovery+replication = 1.10 × 10−6) with evidence of heterogeneity.ConclusionsDespite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.
Published: 2016
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74. Genetic effects and gene-by-education interactions on episodic memory performance and decline in an aging population

Author: Colter Mitchell, Minjung Kho, Jessica D. Faul, Jennifer A. Smith, Miao Yu, and Wei Zhao
Subjects: Aging, Health (social science), Genotype, Memory, Episodic, Apolipoprotein E4, Genome-wide association study, Biology, Article, 03 medical and health sciences, Cognition, 0302 clinical medicine, History and Philosophy of Science, Missing heritability problem, Humans, 030212 general & internal medicine, Gene–environment interaction, Episodic memory, Aged, Genetic association, Genetics, 030503 health policy & services, Membrane Proteins, Health and Retirement Study, Trait, Educational Status, 0305 other medical science, Genome-Wide Association Study
Abstract: Both social and genetic factors contribute to cognitive impairment and decline, yet genetic factors identified through genome-wide association studies (GWAS) explain only a small portion of trait variability. This "missing heritability" may be due to rare, potentially functional, genetic variants not assessed by GWAS, as well as gene-by-social factor interactions not explicitly modeled. Gene-by-social factor interactions may also operate differently across race/ethnic groups. We selected 39 genes that had significant, replicated associations with cognition, dementia, and related traits in published GWAS. Using gene-based analysis (SKAT/iSKAT), we tested whether common and/or rare variants were associated with episodic memory performance and decline either alone or through interaction with education in10,000 European ancestry (EA) and2200 African ancestry (AA) respondents from the Health and Retirement Study (HRS). Nine genes in EA and five genes in AA were associated with memory performance or decline (p 0.05), and these effects did not attenuate after adjusting for education. Interaction between education and CLPTM1 on memory performance was significant in AA (p = 0.003; FDR-adjusted p = 0.038) and nominally significant in EA (p = 0.026). In both ethnicities, low memory performance was associated with CLPTM1 genotype (rs10416261) only for those with less than high school education, and effects persisted after adjusting for APOE ε4. For over 70% of gene-by-education interactions across the genome that were at least nominally significant in either ethnic group (p 0.05), genetic effects were only observed for those with less than high school education. These results suggest that genetic effects on memory identified in this study are not mediated by education, but there may be important gene-by-education interactions across the genome, including in the broader APOE genomic region, which operate independently of APOE ε4. This work illustrates the importance of developing theoretical frameworks and methodological approaches for integrating social and genomic data to study cognition across ethnic groups.
Published: 2021
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75. Correction: The complex genetics of gait speed: genome-wide meta-analysis approach

Author: John D. Eicher, Dena G. Hernandez, Maria Nethander, Russell Thomson, Thomas H. Mosley, Amy M. Matteini, Lenore J. Launer, Gil Atzmon, A.B. Newman, Dan Mellström, Lital Sharvit, Stephen T. Turner, Joe Verghese, Simon P. Mooijaart, Douglas P. Kiel, Jessica D. Faul, Stefania Bandinelli, Jeremy D. Walston, D. S. Knopman, John M. Starr, David R. Weir, Wei Zhao, Jennifer A. Smith, Sharon L.R. Kardia, Ian J. Deary, Beverly G Windham, Joris Deelen, Alice M. Arnold, Denis A. Evans, Eline Slagboom, Gail Davies, Danielle Gutman, Rotem Vered, David C. Liewald, Magnus Karlsson, Alison Pattie, Kathryn L. Lunetta, Velandai Srikanth, Vilmundur Gudnason, Janie Corley, Joanne M. Murabito, Luigi Ferrucci, Vincent J. A. Verlinden, Michele L. Callisaya, Tamara B. Harris, Danny Ben-Avraham, Jos N. van der Geest, Lei Yu, David Karasik, Philip L. De Jager, Gregory J. Tranah, Toshiko Tanaka, Jeanine J. Houwing-Duistermaat, Aron S. Buchman, Hieab H.H. Adams, Myriam Fornage, Albert V. Smith, Matthijs Moed, Claes Ohlsson, Andrew D. Johnson, Marian Beekman, André G. Uitterlinden, Neeta Parimi, M. Arfan Ikram, Steven R. Cummings, Albert Hofman, Rebekah McWhirter, Yongmei Liu, Daniel S. Evans, and David A. Bennett
Subjects: Male, Aging, Pseudogene, Quantitative Trait Loci, Biology, Genome, Polymorphism, Single Nucleotide, GWAS, Humans, Small nucleolar RNA, Enhancer, PTPRT, Gene, Gait, Aged, Genetics, Aged, 80 and over, Serine Endopeptidases, Receptor-Like Protein Tyrosine Phosphatases, Class 2, RNA, Correction, Cell Biology, Middle Aged, Walking Speed, meta-analysis, Phenotype, Female, gait speed, Small nuclear RNA, Research Paper, Genome-Wide Association Study
Abstract: Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.
Published: 2017

76. Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation

Author: Wieland Kiess, Josée Dupuis, Yingchang Lu, Yii-Der Ida Chen, Sara M. Willems, George Dedoussis, Frida Renström, Carolina Medina-Gomez, Tamara B. Harris, Cramer Christensen, Audrey Y. Chu, Nicola L. Beer, Emil V. R. Appel, Niels Grarup, Fredrik Karpe, Mark I. McCarthy, Yuning Chen, Veikko Salomaa, Sylvain Sebert, Richard A. Jensen, Joel N. Hirschhorn, Lars Lind, Jocelyn E. Manning Fox, Caroline Hayward, Patrick E. MacDonald, Matti Uusitupa, Stavroula Kanoni, Carola Marzi, Kenneth Rice, Leslie A. Lange, Ken Sin Lo, Jennifer L. Asimit, Nisa M. Maruthur, Leonard Lipovich, James S. Floyd, Rona J. Strawbridge, Magdalena Zoledziewska, Anne Raimondo, Robert Sladek, Alexandra I. F. Blakemore, Hugoline G. de Haan, Danish Saleheen, Ji Chen, Neil Robertson, Ching-Yu Cheng, Heiner Boeing, Min A. Jhun, Marjo-Riitta Järvelin, Anubha Mahajan, Rainer Rauramaa, Satu Männistö, Paul M. Ridker, Ivan Brandslund, Hester M. den Ruijter, Tien Yin Wong, Alison D. Murray, Jaakko Tuomilehto, Xueling Sim, Igor Rudan, Martijn van de Bunt, Jin Li, Marit E. Jørgensen, Marie-France Hivert, Archie Campbell, Salman M. Tajuddin, Pekka Jousilahti, Lawrence F. Bielak, Juan P. Fernandez, Eleanor Wheeler, Alan B. Zonderman, Anne Clark, Lori L. Bonnycastle, Kurt Lohman, Peter Kovacs, Jung-Jin Lee, Jennifer Wessel, Wesam A Alhejily, Gerard Pasterkamp, John M. Starr, Ping An, Matthias Blüher, Jian'an Luan, Hanieh Yeghootkar, Jakob Stokholm, Michael Roden, Blair H. Smith, Johanna Jakobsdottir, Franco Giulianini, Andrianos M. Yiorkas, Hidetoshi Kitajima, Michael A. Province, Aliki-Eleni Farmaki, Kerrin S. Small, Juha Saltevo, Robert A. Scott, Alena Stančáková, Gaëlle Marenne, Asif Rasheed, Ruth J. F. Loos, David J. Porteous, Cecilia M. Lindgren, Inês Barroso, Gail Davies, Anna L. Gloyn, Shuai Wang, Paul Redmond, Xiuqing Guo, Ele Ferrannini, Mariaelisa Graff, Cornelia M. van Duijn, Juha Auvinen, David R. Weir, Kay-Tee Kaw, Tarunveer S. Ahluwalia, Olov Rolandsson, Wei Zhao, Paul Elliott, Torben Hansen, Abbas Dehghan, Bram P. Prins, Michiel L. Bots, Alison Pattie, Jun Liu, Gonçalo R. Abecasis, Maria Karaleftheri, Claudia Langenberg, Jan-Håkan Jansson, Marja Vääräsmäki, James S. Pankow, Rebecca S. Fine, Jaana Lindström, Ozren Polasek, Vinicius Tragante, Soren K. Thomsen, Jana K. Rundle, Najaf Amin, Saima Afaq, Jennifer A. Smith, Anne U. Jackson, Eirini Marouli, Weihua Zhang, Tim D. Spector, Paul W. Franks, Serena Sanna, Mark J. Caulfield, Heikki A. Koistinen, Jaspal S. Kooner, Tea Skaaby, Francis S. Collins, Eva Rabing Brix Petersen, Arfan Ikram, Sander W. van der Laan, Johanna Kuusisto, Jette Bork-Jensen, Daniel I. Chasman, Michele K. Evans, Emmanouil Tsafantakis, A. I. Tarasov, Ian J. Deary, Hans Bisgaard, Dennis O. Mook-Kanamori, Helen R. Warren, Kent D. Taylor, Andrew D. Morris, Eleftheria Zeggini, Sharon L.R. Kardia, Emma Ahlqvist, Gert J. de Borst, Torben Jørgensen, Antonella Mulas, Man Li, Betina H. Thuesen, Yuan Shi, Timo A. Lakka, Jie Yao, Tapani Ebeling, Natasha H. J. Ng, Sai Chen, Leena Kinnunen, Antje Körner, Klaus Bønnelykke, Lorraine Southam, Anette P. Gjesing, Ilonca Vaartjes, Heather M. Highland, Göran Hallmans, Anke Tönjes, Markku Laakso, Lenore J. Launer, Josef Coresh, Oscar H. Franco, Yongmei Liu, Beverley Balkau, Leena Moilanen, Karl-Heinz Herzig, James G. Wilson, Jennifer A. Brody, Renée de Mutsert, Alisa K. Manning, Anne E. Justice, Matthias B. Schulze, Sandosh Padmanabhan, Jose C. Florez, Shuang Feng, Heather M. Stringham, Bruce M. Psaty, Erwin P. Bottinger, Hannu Puolijoki, Vilmundur Gudnason, Leif Groop, Nicholas J. Wareham, Karina Meidtner, Andrew P. Morris, Taulant Muka, Benoit Hastoy, Panos Deloukas, Pirjo Komulainen, Ayse Demirkan, Francesco Cucca, Stefan Gustafsson, Eric Boerwinkle, Patrik Rorsman, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Allan Linneberg, Tiinamaija Tuomi, Dan E. Arking, Steve Franks, Jonathan Marten, Mark Walker, Ruifang Li-Gao, Kai Savonen, Michael Stumvoll, Andreas Fritsche, E-Shyong Tai, Mark O. Goodarzi, Matt J. Neville, Oluf Pedersen, Eero Kajantie, Ching-Ti Liu, Michael Boehnke, Aaron Leong, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, John C. Chambers, John Danesh, Sirkka Keinänen-Kiukaanniemi, Giorgio Pistis, Karen L. Mohlke, Folkert W. Asselbergs, James B. Meigs, Tibor V. Varga, Erica L. Kleinbrink, Andrew T. Hattersley, Nathan A. Bihlmeyer, Harald Grallert, Albert V. Smith, Konstantin Strauch, Jerome I. Rotter, and Frits R. Rosendaal
Subjects: medicine.medical_specialty, G6PC2, pathways, Adipose tissue, Type 2 diabetes, Biology, effector transcript, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Diabetes mellitus, Internal medicine, 0502 economics and business, medicine, Glucose homeostasis, genetics, 050207 economics, 030304 developmental biology, Glycemic, 0303 health sciences, 050208 finance, Pancreatic islets, 05 social sciences, tissue, Genomics, medicine.disease, Endocrinology, medicine.anatomical_structure, chemistry, glycemic traits, Glycated hemoglobin, type 2 diabetes, 030217 neurology & neurosurgery
Abstract: SummaryMetabolic dysregulation in multiple tissues alters glucose homeostasis and influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits (fasting glucose [FG], fasting insulin [FI], two-hour glucose [2hGlu] and glycated hemoglobin [HbA1c]), we investigated associations of exome-array variants in up to 144,060 individuals without diabetes of multiple ancestries. Single-variant analyses identified novel associations at 21 coding variants in 18 novel loci, whilst gene-based tests revealed signals at two genes, TF (HbA1c) and G6PC (FG, FI). Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and pancreatic islets for FG regulation, implicated adipose tissue in FI and the gut in 2hGlu, and suggested a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that a novel FG/FI association at the liver-enriched G6PC transcript was driven by multiple rare loss-of-function variants. The FG/HbA1c-associated, islet-specific G6PC2 transcript also contained multiple rare functional variants, including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference.Highlights23 novel coding variant associations (single-point and gene-based) for glycemic traits51 effector transcripts highlighted different pathway/tissue signatures for each traitThe exocrine pancreas and gut influence fasting and 2h glucose, respectivelyMultiple variants in liver-enriched G6PC and islet-specific G6PC2 influence glycemia
Published: 2019
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77. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Peter W. Schofield, Dan Rujescu, Gail Davies, Vidar M. Steen, Ahmad R. Hariri, Sara Hägg, Lars Nyberg, Dimitrios Avramopoulos, Nikolaos Smyrnis, Gerardo Heiss, Pamela DeRosse, Russell A. Poldrack, Jingyun Yang, Evangelos Evangelou, Katri Räikkönen, Fred W. Sabb, B. Gwen Windham, Aiden Corvin, Peter R. Schofield, Teemu Palviainen, André G. Uitterlinden, Anders Lundquist, Henry Brodaty, Aarno Palotie, Gary Donohoe, Elisabeth Widen, Teresa Lee, Cornelia M. van Duijn, Harry Campbell, Caroline Hayward, Rebecca F. Gottesman, Shuo Li, Steffi G. Riedel-Heller, M. Arfan Ikram, Sudha Seshadri, Jari Lahti, Joshua C. Bis, Panos Bitsios, Nikos C. Stefanis, Bettina Konte, Steven T. Turner, Edith Hofer, Vilmundur Gudnason, Michael Gill, P. Eline Slagboom, Ozren Polasek, Ida K. Karlsson, Christopher Oldmeadow, Michael Griswold, Ulman Lindenberger, Eric Boerwinkle, Saskia P. Hagenaars, Ingrid Melle, Alfredo Ramirez, Janie Corley, Rodney J. Scott, Sven J. van der Lee, Mika Kähönen, Alison D. Murray, Daniel R. Weinberger, Neil Pendleton, J. Wouter Jukema, Suvi P. Rovio, Wei Zhao, Muralidharan Sargurupremraj, Raha Pazoki, Matthias Schmid, Ina Giegling, Grant W. Montgomery, Daniel E. Gustavson, Jerome I. Rotter, Dan E. Arking, Oscar L. Lopez, David J. Stott, Julian N. Trollor, Chandra A. Reynolds, Tobias Luck, Andrea Christoforou, David J. Porteous, Kent D. Taylor, Simon R. Cox, Yasaman Saba, Matthew A. Scult, Astri J. Lundervold, Aicha Soumare, Antony Payton, Stella Trompet, W. David Hill, Shu-Chen Li, Robert M. Bilder, Eero Vuoksimaa, Jennifer A. Smith, Katherine E. Burdick, Deborah K. Attix, Sudheer Giddaluru, David C. Glahn, Edythe D. London, Stephanie Le Hellard, Terho Lehtimäki, Markus Leber, Katja Petrovic, James F. Wilson, Dwight Dickinson, Elizabeth T. Cirulli, Christophe Tzourio, Panos Roussos, Amelia A. Assareh, Markus Scholz, Alex Hatzimanolis, Tamara B. Harris, Stéphanie Debette, Alison Pattie, Thomas Espeseth, John M. Starr, William E R Ollier, Nicola J. Armstrong, Kjetil Sundet, Michael Wagner, Ian Ford, Simone Reppermund, Qiong Yang, Albert V. Smith, Nicole A. Kochan, Riccardo E. Marioni, Anu Loukola, Igor Rudan, Nicholas G. Martin, Jan Bressler, Tian Liu, K. Hoyan Wen, Natalie Terzikhan, Emma Knowles, Raymond Noordam, Joey W. Trampush, John Attia, Nancy L. Pedersen, Claudia L. Satizabal, Anne C. Böhmer, Chloe Fawns-Ritchie, Adele M. Taylor, Bruce M. Psaty, Paul Elliott, David R. Weir, Catharine R. Gale, Ioanna Tzoulaki, Leonie Weinhold, Anbupalam Thalamuthu, Anders M. Dale, Helena Schmidt, Annette M. Hartmann, Ole A. Andreassen, Ian J. Deary, Arno Villringer, Andrew M. McIntosh, Srdjan Djurovic, Najaf Amin, David C. Liewald, Nathan A. Gillespie, Ivar Reinvang, Thomas H. Mosley, Veronique Vitart, Michelle Luciano, Robert Karlsson, Lenore J. Launer, Eliza Congdon, Karen A. Mather, Marisa Koini, Tyrone D. Cannon, Elizabeth G. Holliday, Goran Papenberg, Reinhold Schmidt, Philippe Amouyel, Holger Wagner, Todd Lencz, Margaret J. Wright, Leo-Pekka Lyytikäinen, Emily Drabant Conley, David A. Bennett, William S. Kremen, M. Kamran Ikram, Catriona L. K. Barnes, Stella G. Giakoumaki, Scott D. Gordon, Johan G. Eriksson, Perminder S. Sachdev, Olli T. Raitakari, Judith A. Okely, Aristotle N. Voineskos, Max Lam, Sarah E. Harris, Luca Kleineidam, Jaakko Kaprio, Derek W. Morris, Sharon L.R. Kardia, Peter K. Joshi, Erin B. Ware, Lars Bertram, Philip L. De Jager, Anna C. Need, Abbas Dehghan, Jin Yu, Jessica D. Faul, N Freimer, Matthew C. Keller, John B.J. Kwok, Anil K. Malhotra, Will Longstreth, Hieab H.H. Adams, Richard J. Rose, Annette L. Fitzpatrick, Richard E. Straub, Christina M. Lill, David Ames, Patricia A. Boyle, David S. Knopman, He Gao, Narelle K. Hansell, Ornit Chiba-Falek, Danielle M. Dick, Stuart J. Ritchie, Ari Ahola-Olli, and Jeannette Simino
Subjects: 0301 basic medicine, Science, MEDLINE, General Physics and Astronomy, 02 engineering and technology, computer.software_genre, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Multidisciplinary, business.industry, Published Erratum, Cognition, General Chemistry, 021001 nanoscience & nanotechnology, 030104 developmental biology, Correction study, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, lcsh:Q, Artificial intelligence, ddc:500, 0210 nano-technology, Psychology, business, computer, Natural language processing
Abstract: Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.
Published: 2019
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78. New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders

Author: Jessica D. Faul, Ilja M. Nolte, Alexandra I. F. Blakemore, Raha Pazoki, Marjo-Riitta Järvelin, Andrew C. Heath, Adrian Rothenfluh, Nicholas G. Martin, Catharina A. Hartman, Paul Blakeley, Michael Boehnke, Paul M. Matthews, Dan E. Arking, Jennifer A. Smith, Yuri Milaneschi, James F. Wilson, Alena Stančáková, Laura J. Scott, Jie Yao, Paul Elliott, Sharon L.R. Kardia, Peter K. Joshi, Niki Dimou, Leo-Pekka Lyytikäinen, Tim D. Spector, Ozren Polasek, Pim van der Harst, Sylvane Desrivières, Bing Yu, Brenda W.J.H. Penninx, Katherine A. Kentistou, Michael Kühne, Mika Kähönen, Hideaki Suzuki, Ioanna Tzoulaki, Daniel Levy, Congying Chu, Johan G. Eriksson, Minna Männikkö, Markku Laakso, Anne U. Jackson, Sebastian E. Baumeister, Hans J. Grabe, Massimo Mangino, Albertine J. Oldehinkel, Evangelos Evangelou, Caroline Hayward, Niek Verweij, Penelope A. Lind, Lorenz Risch, Harold Snieder, Andrianos M. Yiorkas, Andrew R. Butts, David Conen, Toni-Kim Clarke, Harry Campbell, Fotios Koskeridis, Johanna Kuusisto, Alexis C. Wood, Karen L. Mohlke, Mia-Maria Perälä, Jerome I. Rotter, Gunter Schumann, Wei Zhao, Terho Lehtimäki, Ibrahim Karaman, Olli T. Raitakari, Rozenn N. Lemaitre, David J. Porteous, Michael R. Brown, Xiuqing Guo, Igor Rudan, Juha Auvinen, David R. Weir, Christopher P. Nelson, Traci M. Bartz, Peter S. Braund, Bruce M. Psaty, Alanna C. Morrison, Alexander Teumer, Nilesh J. Samani, Georg Homuth, Jennifer A. Brody, Joshua Elliott, John Whitfield, He Gao, Andrew M. McIntosh, Georgios Ntritsos, Samuli Tuominen, Sébastien Thériault, Chunyu Liu, Juha Veijola, Stefanie Aeschbacher, Jimmy D. Bell, Scott M. Ratliff, Jagadish Vangipurapu, Qiang Luo, Jari Lahti, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Academic Medical Center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Digital Health, Imperial College Healthcare NHS Trust- BRC Funding, Health Data Research Uk, National Institute for Health Research, Medical Research Council (MRC), and UK DRI Ltd
Subjects: Male, LOCI, Social Sciences, Genome-wide association study, physiopathology [Brain], VARIANTS, genetics [Mental Disorders], Cardiovascular, Oral and gastrointestinal, genetics [Genes], Behavioral Neuroscience, Alcohol Use and Health, Substance Misuse, 0302 clinical medicine, ddc:150, PARKINSONS-DISEASE, DEPENDENCE, Epidemiology, Psychology, 2.1 Biological and endogenous factors, risk factors, genetics [Schizophrenia], genetics, genetics [Genetic Predisposition to Disease], Aetiology, 610 Medicine & health, Cancer, Genetics, RISK, 0303 health sciences, Psychology, Biological, Psychology, Experimental, Mental Disorders, Brain, Single Nucleotide, Middle Aged, Serious Mental Illness, Biobank, Magnetic Resonance Imaging, Multidisciplinary Sciences, Stroke, physiology [Genes], Alcoholism, Mental Health, Schizophrenia, Meta-analysis, genetics [Polymorphism, Single Nucleotide], Science & Technology - Other Topics, Female, Life Sciences & Biomedicine, Biotechnology, EXPRESSION, Adult, medicine.medical_specialty, Social Psychology, Alcohol Drinking, Quantitative Trait Loci, genetics [White People], Experimental and Cognitive Psychology, Neuroimaging, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Aged, European Continental Ancestry Group, Genes, Genome-Wide Association Study, GENOME-WIDE ASSOCIATION, Polymorphism, METAANALYSIS, 030304 developmental biology, Genetic association, Science & Technology, genetics [Quantitative Trait Loci], Human Genome, Neurosciences, CONSUMPTION, medicine.disease, Genetic architecture, Brain Disorders, Good Health and Well Being, genetics [Alcoholism], genetics [Alcohol Drinking], Neurosciences & Neurology, HIGH-DENSITY-LIPOPROTEIN, 030217 neurology & neurosurgery
Abstract: H.G. was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. I.K. was supported by the EU PhenoMeNal project (Horizon 2020, grant no. 654241) and the UK Dementia Research Institute, which is supported by the MRC, the Alzheimer’s Society and Alzheimer’s Research UK. S. Thériault was supported by the Canadian Institutes of Health Research and Université Laval (Quebec City, Canada). L.R. was supported by Forschungs- und Förder-Stiftung INOVA, Vaduz, Liechtenstein. D.C. holds a McMaster University Department of Medicine Mid-Career Research Award. M.B. is supported by NIH grant R01-DK062370. P.v.d.H. was supported by ICIN-NHI and Marie Skłodowska-Curie GF (call: H2020-MSCA-IF-2014; Project ID: 661395). C.H. was supported by a core MRC grant to the MRCHGU QTL in Health and Disease research programme. N.V. was supported by Marie Skłodowska-Curie GF (grant no. 661395) and ICIN-NHI. Q.L. is partially supported by the National Natural Sciences Foundation of China (No. 81873909), Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01) and ZJLab. P.E. acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141), the Medical Research Council (MRC) and Public Health England (PHE) Centre for Environment and Health (MR/L01341X/1) and Health Data Research (HDR) UK. P.E. is supported by a UK Dementia Research Institute (DRI) professorship, UK DRI at Imperial College London, funded by the MRC, Alzheimer’s Society and Alzheimer’s Research UK. This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology; LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders; grant no. 695313), ERANID (Understanding the interplay between cultural, biological and subjective factors in drug use pathways; PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics; MR/N027558/1), the FP7 projects IMAGEMEND (grant no. 602450; IMAging GEnetics for MENtal Disorders) and MATRICS (grant no. 603016), the Innovative Medicine Initiative Project EU-AIMS (grant. no115300-2), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions; MR/N000390/1), the Swedish Research Council FORMAS, the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; eMED SysAlc01ZX1311A; and Forschungsnetz AERIAL 01EE1406A and 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2 and SFB 940/2), the Medical Research Foundation and Medical Research Council (MR/R00465X/1), the Human Brain Project (HBP SGA 2). Further support was provided by grants from ANR (project AF12-NEUR0008-01-WM2NA, and ANR-12-SAMA-0004), the Fondation de France, the Fondation pour la Recherche Médicale, the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), USA (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1); and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence.
Published: 2019
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79. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Author: Michael R. Brown, Christian Gieger, André G. Uitterlinden, Diana van Heemst, Alison D. Murray, Stephen B. Kritchevsky, Timo A. Lakka, Karen Schwander, Federica Laguzzi, Stephen S. Rich, Rajkumar Dorajoo, Yun Ju Sung, Xiaofeng Zhu, Hugues Aschard, Jing Hua Zhao, Gregory P. Wilson, Kenneth Rice, Barbara Sternfeld, Kent D. Taylor, Paul Elliott, Ei-Ei Khaing Nang, Ilja M. Nolte, Heather M. Stringham, Bruce M. Psaty, Heming Wang, Tangchun Wu, Caroline Hayward, Vilmundur Gudnason, Fernando Pires Hartwig, Paolo Gasparini, Jingjing Liang, Neil Risch, Albertine J. Oldehinkel, Ani Manichaikul, Tibor V. Varga, Michael Y. Tsai, Niek Verweij, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Xiuqing Guo, Traci M. Bartz, Nicholette D. Palmer, Woon-Puay Koh, Rozenn N. Lemaitre, Caizheng Yu, Mike A. Nalls, Mariaelisa Graff, Eric Boerwinkle, Dabeeru C. Rao, Thomas Meitinger, Virginia Fisher, Mario Sims, Charles Kooperberg, Carl D. Langefeld, Jaakko Tuomilehto, Reedik Mägi, Wei Zhao, Wanqing Wen, Donna K. Arnett, Ervin R. Fox, Lynda M. Rose, Maris Alver, Ayse Demirkan, Solomon K. Musani, Dennis O. Mook-Kanamori, Andres Metspalu, Jerome I. Rotter, Barry I. Freedman, Jiang He, Hermina Jakupović, Steven C. Hunt, Marco Brumat, Maria Pina Concas, Rob M. van Dam, Rico Rueedi, Jonathan Marten, Chi Charles Gu, Tõnu Esko, Peter Vollenweider, Zoltán Kutalik, Olli T. Raitakari, Ya X. Wang, Yong-Bing Xiang, Pamela J. Schreiner, Antonietta Robino, Tanika N. Kelly, Igor Rudan, Mathilde Boissel, Claudia Langenberg, Yii-Der Ida Chen, Anne U. Jackson, Lawrence F. Bielak, Brenda W.J.H. Penninx, Brigitte Kühnel, Christopher P. Nelson, Konstantin Strauch, Albert V. Smith, Daniel I. Chasman, Jasmin Divers, Lisa R. Yanek, M. Arfan Ikram, Melissa A. Richard, Nilesh J. Samani, Lisa de las Fuentes, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Yongmei Liu, Peter J. van der Most, Fang-Chi Hsu, Jeffrey R. O'Connell, Alexandre C. Pereira, Raymond Noordam, Changwei Li, Jie Yao, Trudy Voortman, Zhe Wang, Thomas H. Mosley, Diane M. Becker, Charles N. Rotimi, Sami Heikkinen, Archie Campbell, John M. C. Connell, Lenore J. Launer, Hua Tang, Rainer Rauramaa, Ruth J. F. Loos, Pirjo Komulainen, Amy R. Bentley, Patrik Wennberg, Chew-Kiat Heng, Kari E. North, Salman M. Tajuddin, Renée de Mutsert, David J. Porteous, Susan Redline, Sarah E. Harris, Tamara B. Harris, Raha Pazoki, Mickaël Canouil, Robert A. Scott, Jingzhong Ding, Mary F. Feitosa, Jost B. Jonas, José Eduardo Krieger, John M. Starr, Karin Leander, Jennifer A. Smith, Paul W. Franks, Charles B. Eaton, Sharon L.R. Kardia, E. Shyong Tai, Jill M. Norris, Annette Peters, Chiamaka Vivian Nwuba, Jianjun Liu, Stella Aslibekyan, Nora Franceschini, Kurt Lohman, Myriam Fornage, Dina Vojinovic, Erin B. Ware, Xiaoyin Li, Najaf Amin, Johanna Kuusisto, M. Yldau van der Ende, Cora E. Lewis, Lynne E. Wagenknecht, Jennifer G. Robinson, Franco Giulianini, Ulf de Faire, Yechiel Friedlander, Nicholas J. Wareham, Meian He, George J. Papanicolau, Nancy L. Pedersen, Bernardo L. Horta, Karen L. Mohlke, Kelley Pettee Gabriel, Minjung Kho, Michele K. Evans, Ozren Polasek, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Ioanna Ntalla, Cornelia M. van Duijn, L. Adrienne Cupples, Yuri Milaneschi, Stephen Sidney, Alan B. Zonderman, Leo-Pekka Lyytikäinen, Mohsen Ghanbari, Harold Snieder, Donald W. Bowden, Aldi T. Kraja, Alaitz Poveda, Terho Lehtimäki, Paul S. de Vries, Dongfeng Gu, Sotoodehnia Nona, Thomas W. Winkler, Muhammad Riaz, Ian J. Deary, Fumihiko Takeuchi, Pim van der Harst, Alisa K. Manning, Michael A. Province, Andrea R. V. R. Horimoto, David R. Weir, Wei Zheng, Alanna C. Morrison, Marzyeh Amini, Jian-Min Yuan, W. James Gauderman, Paul M. Ridker, Melanie Waldenberger, Chuan Gao, Xiao-Ou Shu, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, Tamar Sofer, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Digital Health, IT University of Copenhagen, Icahn School of Medicine at Mount Sinai [New York] (MSSM), National Institutes of Health [Bethesda] (NIH), Leiden University Medical Center (LUMC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), University of Regensburg, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Massachusetts General Hospital [Boston], Queen Mary University of London (QMUL), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), University of Washington [Seattle], The present work was largely supported by a grant from the US National Heart, Lung,and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305)., Kilpeläinen, Tuomas O., Bentley, Amy R., Noordam, Raymond, Sung, Yun Ju, Schwander, Karen, Winkler, Thomas W., Jakupović, Hermina, Chasman, Daniel I., Manning, Alisa, Ntalla, Ioanna, Aschard, Hugue, Brown, Michael R., de las Fuentes, Lisa, Franceschini, Nora, Guo, Xiuqing, Vojinovic, Dina, Aslibekyan, Stella, Feitosa, Mary F., Kho, Minjung, Musani, Solomon K., Richard, Melissa, Wang, Heming, Wang, Zhe, Bartz, Traci M., Bielak, Lawrence F., Campbell, Archie, Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P., Horimoto, Andrea R. V. R., Li, Changwei, Lohman, Kurt K., Marten, Jonathan, Sim, Xueling, Smith, Albert V., Tajuddin, Salman M., Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Evangelou, Evangelo, Gao, Chuan, Graff, Mariaelisa, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Jackson, Anne U., Zhao, Jing Hua, Kraja, Aldi T., Kühnel, Brigitte, Laguzzi, Federica, Lyytikäinen, Leo-Pekka, Nolte, Ilja M., Rauramaa, Rainer, Riaz, Muhammad, Robino, Antonietta, Rueedi, Rico, Stringham, Heather M., Takeuchi, Fumihiko, van der Most, Peter J., Varga, Tibor V., Verweij, Niek, Ware, Erin B., Wen, Wanqing, Li, Xiaoyin, Yanek, Lisa R., Amin, Najaf, Arnett, Donna K., Boerwinkle, Eric, Brumat, Marco, Cade, Brian, Canouil, Mickaël, Chen, Yii-Der Ida, Concas, Maria Pina, Connell, John, de Mutsert, Renée, de Silva, H. Janaka, de Vries, Paul S., Demirkan, Ayşe, Ding, Jingzhong, Eaton, Charles B., Faul, Jessica D., Friedlander, Yechiel, Gabriel, Kelley P., Ghanbari, Mohsen, Giulianini, Franco, Gu, Chi Charle, Gu, Dongfeng, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven C., Ikram, M. Arfan, Jonas, Jost B., Koh, Woon-Puay, Komulainen, Pirjo, Krieger, Jose E., Kritchevsky, Stephen B., Kutalik, Zoltán, Kuusisto, Johanna, Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Leander, Karin, Lemaitre, Rozenn N., Lewis, Cora E., Liang, Jingjing, Alizadeh, Behrooz Z., Boezen, H. Marike, Franke, Lude, Navis, Gerjan, Rots, Marianne, Swertz, Morri, Wolffenbuttel, Bruce H. R., Wijmenga, Cisca, Liu, Jianjun, Mägi, Reedik, Manichaikul, Ani, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Mohlke, Karen L., Mosley, Thomas H., Murray, Alison D., Nalls, Mike A., Nang, Ei-Ei Khaing, Nelson, Christopher P., Nona, Sotoodehnia, Norris, Jill M., Nwuba, Chiamaka Vivian, O’Connell, Jeff, Palmer, Nicholette D., Papanicolau, George J., Pazoki, Raha, Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Porteous, David J., Poveda, Alaitz, Raitakari, Olli T., Rich, Stephen S., Risch, Neil, Robinson, Jennifer G., Rose, Lynda M., Rudan, Igor, Schreiner, Pamela J., Scott, Robert A., Sidney, Stephen S., Sims, Mario, Smith, Jennifer A., Snieder, Harold, Sofer, Tamar, Starr, John M., Sternfeld, Barbara, Strauch, Konstantin, Tang, Hua, Taylor, Kent D., Tsai, Michael Y., Tuomilehto, Jaakko, Uitterlinden, André G., van der Ende, M. Yldau, van Heemst, Diana, Voortman, Trudy, Waldenberger, Melanie, Wennberg, Patrik, Wilson, Gregory, Xiang, Yong-Bing, Yao, Jie, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., de Faire, Ulf, Deary, Ian J., Elliott, Paul, Esko, Tõnu, Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Kato, Norihiro, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Magnusson, Patrik K. E., Oldehinkel, Albertine J., Penninx, Brenda W. J. H., Samani, Nilesh J., Shu, Xiao-Ou, van der Harst, Pim, Van Vliet-Ostaptchouk, Jana V., Vollenweider, Peter, Wagenknecht, Lynne E., Wang, Ya X., Wareham, Nicholas J., Weir, David R., Wu, Tangchun, Zheng, Wei, Zhu, Xiaofeng, Evans, Michele K., Franks, Paul W., Gudnason, Vilmundur, Hayward, Caroline, Horta, Bernardo L., Kelly, Tanika N., Liu, Yongmei, North, Kari E., Pereira, Alexandre C., Ridker, Paul M., Tai, E. Shyong, van Dam, Rob M., Fox, Ervin R., Kardia, Sharon L. R., Liu, Ching-Ti, Mook-Kanamori, Dennis O., Province, Michael A., Redline, Susan, van Duijn, Cornelia M., Rotter, Jerome I., Kooperberg, Charles B., Gauderman, W. Jame, Psaty, Bruce M., Rice, Kenneth, Munroe, Patricia B., Fornage, Myriam, Cupples, L. Adrienne, Rotimi, Charles N., Morrison, Alanna C., Rao, Dabeeru C., Loos, Ruth J. F., Bentley, Amy R [0000-0002-0827-9101], Jakupović, Hermina [0000-0001-9667-9406], Manning, Alisa [0000-0003-0247-902X], Aschard, Hugues [0000-0003-0907-2548], de Las Fuentes, Lisa [0000-0002-4689-325X], Richard, Melissa [0000-0003-0129-9860], Liu, Ching-Ti [0000-0002-0703-0742], Rice, Kenneth [0000-0002-3071-7278], Munroe, Patricia B [0000-0002-4176-2947], Loos, Ruth JF [0000-0002-8532-5087], Apollo - University of Cambridge Repository, Epidemiology, Radiology & Nuclear Medicine, Erasmus MC other, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, IT University of Copenhagen (ITU), Universiteit Leiden, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Value, Affordability and Sustainability (VALUE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Lifelines Cohort Study, Alizadeh, B.Z., Boezen, H.M., Franke, L., Navis, G., Rots, M., Swertz, M., Wolffenbuttel, BHR, and Wijmenga, C.
Subjects: Genetics and Molecular Biology (all), Male, Genome-wide association study, 02 engineering and technology, Biochemistry, MESH: Genotype, MESH: Nerve Tissue Proteins, lcsh:Science, MESH: Lipid Metabolism, Aged, 80 and over, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Asian Continental Ancestry Group, Kólesteról, Hispanic or Latino, MESH: Transcription Factors, MESH: European Continental Ancestry Group, Lipids, ddc, 3. Good health, REVEAL, Cholesterol, MESH: Young Adult, Science & Technology - Other Topics, MESH: Membrane Proteins, MESH: Cholesterol, HDL, Hispanic Americans, 0210 nano-technology, Erfðarannsóknir, MESH: Cholesterol, LDL, MESH: Triglycerides, Genotype, Genetic Loci, Lipid Metabolism, Science, European Continental Ancestry Group, LIM-Homeodomain Proteins, Locus (genetics), EXERCISE, Adolescent, Adult, African Continental Ancestry Group/genetics, Aged, Asian Continental Ancestry Group/genetics, Brazil, Calcium-Binding Proteins/genetics, Cholesterol/blood, Cholesterol, HDL/blood, Cholesterol, HDL/genetics, Cholesterol, LDL/blood, Cholesterol, LDL/genetics, European Continental Ancestry Group/genetics, Exercise, Female, Genetic Loci/genetics, Genome-Wide Association Study, Hispanic Americans/genetics, Humans, LIM-Homeodomain Proteins/genetics, Lipid Metabolism/genetics, Lipids/blood, Lipids/genetics, Membrane Proteins/genetics, Microtubule-Associated Proteins/genetics, Middle Aged, Muscle Proteins/genetics, Nerve Tissue Proteins/genetics, Transcription Factors/genetics, Triglycerides/blood, Triglycerides/genetics, Young Adult, General Biochemistry, Genetics and Molecular Biology, Article, White People, CARBOXYLASE, 03 medical and health sciences, Physics and Astronomy (all), MESH: Muscle Proteins, Asian People, Lifelines Cohort Study, SNP, METAANALYSIS, Ancestry, MESH: Adolescent, Biochemistry, Genetics and Molecular Biology (all), MESH: Humans, Science & Technology, Calcium-Binding Proteins, MESH: Adult, MESH: Microtubule-Associated Proteins, 030104 developmental biology, chemistry, MESH: Genome-Wide Association Study, lcsh:Q, MESH: African Continental Ancestry Group, Chemistry (all), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Brazil, MESH: Female, Transcription Factors, 0301 basic medicine, General Physics and Astronomy, Blood lipids, Muscle Proteins, MESH: Calcium-Binding Proteins, chemistry.chemical_compound, MESH: Aged, 80 and over, MESH: Cholesterol, WIDE ASSOCIATION, African Continental Ancestry Group, Genetics, MESH: Aged, Multidisciplinary, Public Health, Global Health, Social Medicine and Epidemiology, 021001 nanoscience & nanotechnology, Multidisciplinary Sciences, lipids (amino acids, peptides, and proteins), Medical Genetics, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Microtubule-Associated Proteins, Asian Continental Ancestry Group, Black People, Nerve Tissue Proteins, Biology, MESH: Genetic Loci, MD Multidisciplinary, Triglycerides, Medicinsk genetik, MESH: LIM-Homeodomain Proteins, Triglyceride, MESH: Hispanic Americans, Cholesterol, HDL, Genome-wide analyses, Membrane Proteins, Lipid metabolism, General Chemistry, Cholesterol, LDL, Arfgengi, MESH: Lipids, MESH: Male, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Exercise, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract: Publisher's version (útgefin grein), Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels., The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4.
Published: 2018
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80. CELLULAR, MOLECULAR AND EPIGENETIC AGING IN THE HRS

Author: Jessica D. Faul
Subjects: Abstracts, Health (social science), Text mining, business.industry, Computational biology, Epigenetics, Biology, Life-span and Life-course Studies, business, Health Professions (miscellaneous)
Abstract: Biological aging can be characterized by molecular, cellular, and epigenetic changes that in addition to being related to chronologic age, are also associated with social disadvantage and associated morbidity and mortality. These biological markers can help explain at a biological level why socially disadvantaged individuals are at greater risk of aging-related disease and premature death. From DNA and RNA extracted from venous blood collected from over 4,000 HRS participants we measured DNA methylation, mtDNA copy number, and telomere length from DNA and gene expression from RNA. These assessments were made from unsorted cells, but are adjusted for individual cell composition measured from flow cytometry. We present genome-wide methylation and gene expression differentials by age, race/ethnicity and SES using the largest, nationally representative sample with these data available to date. Understanding basic biological changes related to age and social disadvantage is essential for identifying translational opportunities to improve health.
Published: 2018

81. Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders

Author: Raha Pazoki, Michael R. Brown, Albertine J. Oldehinkel, Evangelos Evangelou, Bruce M. Psaty, Caroline Hayward, Penelope A. Lind, Harry Campbell, Sylvane Desrivières, Leo-Pekka Lyytikäinen, Harold Snieder, Niek Verweij, Igor Rudan, Rozenn N. Lemaitre, Andrianos M. Yiorkas, David Conen, Ozren Polasek, Mia-Maria Perälä, Jennifer A. Smith, Christopher P. Nelson, Wei Zhao, Ilja M. Nolte, Michael Kühne, Mika Kähönen, Jessica D. Faul, Sharon L.R. Kardia, Peter K. Joshi, Ibrahim Karaman, Paul M. Matthews, Adrian Rothenfluh, Jari Lahti, Alexandra I. F. Blakemore, John Whitfield, Alexander Teumer, James F. Wilson, Alena Stančáková, Marjo-Riitta Järvelin, David R. Weir, Peter S. Braund, Andrew M. McIntosh, Scott M. Ratliff, Nicholas G. Martin, Hideaki Suzuki, Georgios Ntritsos, Niki Dimou, Bing Yu, Andrew R. Butts, Alanna C. Morrison, Gunter Schumann, Michael Boehnke, Paul Elliott, Samuli Tuominen, Paul Blakeley, Xiuqing Guo, Massimo Mangino, Yuri Milaneschi, Brenda W.J.H. Penninx, Daniel Levy, Juha Auvinen, Jie Yao, Hans J. Grabe, David J. Porteous, Laura J. Scott, Lorenz Risch, Katherine A. Kentistou, Jagadish Vangipurapu, Stefanie Aeschbacher, Terho Lehtimäki, Markku Laakso, Jimmy D. Bell, Fotios Koskeridis, Anne U. Jackson, Karen L. Mohlke, Catharina A. Hartman, Ioanna Tzoulaki, Sebastian E. Baumeister, Dan E. Arking, Alexis C. Wood, Sébastien Thériault, Johanna Kuusisto, Pim van der Harst, Chunyu Liu, Juha Veijola, Georg Homuth, Jennifer A. Brody, Traci M. Bartz, Andrew C. Heath, He Gao, Toni-Kim Clarke, Jerome I. Rotter, Tim D. Spector, Congying Chu, Johan G. Eriksson, Minna Männikkö, Olli T. Raitakari, Nilesh J. Samani, and Joshua Elliott
Subjects: Genetics, 0303 health sciences, Genome-wide association study, Biology, medicine.disease, Excessive alcohol consumption, Genetic architecture, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Schizophrenia, Trait, medicine, Functional significance, Functional studies, Alcohol consumption, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and investigated their potential functional significance using magnetic resonance imaging data, gene expression and behavioral studies in Drosophila. Our results identify new genetic pathways associated with alcohol consumption and suggest common genetic mechanisms with several neuropsychiatric disorders including schizophrenia.
Published: 2018
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82. P1‐570: RACIAL/ETHNIC DIFFERENCES IN KNOWLEDGE ABOUT DEMENTIA AND TREATMENT

Author: Paige Lin, Joanna Emerson, and Jessica D. Faul
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, medicine, Dementia, Neurology (clinical), Racial/ethnic difference, Geriatrics and Gerontology, medicine.disease, Psychology, Clinical psychology
Published: 2018
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83. A Practical Cryopreservation and Staining Protocol for Immunophenotyping in Population Studies

Author: Eileen M. Crimmins, Bharat Thyagarajan, Jessica D. Faul, and Helene Barcelo
Subjects: 0301 basic medicine, Histology, Population, Biochemistry, Peripheral blood mononuclear cell, Article, Cryopreservation, Immunophenotyping, Flow cytometry, 03 medical and health sciences, Immune system, medicine, Humans, education, Protocol (science), education.field_of_study, Staining and Labeling, medicine.diagnostic_test, business.industry, General Medicine, Staining, Medical Laboratory Technology, 030104 developmental biology, Blood Preservation, Immunology, Leukocytes, Mononuclear, business
Abstract: Large population-based cohort studies, through their prospective collection of a broad range of health information, represent an invaluable resource for novel insights into the pathogenesis of human diseases. Collection and cryopreservation of viable cells from blood samples is becoming increasingly common in large cohorts as these cells are a valuable resource for immunophenotyping and functional studies. The cryopreservation of peripheral blood mononuclear cells (PBMCs), thawing, and immunophenotyping protocols used to immunophenotype 9938 participants in the Health and Retirement Study (HRS) are described. The extensive quality control involved in a large-scale immunophenotyping epidemiological study is also outlined. The existing literature on the effect of cryopreservation on various immune cell subsets including T, B, NK cells, monocytes, and dendritic cells is provided. © 2018 by John Wiley & Sons, Inc.
Published: 2018
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84. Effect of delayed cell processing and cryopreservation on immunophenotyping in multicenter population studies

Author: Sithara Vivek, Sharon R. Minnerath, Bharat Thyagarajan, Eileen M. Crimmins, David R. Weir, Helene Barcelo, and Jessica D. Faul
Subjects: 0301 basic medicine, Adult, Male, Time Factors, Cell processing, Immunology, Cell, Population, Cell Separation, Biology, Peripheral blood mononuclear cell, Cryopreservation, Article, Immunophenotyping, Andrology, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Leukocytes, Immunology and Allergy, Humans, education, Whole blood, Aged, Aged, 80 and over, education.field_of_study, Middle Aged, 030104 developmental biology, medicine.anatomical_structure, Female, 030215 immunology
Abstract: Variability induced by delayed cell processing and cell cryopreservation presents unique challenges for immunophenotyping in large population studies. We conducted a pilot study to evaluate the effect of delayed cell processing and cryopreservation on cell percentages obtained by immunophenotyping. We collected blood from 20 volunteers and compared the effect of (a) delayed cell processing up to 72 hours (b) cryopreservation and (c) the combined effect of delayed cell processing and cryopreservation on immunophenotyping of 31 cell subsets that included several subsets of T, B, Natural Killer (NK) cells, monocytes and dendritic cells using both whole blood collected in EDTA tubes and peripheral blood mononuclear cells collected in CPT tubes. We found the delayed cell processing up to 72 hours or cryopreservation alone did not significantly affect the percentages T cells, dendritic cells or monocytes but significantly increased the percentage of B cells and NK cells (p for trend ≤0.01) but. However combination of delayed cell processing up to 72 hours and cryopreservation significantly increased the percentage of T cells as compared to cells processed immediately (p for trend
Published: 2018

85. P3-558: EXPOSURES PRIOR TO AGE 16 ARE ASSOCIATED WITH DEMENTIA STATUS IN THE HEALTH AND RETIREMENT STUDY

Author: Jessica D. Faul, Harita S. Vadari, Erin B. Ware, Kelly M. Bakulski, Bradley Petrowiz, and Kelly S. Benke
Subjects: Gerontology, Epidemiology, business.industry, Health Policy, Health and Retirement Study, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2019
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86. Estimating Telomere Length Heritability in an Unrelated Sample of Adults: Is Heritability of Telomere Length Modified by Life Course Socioeconomic Status?

Author: Jennifer A. Smith, Colter Mitchell, Jessica D. Faul, and Wei Zhao
Subjects: Adult, Male, 0301 basic medicine, Aging, Genotype, Biology, Real-Time Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetic variation, Genetics, Humans, Prospective Studies, Sibling, Socioeconomic status, Ecology, Evolution, Behavior and Systematics, Aged, Demography, Estimation, Middle Aged, Telomere, Health and Retirement Study, Heritability, United States, 030104 developmental biology, Social Class, Anthropology, Cohort, Income, Educational Status, Life course approach, Female
Abstract: Telomere length (TL) is a widely used marker of biological aging and is associated with an increased risk of morbidity and mortality. Recently, there has been evidence for an association between TL and socioeconomic status (SES), particularly for measures of education and childhood SES. Individual differences in TL are also influenced by genetic factors, with heritability estimates from twin and sibling studies ranging from 34 to 82 percent. Yet the additive heritability of TL as a result of measured genetic variations and the extent to which heritability is modified by SES is still unknown. Data from the Health and Retirement Study, a nationally representative cohort of older adults (mean age 69 years), were used to provide the first estimates of molecular-based heritability of TL using genome-wide complex trait analysis (GCTA). We found that additive genetic variance contributed 28 percent (p = .012) of total phenotypic variance of TL in the European American sample (n = 3,290). Estimation using the GCTA and KING Robust relationship inference methods did not differ significantly in this sample. None of the variance from the gene-by-SES interactions examined contributed significantly to the total TL variance. Estimation of heritability and genetic interaction with SES in the African American sample (n = 442) was too unstable to provide reliable estimates.
Published: 2016
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87. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Author: Paul M. Ridker, Han Chen, Nathan O. Stitziel, Joshua C. Bis, Charles Kooperberg, Stephan B. Felix, Digna R. Velez Edwards, Cristian Pattaro, Alanna C. Morrison, Praveen Surendran, Adolfo Correa, Nilesh J. Samani, Johanna Jakobsdottir, Gulum Kosova, Fotios Drenos, Heribert Schunkert, Li-An Lin, Bruce M. Psaty, Vilmundur Gudnason, Jerome I. Rotter, Panos Deloukas, Uwe Völker, Ayush Giri, George J. Papanicolaou, Todd L. Edwards, E. Warwick Daw, André G. Uitterlinden, Eric Boerwinkle, Elias Salfati, Chunyu Liu, Tianxiao Huan, Eric Kim, Daniel Levy, Krystal S Tsosie, Albert V. Smith, Martin G. Larson, Georg Ehret, Cornelia M. van Duijn, Christopher J. O'Donnell, Stefan Weiss, Kiang Liu, Omri Gottesman, Wei Zhao, Claude Bouchard, Walter Palmas, Santhi K. Ganesh, Alexander P. Reiner, Kent D. Taylor, Mathias Gorski, Megan L. Grove, Wayne H-H Sheu, Wen-Jane Lee, Jennifer A. Brody, James P. Cook, Jacques E. Rossouw, Oscar H. Franco, Yongmei Liu, Erwin P. Bottinger, Christopher Newton-Cheh, Lisa W. Martin, Jie Yao, Paul L. Auer, Aldi T. Kraja, Kenneth Rice, Marcus Dörr, Hao Mei, Myriam Fornage, Najaf Amin, Lenore J. Launer, Jessica D. Faul, Arend Voorman, Shih-Jen Hwang, Nora Franceschini, Ingrid B. Borecki, Aravinda Chakravarti, Yingchang Lu, Yii-Der Ida Chen, Tamara B. Harris, Audrey Y. Chu, Sharon L.R. Kardia, Xiuqing Guo, David R. Weir, Rainer Rettig, Sekar Kathiresan, Ramachandran S. Vasan, Franco Giulianini, Leslie J. Raffel, Christian Fuchsberger, Daniel I. Chasman, Jeanette M. Stafford, Man Li, I-Te Lee, Henry Völzke, Ruth J. F. Loos, Jennifer A. Smith, Epidemiology, and Internal Medicine
Subjects: 0301 basic medicine, Blood Pressure/genetics, Genotype, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Genetics, Missense mutation, Humans, Exome, Polymorphism, Gene, Oligonucleotide Array Sequence Analysis, ddc:616, Genome, Genome, Human, Genetic Variation, Single Nucleotide, 030104 developmental biology, Blood pressure, Hypertension, Human genome, Hypertension/genetics, Human, Genome-Wide Association Study
Abstract: Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
Published: 2016
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88. Personality Polygenes, Positive Affect, and Life Satisfaction

Author: John M. Starr, Catharina A. Hartman, Saskia P. Hagenaars, Michelle Luciano, Magnus Johannesson, Matt McGue, Nancy L. Pedersen, Reinhold Schmidt, David Cesarini, Wei Zhao, Henning Tiemeier, Miriam A. Mosing, Nicholas G. Martin, Helena Schmidt, Aysu Okbay, William G. Iacono, Bart M. L. Baselmans, Laura Pulkki-Råback, Lindsay K. Matteson, Gail Davies, Patricia A. Boyle, Markus Jokela, Ian J. Deary, Albertine J. Oldehinkel, Dorret I. Boomsma, Alexander Weiss, Alison Pattie, David C. Liewald, Jennifer A. Smith, Penelope A. Lind, Michael B. Miller, Sarah E. Harris, Jessica D. Faul, Patrik K. E. Magnusson, Meike Bartels, Jacqui Smith, Jingyun Yang, David A. Bennett, Ilja M. Nolte, Harold Snieder, Andrew C. Heath, Philip L. De Jager, Jouke-Jan Hottenga, Liisa Keltikangas-Järvinen, Edith Hofer, Albert Hofman, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Life Course Epidemiology (LCE), and Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE)
Subjects: Male, 0301 basic medicine, DISORDER, Netherlands Twin Register (NTR), Multifactorial Inheritance, GENETICS, media_common.quotation_subject, Personality development, TWIN, Personal Satisfaction, VARIANTS, Affect (psychology), Article, Developmental psychology, Cohort Studies, 03 medical and health sciences, wellbeing, Meta-Analysis as Topic, NEUROTICISM, mental disorders, Humans, Personality, Big Five personality traits, GENOME-WIDE ASSOCIATION, Genetics (clinical), METAANALYSIS, media_common, HAPPINESS, Extraversion and introversion, HERITABILITY, Obstetrics and Gynecology, Life satisfaction, Neuroticism, Twin study, genetic correlation, United Kingdom, Affect, polygenic prediction, Personality Development, 030104 developmental biology, Pediatrics, Perinatology and Child Health, Female, Psychology, TRAITS, Genome-Wide Association Study, Clinical psychology
Abstract: Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximalN= 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes
Published: 2016
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89. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center
Subjects: 0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Published: 2018
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90. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

Author: Patricia A. Peyser, Jessica D. Faul, Sing Hui Lim, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Marzyeh Amini, Benjamin Lehne, W. James Gauderman, Wei Zhao, Andres Metspalu, R. Graham Barr, Albertine J. Oldehinkel, Xueling Sim, Norihiro Kato, Daniel I. Chasman, Jasmin Divers, Fernando Pires Hartwig, Jing Hua Zhao, Yu Caizheng, Roby Joehanes, Nora Franceschini, Nita G. Forouhi, Charumathi Sabanayagam, Paul M. Ridker, Yun J. Sung, Mary F. Feitosa, Barbara V. Howard, Vilmundur Gudnason, Jost B. Jonas, Hua Tang, Yukihide Momozawa, Michael R. Brown, Tibor V. Varga, Franco Giulianini, Francis S. Collins, Alexander P. Reiner, Ulrich Broeckel, Tuomo Rankinen, Preeti Gupta, Tin Louie, Eric Boerwinkle, Saskia P. Hagenaars, Mark J. Caulfield, Albert Hofman, Aravinda Chakravarti, Paul W. Franks, Nicole Schupf, E. Shyong Tai, Carl D. Langefeld, Carsten Oliver Schmidt, Lawrence F. Bielak, Treva Rice, Anne B. Newman, Ioanna Ntalla, Kae-Woei Liang, Nilesh J. Samani, Alena Stančáková, Thomas H. Mosley, Dan E. Arking, Kenneth Rice, Bruce M. Psaty, Jirong Long, Yechiel Friedlander, Jianjun Liu, Donna K. Arnett, Ya X. Wang, Xiuqing Guo, Anne E. Justice, Pamela J. Schreiner, Renée de Mutsert, Lisa de las Fuentes, Marcus Dörr, Amy R. Bentley, Susan Redline, Cornelia M. van Duijn, Melissa A. Richard, Sarah E. Harris, Pirjo Komulainen, Nicholette D. Palmer, Alexandre C. Pereira, Michele K. Evans, Jie Yao, Adesola Ogunniyi, Wen Bin Wei, Anuradhani Kasturiratne, Yoichiro Kamatani, Charles Kooperberg, Helen R. Warren, Shiow Lin, Ozren Polasek, Makoto Hirata, Anubha Mahajan, Yingchang Lu, Jonathan Marten, Claudia P. Cabrera, Chuan Gao, Oscar H. Franco, Yongmei Liu, Mathilde Boissel, Olli T. Raitakari, Xiao-Ou Shu, Yii-Der Ida Chen, Y Liu, Claudia Langenberg, C. Charles Gu, Cathy C. Laurie, Tamuno Alfred, L. Adrienne Cupples, Yajuan Wang, Colin A. McKenzie, Mika Kähönen, Yize Li, Xiaofeng Zhu, Nana Matoba, James Scott, Marguerite R. Irvin, Markku Laakso, Frida Renström, Woon-Puay Koh, Dabeeru C. Rao, Yucheng Jia, Paul Elliott, Tangchun Wu, Caroline Hayward, Tamara B. Harris, Alison D. Murray, Karin Leander, Reedik Mägi, Keng-Hung Lin, Harold Snieder, Laura J. Bierut, Christine Williams, Solomon K. Musani, Michael A. Province, Charles B. Eaton, Sharon L.R. Kardia, Mario Sims, Steven C. Hunt, Stephen B. Kritchevsky, Weihua Zhang, David R. Weir, Andrea R. V. R. Horimoto, Saima Afaq, Hugues Aschard, Ilaria Gandin, Michiaki Kubo, Jaspal S. Kooner, Peter S. Braund, Jeffrey R. O'Connell, Kent D. Taylor, Annette Peters, Wei Zheng, Rainer Rettig, Nicola D. Kerrison, Donald W. Bowden, Ruth J. F. Loos, Tanika N. Kelly, Dennis O. Mook-Kanamori, Terrence Forrester, Igor Rudan, Brigitte Kühnel, Christopher P. Nelson, Ching-Yu Cheng, Alanna C. Morrison, Tuomas O. Kilpeläinen, Jian-Min Yuan, Bruna Gigante, Lisa R. Yanek, Ching-Ti Liu, Ananda R. Wickremasinghe, Michael Boehnke, Tin Aung, Jin-Fang Chai, Kaare Christensen, Wen-Jane Lee, Stéphanie Debette, Jennifer A. Brody, Wayne Huey-Herng Sheu, John M. C. Connell, Ganesh Chauhan, Jian'an Luan, Melanie Waldenberger, Erin B. Ware, Paolo Gasparini, Chew-Kiat Heng, Lili Milani, Alisa K. Manning, José Eduardo Krieger, Kiang Liu, Mickaël Canouil, Robert A. Scott, Yik Ying Teo, Gregory P. Wilson, Stella Aslibekyan, Andrew P. Morris, Thomas Meitinger, Jennifer A. Smith, Yi-Jen Hung, Myriam Fornage, Dina Vojinovic, William R. Scott, Virginia Fisher, Peter S. Sever, André G. Uitterlinden, Najaf Amin, Lenore J. Launer, Hugh Watkins, Johanna Kuusisto, Rajkumar Dorajoo, Georg Ehret, Heming Wang, Sandosh Padmanabhan, Jingmin Liu, Colleen M. Sitlani, Anuj Goel, Bamidele O. Tayo, Daniel Levy, Barry I. Freedman, Marie Loh, Yanhua Zhou, Charles N. Rotimi, Qing Duan, Aldi T. Kraja, He Meian, Archie Campbell, Kari E. North, Tien Yin Wong, Salman M. Tajuddin, Traci M. Bartz, Mike A. Nalls, Misa Graff, Dongfeng Gu, Sudha Seshadri, Tõnu Esko, Antonietta Robino, Anne U. Jackson, H. Janaka de Silva, Peter J. van der Most, Fang-Chi Hsu, Chiea Chuen Khor, Changwei Li, Sami Heikkinen, Maris Alver, Karen Schwander, Wanqing Wen, Rainer Rauramaa, Lynne E. Wagenknecht, Ubaydah Nasri, Peter J. Munson, He Gao, Evangelos Evangelou, Philippe Froguel, Ervin R. Fox, Christian Gieger, Kurt Lohman, James S. Pankow, Nicholas J. Wareham, Lynda M. Rose, Massimiliano Cocca, Rob M. van Dam, John M. Starr, Martin Farrall, Stefan Weiss, Konstantin Strauch, Albert V. Smith, Jill M. Norris, Raymond Noordam, Cora E. Lewis, Claude Bouchard, Ulf de Faire, Walter Palmas, Diane M. Becker, Kevin Sandow, Tomohiro Katsuya, Jiang He, Nancy L. Pedersen, Bernardo L. Horta, Joel D. Kaufman, Terho Lehtimäki, Heikki A. Koistinen, Thomas W. Winkler, Ian J. Deary, Richard S. Cooper, Fumihiko Takeuchi, Jerome I. Rotter, Lihua Wang, Yih Chung Tham, Babatunde L. Salako, Mary K. Wojczynski, Pim van der Harst, Jennifer G. Robinson, Erwin P. Bottinger, Alan B. Zonderman, Patricia B. Munroe, Ehret, Georg Benedikt, Harvard School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), 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), The various Gene-Lifestyle Interaction projects, including this one, are largely supported by a grant from the U.S. National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health, R01HL118305. A Career Development Award (K25HL121091), also from the NHLBI, enabled Y.J.S. to lead this project. Full set of study-specific funding sources and acknowledgments appear in the Supplemental Note., Sung, Yun J., Winkler, Thomas W., de las Fuentes, Lisa, Bentley, Amy R., Brown, Michael R., Kraja, Aldi T., Schwander, Karen, Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K., Li, Changwei, Feitosa, Mary F., Kilpeläinen, Tuomas O., Richard, Melissa A., Noordam, Raymond, Aslibekyan, Stella, Aschard, Hugue, Bartz, Traci M., Dorajoo, Rajkumar, Liu, Yongmei, Manning, Alisa K., Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M., Tayo, Bamidele O., Warren, Helen R., Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E., Hartwig, Fernando Pire, Horimoto, Andrea R. V. R., Hsu, Fang-Chi, Jackson, Anne U., Kähönen, Mika, Kasturiratne, Anuradhani, Kühnel, Brigitte, Leander, Karin, Lee, Wen-Jane, Lin, Keng-Hung, ’an Luan, Jian, Mckenzie, Colin A., Meian, He, Nelson, Christopher P., Rauramaa, Rainer, Schupf, Nicole, Scott, Robert A., Sheu, Wayne H. H., Stančáková, Alena, Takeuchi, Fumihiko, van der Most, Peter J., Varga, Tibor V., Wang, Heming, Wang, Yajuan, Ware, Erin B., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Alfred, Tamuno, Amin, Najaf, Arking, Dan, Aung, Tin, Barr, R. Graham, Bielak, Lawrence F., Boerwinkle, Eric, Bottinger, Erwin P., Braund, Peter S., Brody, Jennifer A., Broeckel, Ulrich, Cabrera, Claudia P., Cade, Brian, Caizheng, Yu, Campbell, Archie, Canouil, Mickaël, Chakravarti, Aravinda, Chauhan, Ganesh, Christensen, Kaare, Cocca, Massimiliano, Collins, Francis S., Connell, John M., de Mutsert, Renée, de Silva, H. Janaka, Debette, Stephanie, Dörr, Marcu, Duan, Qing, Eaton, Charles B., Ehret, Georg, Evangelou, Evangelo, Faul, Jessica D., Fisher, Virginia A., Forouhi, Nita G., Franco, Oscar H., Friedlander, Yechiel, Gao, He, Gigante, Bruna, Graff, Misa, Gu, C. Charle, Gu, Dongfeng, Gupta, Preeti, Hagenaars, Saskia P., Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hofman, Albert, Howard, Barbara V., Hunt, Steven, Irvin, Marguerite R., Jia, Yucheng, Joehanes, Roby, Justice, Anne E., Katsuya, Tomohiro, Kaufman, Joel, Kerrison, Nicola D., Khor, Chiea Chuen, Koh, Woon-Puay, Koistinen, Heikki A., Komulainen, Pirjo, Kooperberg, Charle, Krieger, Jose E., Kubo, Michiaki, Kuusisto, Johanna, Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lehne, Benjamin, Lewis, Cora E., Li, Yize, Lim, Sing Hui, Lin, Shiow, Liu, Ching-Ti, Liu, Jianjun, Liu, Jingmin, Liu, Kiang, Liu, Yeheng, Loh, Marie, Lohman, Kurt K., Long, Jirong, Louie, Tin, Mägi, Reedik, Mahajan, Anubha, Meitinger, Thoma, Metspalu, Andre, Milani, Lili, Momozawa, Yukihide, Morris, Andrew P., Mosley, Thomas H., Munson, Peter, Murray, Alison D., Nalls, Mike A., Nasri, Ubaydah, Norris, Jill M., North, Kari, Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmas, Walter R., Palmer, Nicholette D., Pankow, James S., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Raitakari, Olli T., Renström, Frida, Rice, Treva K., Ridker, Paul M., Robino, Antonietta, Robinson, Jennifer G., Rose, Lynda M., Rudan, Igor, Sabanayagam, Charumathi, Salako, Babatunde L., Sandow, Kevin, Schmidt, Carsten O., Schreiner, Pamela J., Scott, William R., Seshadri, Sudha, Sever, Peter, Sitlani, Colleen M., Smith, Jennifer A., Snieder, Harold, Starr, John M., Strauch, Konstantin, Tang, Hua, Taylor, Kent D., Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G., Waldenberger, Melanie, Wang, Lihua, Wang, Ya X., Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K., Yao, Jie, Yuan, Jian-Min, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., Chambers, John C., Chen, Yii-Der Ida, de Faire, Ulf, Deary, Ian J., Esko, Tõnu, Farrall, Martin, Forrester, Terrence, Franks, Paul W., Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo Lessa, Hung, Yi-Jen, Jonas, Jost B., Kato, Norihiro, Kooner, Jaspal S., Laakso, Markku, Lehtimäki, Terho, Liang, Kae-Woei, Magnusson, Patrik K. E., Newman, Anne B., Oldehinkel, Albertine J., Pereira, Alexandre C., Redline, Susan, Rettig, Rainer, Samani, Nilesh J., Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E., Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wickremasinghe, Ananda R., Wu, Tangchun, Zheng, Wei, Kamatani, Yoichiro, Laurie, Cathy C., Bouchard, Claude, Cooper, Richard S., Evans, Michele K., Gudnason, Vilmundur, Kardia, Sharon L. R., Kritchevsky, Stephen B., Levy, Daniel, O'Connell, Jeff R., Psaty, Bruce M., van Dam, Rob M., Sims, Mario, Arnett, Donna K., Mook-Kanamori, Dennis O., Kelly, Tanika N., Fox, Ervin R., Hayward, Caroline, Fornage, Myriam, Rotimi, Charles N., Province, Michael A., van Duijn, Cornelia M., Tai, E. Shyong, Wong, Tien Yin, Loos, Ruth J. F., Reiner, Alex P., Rotter, Jerome I., Zhu, Xiaofeng, Bierut, Laura J., Gauderman, W. Jame, Caulfield, Mark J., Elliott, Paul, Rice, Kenneth, Munroe, Patricia B., Morrison, Alanna C., Cupples, L. Adrienne, Rao, Dabeeru C., Chasman, Daniel I., Marten, Jonathan [0000-0001-6916-2014], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Epidemiology, Internal Medicine, Gastroenterology & Hepatology, Clinicum, Department of Medicine, Endokrinologian yksikkö, HUS Internal Medicine and Rehabilitation, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, multi-ancestry, Smoking/genetics, Genome-wide association study, Continental Population Groups/genetics, INTIMA-MEDIA THICKNESS, Cohort Studies, Diastole, Polymorphism (computer science), GWAS, TRANSTORNOS RELACIONADOS AO USO DE ÁLCOOL, GENE-ENVIRONMENT INTERACTION, Genetics (clinical), ddc:616, INSULIN-RESISTANCE, Multi-ancestry, Smoking, 1184 Genetics, developmental biology, physiology, blood pressure, GxE interaction, Diastole/genetics, 3. Good health, FALSE DISCOVERY RATE, Blood pressure, Medical genetics, CORONARY-ARTERY-DISEASE, Female, Single Nucleotide/genetics, Systole/genetics, BODY-MASS INDEX, ASSOCIATION ANALYSIS, COMMON VARIANTS, METAANALYSIS, DISEASE, OBESITY, JOINT, medicine.medical_specialty, lifestyle, SUSCEPTIBILITY LOCI, Blood Pressure/genetics, Systole, Quantitative Trait Loci, Single-nucleotide polymorphism, Accounting, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, GxE interactions, Article, smoking, 03 medical and health sciences, Genetic, medicine, Genetics, Journal Article, Humans, Polymorphism, Genetic association, ALCOHOL DEPENDENCE, business.industry, Racial Groups, Reproducibility of Results, Epistasis, Genetic, ta3121, Lifestyle, Genetic architecture, NICOTINE DEPENDENCE, 030104 developmental biology, Genetic Loci, Epistasis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, business, Quantitative Trait Loci/genetics, Genome-Wide Association Study
Abstract: The authors declare no competing financial interests except for the following. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health); L.J.B. is listed as an inventor on Issued U.S. Patent 8,080,371,“Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction; P.S. has received research awards from Pfizer Inc., is a consultant for Mundipharma Co. (Cambridge, UK), is a patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor; Patent number: 20120263794), and has a patent application with University of Heidelberg (Heidelberg, Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Europäische Patentanmeldung 15 000 771.4); P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project; M.A.N.’s participation is supported by a consulting contract between Data Tecnica Internation and the National Institute on Aging (NIH, Bethesda, MD, USA), and he also consults for Illumina, Inc., the Michael J. Fox Foundation, and University of California Healthcare among others; and M.J.C. is Chief Scientist for Genomics England, a UK government company.; International audience; Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined approximately 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
Published: 2018
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91. Gene-by-Psychosocial Factor Interactions Influence Diastolic Blood Pressure in European and African Ancestry Populations: Meta-Analysis of Four Cohort Studies

Author: Mario Sims, Kalyn Yasutake, Ana V. Diez Roux, Alanna C. Morrison, Jennifer A. Smith, Scott M. Ratliff, Sharon L.R. Kardia, Solomon K. Musani, Wei Zhao, Gerardo Heiss, Kari E. North, Stanford Mwasongwe, Michael Griswold, Jessica D. Faul, Yan Gao, David R. Weir, Kathryn M. Rose, Carmella August, Yan V. Sun, Aravinda Chakravarti, Eric Boerwinkle, and Belinda L. Needham
Subjects: 0301 basic medicine, Health, Toxicology and Mutagenesis, lcsh:Medicine, Blood Pressure, 030204 cardiovascular system & hematology, Toxicology, gene-by-environment interaction, Cohort Studies, 0302 clinical medicine, Risk Factors, 2.1 Biological and endogenous factors, Medicine, Psychology, genetics, Aetiology, Gene–environment interaction, education.field_of_study, Depression, blood pressure, hypertension, non-burden test, socioeconomic status, psychosocial factors, depression, chronic burden, Mental Health, Meta-analysis, Trait, Psychosocial, Cohort study, Population, White People, Article, 03 medical and health sciences, Clinical Research, Behavioral and Social Science, Genetics, Humans, education, Socioeconomic status, business.industry, Human Genome, lcsh:R, Public Health, Environmental and Occupational Health, United States, Black or African American, 030104 developmental biology, Blood pressure, Socioeconomic Factors, Gene-Environment Interaction, business, Demography
Abstract: Inter-individual variability in blood pressure (BP) is influenced by both genetic and non-genetic factors including socioeconomic and psychosocial stressors. A deeper understanding of the gene-by-socioeconomic/psychosocial factor interactions on BP may help to identify individuals that are genetically susceptible to high BP in specific social contexts. In this study, we used a genomic region-based method for longitudinal analysis, Longitudinal Gene-Environment-Wide Interaction Studies (LGEWIS), to evaluate the effects of interactions between known socioeconomic/psychosocial and genetic risk factors on systolic and diastolic BP in four large epidemiologic cohorts of European and/or African ancestry. After correction for multiple testing, two interactions were significantly associated with diastolic BP. In European ancestry participants, outward/trait anger score had a significant interaction with the C10orf107 genomic region (p = 0.0019). In African ancestry participants, depressive symptom score had a significant interaction with the HFE genomic region (p = 0.0048). This study provides a foundation for using genomic region-based longitudinal analysis to identify subgroups of the population that may be at greater risk of elevated BP due to the combined influence of genetic and socioeconomic/psychosocial risk factors.
Published: 2017
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92. Exome chip meta-analysis elucidates the genetic architecture of rare coding variants in smoking and drinking behavior

Author: Jean-Claude Tardif, Andries R. van der Leij, Hilary A. Tindle, Nicholas G. Martin, Rebecca Rohde, Charles Kooperberg, Francesco Cucca, Jian Gong, Jenny Chang-Claude, Tatiana Foroud, Dajiang J. Liu, Sarah Bertelsen, Gonçalo R. Abecasis, Christopher A. Haiman, Massimo Mangino, Daniel O. Stram, Jaakko Kaprio, Guillaume Lettre, Leah Wetherill, Daniel R. Barnes, Yaming Shao, David M. Brazel, Heather M. Stringham, Tinca J. C. Polderman, Wei Zhao, Andrew C. Heath, Matt McGue, Christiaan de Leeuw, Alison Goate, Danielle Posthuma, Xiaowei Zhan, Sean P. David, Laura J. Bierut, Yi Ling Chou, Pamela A. F. Madden, Manav Kapoor, Jessica D. Faul, Anu Loukola, John P. Rice, H. Steven Scholte, Arpana Agrawal, Jeff Haessler, William G. Iacono, Giorgio Pistis, Michael Boehnke, Tim D. Spector, Anke R. Hammerschlag, Charles B. Eaton, Sharon L.R. Kardia, David Schlessinger, David R. Weir, Dongbing Lai, Scott I. Vrieze, Markku Laakso, Chu Chen, Turcot, Nhung Le, Alex P. Reiner, Beenish Qaiser, Chris Hsu, A. Mesut Erzurumluoglu, Kari E. North, Carl A. Melbourne, and Jennifer A. Smith
Subjects: Nonsynonymous substitution, Genetics, 0303 health sciences, Biology, Genetic architecture, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, Genotype, Exome, Genotyping, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Common disease-common variant
Abstract: BackgroundSmoking and alcohol use behaviors in humans have been associated with common genetic variants within multiple genomic loci. Investigation of rare variation within these loci holds promise for identifying causal variants impacting biological mechanisms in the etiology of disordered behavior. Microarrays have been designed to genotype rare nonsynonymous and putative loss of function variants. Such variants are expected to have greater deleterious consequences on gene function than other variants, and significantly contribute to disease risk.MethodsIn the present study, we analyzed ∼250,000 rare variants from 17 independent studies. Each variant was tested for association with five addiction-related phenotypes: cigarettes per day, pack years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted single variant tests of all variants, and gene-based burden tests of nonsynonymous or putative loss of function variants with minor allele frequency less than 1%.ResultsMeta-analytic sample sizes ranged from 70,847 to 164,142 individuals, depending on the phenotype. Known loci tagged by common variants replicated, but there was no robust evidence for individually associated rare variants, either in gene based or single variant tests. Using a modified method-of-moment approach, we found that all low frequency coding variants, in aggregate, contributed 1.7% to 3.6% of the phenotypic variation for the five traits (pConclusionsThe findings indicate that rare coding variants contribute to phenotypic variation, but that much larger samples and/or denser genotyping of rare variants will be required to successfully identify associations with these phenotypes, whether individual variants or gene‐ based associations.
Published: 2017
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93. An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

Author: Katri Räikkönen, Myriam Fornage, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Jordan W. Smoller, Tõnu Esko, Wei Zhao, Carsten Horn, Andres Metspalu, Harold Snieder, Enrique Castelao, Luigi Ferrucci, Catharina A. Hartman, Thomas G. Schulze, Stanley I. Shyn, Joanne M. Murabito, James B. Potash, Cathryn M. Lewis, Karestan C. Koenen, Azmeraw T. Amare, Jari Lahti, Stephan Ripke, Michele L. Pergadia, Cornelia M. van Duijn, Michael Conlon O'Donovan, Markus M. Nöthen, Grant C.B. Sinnamon, Rudolf Uher, Roy H. Perlis, Qingqin S. Li, Hans-Jörgen Grabe, Johannes H. Smit, Bernhard T. Baune, Donald J. MacIntyre, Erin C. Dunn, Alexander Teumer, Gonneke Willemsen, Nicholas G. Martin, Udo Dannlowski, Karin Hek, Shaun Purcell, Toni-Kim Clarke, Toshiko Tanaka, Jorge A. Quiroz, Myrna M. Weissman, Andrew M. McIntosh, Kathryn L. Lunetta, Scott D. Gordon, David R. Weir, Daniel Umbricht, Marcella Rietschel, Zoltán Kutalik, Stephanie Williams, Michael Gill, Albert Hofman, Enrico Domenici, Margarita Rivera, Pamela A. F. Madden, Jingyun Yang, John P. Rice, Sandra Van der Auwera, Steven P. Hamilton, Georg Homuth, David A. Bennett, Stefan Kloiber, Sharon L.R. Kardia, Anders D. Børglum, Sven Cichon, Nese Direk, Jessica D. Faul, Susanne Lucae, Dorret I. Boomsma, Douglas Blackwood, Jouke-Jan Hottenga, Marilyn C. Cornelis, Erin B. Ware, Enda M. Byrne, Andrew C. Heath, Philip L. De Jager, Ole Mors, Karl-Heinz Ladwig, Bertram Müller-Myhsok, Thomas H. Mosley, Jennifer A. Smith, Tracy Air, Yuri Milaneschi, Glyn Lewis, Brenda W.J.H. Penninx, David J. Llewellyn, Gerard van Grootheest, Eco J. C. de Geus, Henning Tiemeier, Grant W. Montgomery, Martin Preisig, Katherine E. Tansey, Patrick F. Sullivan, Douglas F. Levinson, Henriette N. Buttenschøn, Gerome Breen, Johan G. Eriksson, Ayse Demirkan, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Methodology, APH - Digital Health, Epidemiology, Child and Adolescent Psychiatry / Psychology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Medicum, Department of Psychology and Logopedics, and Developmental Psychology Research Group
Subjects: DISORDER, Netherlands Twin Register (NTR), Linkage disequilibrium, SYMPTOMS, STRESS, CHARGE consortium, genetics [Depressive Disorder], Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, Neoplasm Proteins/genetics, MINOR DEPRESSION, European Continental Ancestry Group/genetics, POPULATION, RISK, Genetics, education.field_of_study, HERITABILITY, Depression, Depressive symptoms, Depression/genetics, Acid Anhydride Hydrolases, Neoplasm Proteins, 3. Good health, genetics [European Continental Ancestry Group], Phenotype, fragile histidine triad protein, Major depressive disorder, genetics [Depression], Psychology, 515 Psychology, Population, genetics [White People], Single-nucleotide polymorphism, Locus (genetics), White People, Psychiatric Genomics Consortium, FHIT gene, 03 medical and health sciences, SDG 3 - Good Health and Well-being, ddc:570, Depressive Disorder/genetics, NATIONAL COMORBIDITY SURVEY, medicine, Journal Article, Humans, SNP, genetics [Acid Anhydride Hydrolases], Genetic Predisposition to Disease, ddc:610, education, Biological Psychiatry, Genetic association, Depressive Disorder, genetics [Neoplasm Proteins], major depressive disorder, 3112 Neurosciences, MAJOR DEPRESSION, medicine.disease, SUBTHRESHOLD DEPRESSION, 030227 psychiatry, Acid Anhydride Hydrolases/genetics, Genetic Loci, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10(-9)) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10(-9)).CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.
Published: 2017
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94. Ninety-nine independent genetic loci influencing general cognitive function include genes associated with brain health and structure (N = 280,360)

Author: Nancy L. Pedersen, John M. Starr, Kjetil Sundet, Qiong Yang, Nicole A. Kochan, Beverly Gwen Windham, Ida K. Karlsson, Daniel E. Gustavson, Jerome I. Rotter, Antony Payton, M. Arfan Ikram, Alison D. Murray, Edith Hofer, Ozren Polasek, Markus Leber, Will Longstreth, Stephanie Le Hellard, Peter W. Schofield, Raha Pazoki, Janie Corley, Max Lam, Deborah K. Attix, Hieab H.H. Adams, Tobias Luck, Ian J. Deary, Panos Roussos, Amelia A. Assareh, Katja Petrovic, Dwight Dickinson, Elizabeth T. Cirulli, Thomas Espeseth, Richard J. Rose, Annette L. Fitzpatrick, Robert M. Bilder, Rodney J. Scott, Katherine E. Burdick, William S. Kremen, Christophe Tzourio, Richard E. Straub, Thomas H. Mosley, Michael Griswold, Ulman Lindenberger, Peter R. Schofield, Riccardo E. Marioni, Stéphanie Debette, Jennifer A. Smith, M. Kamran Ikram, Pamela DeRosse, Russell A. Poldrack, Teemu Palviainen, Panos Bitsios, Nikos C. Stefanis, Anu Loukola, Nikolaos Smyrnis, Todd Lencz, Michelle Luciano, Robert Karlsson, Bettina Konte, Dan Rujescu, Mika Kähönen, James F. Wilson, Steven T. Turner, David A. Bennett, Jingyun Yang, Cornelia M. van Duijn, David S. Knopman, Harry Campbell, R. F. Gottesman, Vidar M. Steen, Nicola J. Armstrong, Alfredo Ramirez, Ina Giegling, Jari Lahti, Marisa Koini, Tyrone D. Cannon, Gerardo Heiss, Ian Ford, Vilmundur Gudnason, Alex Hatzimanolis, Joshua C. Bis, Albert V. Smith, David Ames, Jan Bressler, Catriona L. K. Barnes, Emily Drabant Conley, Raymond Noordam, Ornit Chiba-Falek, Michael Gill, Simone Reppermund, Katri Räikkönen, Christopher Oldmeadow, Kent D. Taylor, Holger Wagner, Claudia L. Satizabal, Chandra A. Reynolds, Tian Liu, Daniel R. Weinberger, Neil Pendleton, Scott D. Gordon, Eric Boerwinkle, Saskia P. Hagenaars, Andrew M. McIntosh, Igor Rudan, Joey W. Trampush, John Attia, Michael Wagner, K. Hoyan Wen, Judith A. Okely, Aristotle N. Voineskos, Patricia A. Boyle, Danielle M. Dick, Anna C. Need, Markus Scholz, Luca Kleineidam, Aiden Corvin, Ingrid Melle, Margaret J. Wright, Helena Schmidt, Leo-Pekka Lyytikäinen, Natalie Terzikhan, Stuart J. Ritchie, He Gao, Anne C. Böhmer, Dan E. Arking, Narelle K. Hansell, Nicholas G. Martin, Fred W. Sabb, Nathan A. Gillespie, Evangelos Evangelou, Bruce M. Psaty, Anders Lundquist, Oscar L. Lopez, Emma Knowles, Matthew C. Keller, Henry Brodaty, Julian N. Trollor, Gary Donohoe, Ivar Reinvang, Ari Ahola-Olli, Tamara B. Harris, André G. Uitterlinden, David R. Weir, Abbas Dehghan, Sarah E. Harris, P. Eline Slagboom, Chloe Fawns-Ritchie, Paul Elliott, William Ollier, Edythe D. London, Anders M. Dale, Jaakko Kaprio, Catharine R. Gale, Karen A. Mather, Aarno Palotie, Stella G. Giakoumaki, Sven J. van der Lee, Jeannette Simino, Elisabeth Widen, Teresa Lee, Sudheer Giddaluru, Anil K. Malhotra, Philippe Amouyel, Caroline Hayward, Shuo Li, Goran Papenberg, Steffi G. Riedel-Heller, Wei Zhao, Nelson A. Freimer, Simon R. Cox, Yasaman Saba, Andrea Christoforou, Johan G. Eriksson, Eliza Congdon, David J. Porteous, Matthew A. Scult, Eero Vuoksimaa, Veronique Vitart, Derek W. Morris, Sharon L.R. Kardia, Elizabeth G. Holliday, Peter K. Joshi, Suvi P. Rovio, Astri J. Lundervold, J. Wouter Jukema, Aicha Soumare, Stella Trompet, Annette M. Hartmann, Ole A. Andreassen, Erin B. Ware, Matthias Schmid, Perminder S. Sachdev, Grant W. Montgomery, Lars Bertram, Philip L. De Jager, Olli T. Raitakari, Terho Lehtimäki, Arno Villringer, Srdjan Djurovic, David C. Liewald, Sudha Seshadri, Gail Davies, Ahmad R. Hariri, Sara Hägg, Lars Nyberg, Dimitrios Avramopoulos, Muralidharan Sargurupremraj, W. David Hill, Shu-Chen Li, Leonie Weinhold, David J. Stott, David C. Glahn, John B.J. Kwok, Ioanna Tzoulaki, Reinhold Schmidt, Najaf Amin, Lenore J. Launer, Jin Yu, Jessica D. Faul, Adele M. Taylor, Anbupalam Thalamuthu, and Alison Pattie
Subjects: Genetics, 0303 health sciences, media_common.quotation_subject, Longevity, Genetic data, Cognition, Heritability, Significant snps, Biology, Biobank, 03 medical and health sciences, 0302 clinical medicine, Trait, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Abstract: General cognitive function is a prominent human trait associated with many important life outcomes1,2, including longevity3. The substantial heritability of general cognitive function is known to be polygenic, but it has had little explication in terms of the contributing genetic variants4,5,6. Here, we combined cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N=280,360; age range = 16 to 102). We found 9,714 genome-wide significant SNPs (P−8) in 99 independent loci. Most showed clear evidence of functional importance. Among many novel genes associated with general cognitive function wereSGCZ,ATXN1,MAPT,AUTS2, andP2RY6. Within the novel genetic loci were variants associated with neurodegenerative disorders, neurodevelopmental disorders, physical and psychiatric illnesses, brain structure, and BMI. Gene-based analyses found 536 genes significantly associated with general cognitive function; many were highly expressed in the brain, and associated with neurogenesis and dendrite gene sets. Genetic association results predicted up to 4% of general cognitive function variance in independent samples. There was significant genetic overlap between general cognitive function and information processing speed, as well as many health variables including longevity.
Published: 2017
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95. Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations

Author: Colin A. McKenzie, Nora Franceschini, Aravinda Chakravarti, Walter Palmas, Richard S. Cooper, Kyle J. Gaulton, Jerome I. Rotter, Kenneth Rice, George J. Papanicolaou, Xiaofeng Zhu, Joshua C. Denny, Hua Tang, Michele K. Evans, Lisa R. Yanek, Sylvia Cechova, Yan V. Sun, Yingchang Lu, Alanna C. Morrison, Kiang Liu, Juyoung Lee, Ervin R. Fox, Jianwen Cai, Xiuqing Guo, Eric Boerwinkle, Wei Zhao, Adebowale Adeyemo, Sharon L.R. Kardia, J. Hunter Young, Anne R. Cappola, Lisa W. Martin, Ruth J. F. Loos, Charles Kooperberg, Kerri L. Wiggins, Pei-Lun Chu, Jessica D. Faul, Albert W. Dreisbach, Erin B. Ware, Terrence Forrester, Thu H. Le, Myriam Fornage, Rebecca D. Jackson, Thomas H. Mosley, Donna K. Arnett, Susan Redline, Daniel Levy, Tamar Sofer, Todd L. Edwards, Heming Wang, Cathy C. Laurie, Alexander P. Reiner, Jennifer A. Smith, Neil Risch, Sungho Won, Bruce M. Psaty, Jie Zhou, Wonji Kim, Richard A. Jensen, Dabeeru C. Rao, Solomon K. Musani, Karen Schwander, Guanjie Chen, Alan D. Penman, Jacqueline M. Lane, Qin Hui, Mike A. Nalls, Joseph F. Polak, David R. Weir, Steven C. Hunt, Digna R. Velez Edwards, Bamidele O. Tayo, Salman M. Tajuddin, K. D. Taylor, Charles N. Rotimi, Jingjing Liang, James Kayima, Erwin P. Bottinger, Michael J. Bray, Diane M. Becker, and Alan B. Zonderman
Subjects: 0301 basic medicine, Male, Cancer Research, Multifactorial Inheritance, Kidney Disease, Gene Expression, Genome-wide association study, Blood Pressure, Cardiovascular, Bioinformatics, Vascular Medicine, Mice, Mathematical and Statistical Techniques, Basic Helix-Loop-Helix Transcription Factors, Medicine and Health Sciences, 2.1 Biological and endogenous factors, Ethnicities, Genetics (clinical), African Americans, Genetics, Mammalian Genomics, Single Nucleotide, Genomics, Cadherins, 3. Good health, Hypertension, Physical Sciences, Female, Anatomy, Statistics (Mathematics), Biotechnology, Research Article, lcsh:QH426-470, Single-nucleotide polymorphism, Locus (genetics), Biology, Research and Analysis Methods, Polymorphism, Single Nucleotide, 03 medical and health sciences, Clinical Research, Genome-Wide Association Studies, Animals, Humans, Polymorphism, Allele, Statistical Methods, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Genetic association, Human Genome, Case-control study, Membrane Proteins, Correction, Biology and Life Sciences, Computational Biology, Kidneys, Human Genetics, Renal System, Genome Analysis, Human genetics, Black or African American, lcsh:Genetics, 030104 developmental biology, Blood pressure, Genetic Loci, Animal Genomics, Case-Control Studies, People and Places, Population Groupings, Mathematics, Developmental Biology, Genome-Wide Association Study, Africans, Meta-Analysis
Abstract: Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10−8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension., Author summary Hypertension is a global health problem which affects disproportionally people of African descent. We conducted a genome-wide association study of blood pressure in 31,968 Africans and African Americans to identify genes conferring susceptibility to increased blood pressure. This research identified three novel genomic regions associated with blood pressure which have not been previously reported in studies of other race/ethnicity. Using experimental models, we also showed an altered expression of these genes in kidney tissue in hypertension. These findings provide new evidence for genes influencing hypertension risk and supports the need to study diverse ancestry populations in order to identify biologic factors contributing to hypertension.
Published: 2017
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96. 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
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97. Cohort Profile: the Health and Retirement Study (HRS)

Author: John W.R. Phillips, Jessica D. Faul, Amanda Sonnega, Kenneth M. Langa, David R. Weir, and Mary Beth Ofstedal
Subjects: Male, Gerontology, Epidemiology, Health Status, Population, National Death Index, Health care, Humans, Medicine, Genetic Predisposition to Disease, Longitudinal Studies, education, Cohort Profiles, Aged, Retirement, education.field_of_study, business.industry, Social environment, General Medicine, Middle Aged, Health and Retirement Study, Mental health, United States, Social security, Mental Health, Physical Fitness, Female, business, Psychosocial
Abstract: The Health and Retirement Study (HRS) is a nationally representative longitudinal survey of more than 37 000 individuals over age 50 in 23 000 households in the USA. The survey, which has been fielded every 2 years since 1992, was established to provide a national resource for data on the changing health and economic circumstances associated with ageing at both individual and population levels. Its multidisciplinary approach is focused on four broad topics-income and wealth; health, cognition and use of healthcare services; work and retirement; and family connections. HRS data are also linked at the individual level to administrative records from Social Security and Medicare, Veteran's Administration, the National Death Index and employer-provided pension plan information. Since 2006, data collection has expanded to include biomarkers and genetics as well as much greater depth in psychology and social context. This blend of economic, health and psychosocial information provides unprecedented potential to study increasingly complex questions about ageing and retirement. The HRS has been a leading force for rapid release of data while simultaneously protecting the confidentiality of respondents. Three categories of data-public, sensitive and restricted-can be accessed through procedures described on the HRS website (hrsonline.isr.umich.edu).
Published: 2014
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98. BIOMARKER DATA INNOVATIONS IN THE HEALTH AND RETIREMENT STUDY

Author: Jessica D. Faul, Eileen M. Crimmins, and Morgan E. Levine
Subjects: Gerontology, Abstracts, Health (social science), business.industry, Medicine, Biomarker (medicine), Health and Retirement Study, Life-span and Life-course Studies, business, Health Professions (miscellaneous)
Abstract: This symposium presents early results on a new data set that allows examination of the physiological, immunological, epigenetic, transcriptomic, and cellular pathways through which socioeconomic conditions influence the human aging process. This level of integration of biological data to address social disparities has not been accomplished before on a large nationally representative sample of Americans. The Health and Retirement Study is a biannual survey of the 51+ population that has been ongoing since 1992. In 2016 HRS collected 6 tubes of blood from people who completed the 2016 interview, had been in the sample at the prior wave and were not in a nursing home (n=9,874) to maintain a nationally representative sample. These blood samples were analyzed for a wide variety of biomarkers that were shown to be related to both social and economic circumstances and health outcomes at older ages in prior research. The symposium will describe the utility of measuring age related biomarkers in a nationally representative population study such as HRS and the potential research opportunities that can be pursued using this publicly available resource. It will provide an overview of the collection and processing of blood samples in HRS and describe the measurement and distribution of more than 50 biomarkers in HRS belonging to the domains of (a) physiological status and systemic functioning (b) immune functioning and (c) cellular, molecular and epigenetic aging. It will also describe the utility of these biomarkers in further understanding the biological underpinnings of socioeconomic differences in health and mortality.
Published: 2018
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99. MUSCLE WEAKNESS IS ASSOCIATED WITH DISABILITY AND CHRONIC MULTIMORBIDITY IN MIDDLE-AGED AND OLDER AMERICANS

Author: Jessica D. Faul and Mark D. Peterson
Subjects: Weakness, medicine.medical_specialty, Health (social science), Activities of daily living, business.industry, Psychological intervention, Muscle weakness, Multimorbidity, Health and Retirement Study, medicine.disease, Health Professions (miscellaneous), Odds, Grip strength, Abstracts, Session 1395 (Poster), Internal medicine, Medicine, Dementia, medicine.symptom, Life-span and Life-course Studies, business
Abstract: Background: The objective of this study was to use nationally-representative data on Americans age 50+ to determine the association between grip strength and inflammation as independent predictors of incident disability, chronic multimorbidity and dementia. Methods: Older adults (n=12,618) from the 2006-2008 waves of the Health and Retirement Study with 8-years of follow-up were included. Longitudinal modeling was performed to examine the association between baseline grip strength (normalized to body mass: NGS) and high sensitivity c-reactive protein (hs-CRP) (≥3.0 mg/L) with incident physical disabilities (i.e., ≥2 limitations to activities of daily living), chronic multimorbidity (≥2 of chronic conditions), and dementia. Results: The odds of incident disability were 1.28 (95% CI: 1.19-1.37) and 1.27 (95% CI: 1.21-1.36) for men and women respectively, for each 0.05-unit lower NGS. The odds of incident chronic multimorbidity were 1.22 (95% CI: 1.06-1.18) and 1.12 (95% CI: 1.06-1.17) for men and women respectively for each 0.05-unit lower NGS. The odds of incident dementia were 1.10 for men (95% CI: 1.02-1.20) for each 0.05-unit lower NGS, but there was no significant effect for women. Elevated hs-CRP was only associated with chronic multimorbidity among women (OR=1.60; 95%CI: 1.26-2.02). Conclusions: Our findings indicate a robust inverse association between NGS and disability and chronic, multimorbidity in older men and women, and dementia in men. Elevated hs-CRP was only associated with chronic multimorbidity among women. Healthcare providers should implement measures of handgrip strength in routine health assessments and discuss the potential dangers of weakness and interventions to improve strength with their patients.
Published: 2019

100. COMBINED EFFECT OF CMV SEROPOSITIVITY AND SYSTEMIC INFLAMMATION ON DEMENTIA PREVALENCE IN CANCER SURVIVORS

Author: Eileen M. Crimmins, Sithara Vivek, Jessica D. Faul, Bharat Thyagarajan, Anna E. Prizment, and Heather H. Nelson
Subjects: Oncology, medicine.medical_specialty, Health (social science), Session 2345 (Poster), business.industry, Cancer, medicine.disease, Systemic inflammation, Health Professions (miscellaneous), Cancer and End-of-Life Care, Abstracts, Text mining, Internal medicine, mental disorders, medicine, Session 710 (Paper), Dementia, medicine.symptom, business, Life-span and Life-course Studies
Abstract: Though cancer patients treated with multi-modal therapies demonstrate higher levels of systemic inflammation, which is associated with dementia, cancer survivors have not shown a consistent association with dementia. Since several studies reported an independent association between cytomegalovirus (CMV) infection, inflammation and dementia in non-cancer populations, we have evaluated whether CMV infection and systemic inflammation were associated with increased prevalence of dementia in cancer survivors in Health and Retirement Study (HRS). We evaluated prevalence of dementia (using score ≤7 on the 27-point scale) among 1607 cancer survivors, in whom we measured CMV seropositivity and two biomarkers of systemic inflammation: C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR). The prevalence of CMV seropositivity was 68.26% (n=1097), while prevalence of increased systemic inflammation [CRP >5mg/L and NLR >4] was 4.23% (n=68). Using survey logistic regression, adjusted for age, race, gender, BMI (Body Mass Index) and sampling design, cancer survivors who were both CMV seropositive and had increased systemic inflammation had the highest odds of dementia compared to those who were CMV seronegative and had low levels of systemic inflammation (OR=6.59; 95% CI [2.81, 15.44]; p
Published: 2019

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