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1. Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

Author

Mathieson, Iain, Day, Felix R, Barban, Nicola, Tropf, Felix C, Brazel, David M, EQTLGen Consortium, BIOS Consortium, Vaez, Ahmad, Van Zuydam, Natalie, Bitarello, Bárbara D, Gardner, Eugene J, Akimova, Evelina T, Azad, Ajuna, Bergmann, Sven, Bielak, Lawrence F, Boomsma, Dorret I, Bosak, Kristina, Brumat, Marco, Buring, Julie E, Cesarini, David, Chasman, Daniel I, Chavarro, Jorge E, Cocca, Massimiliano, Concas, Maria Pina, Davey Smith, George, Davies, Gail, Deary, Ian J, Esko, Tõnu, Faul, Jessica D, FinnGen Study, Franco, Oscar, Ganna, Andrea, Gaskins, Audrey J, Gelemanovic, Andrea, De Geus, Eco JC, Gieger, Christian, Girotto, Giorgia, Gopinath, Bamini, Grabe, Hans Jörgen, Gunderson, Erica P, Hayward, Caroline, He, Chunyan, Van Heemst, Diana, Hill, W David, Hoffmann, Eva R, Homuth, Georg, Hottenga, Jouke Jan, Huang, Hongyang, Hyppӧnen, Elina, Ikram, M Arfan, Jansen, Rick, Johannesson, Magnus, Kamali, Zoha, Kardia, Sharon LR, Kavousi, Maryam, Kifley, Annette, Kiiskinen, Tuomo, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Liew, Gerald, Lifelines Cohort Study, Lind, Penelope A, Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik KE, Mahajan, Anubha, Martin, Nicholas G, Mbarek, Hamdi, McCarthy, Mark I, McMahon, George, Medland, Sarah E, Meitinger, Thomas, Metspalu, Andres, Mihailov, Evelin, Milani, Lili, Missmer, Stacey A, Mitchell, Paul, Møllegaard, Stine, Mook-Kanamori, Dennis O, Morgan, Anna, Van Der Most, Peter J, De Mutsert, Renée, Nauck, Matthias, Nolte, Ilja M, Noordam, Raymond, Penninx, Brenda WJH, Peters, Annette, Peyser, Patricia A, Polašek, Ozren, Power, Chris, Pribisalic, Ajka, Redmond, Paul, Rich-Edwards, Janet W, Ridker, Paul M, Rietveld, Cornelius A, Ring, Susan M, Rose, Lynda M, Rueedi, Rico, Shukla, Vallari, Smith, Jennifer A, Stankovic, Stasa, Stefánsson, Kári, Stöckl, Doris, Strauch, Konstantin, Swertz, Morris A, Teumer, Alexander, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A Roy, Timpson, Nicholas J, Turman, Constance, Uitterlinden, André G, Waldenberger, Melanie, Wareham, Nicholas J, Weir, David R, Willemsen, Gonneke, Zhao, Jing Hau, Zhao, Wei, Zhao, Yajie, Snieder, Harold, Den Hoed, Marcel, Ong, Ken K, Mills, Melinda C, Perry, John RB, Mathieson, Iain [0000-0002-4256-3982], Day, Felix R [0000-0003-3789-7651], Vaez, Ahmad [0000-0001-9048-3795], Bitarello, Bárbara D [0000-0001-7676-9367], Gardner, Eugene J [0000-0001-9671-1533], Akimova, Evelina T [0000-0001-8733-3745], Bergmann, Sven [0000-0002-6785-9034], Bielak, Lawrence F [0000-0002-3443-8030], Boomsma, Dorret I [0000-0002-7099-7972], Chasman, Daniel I [0000-0003-3357-0862], Chavarro, Jorge E [0000-0002-4436-9630], Cocca, Massimiliano [0000-0002-1127-7596], Concas, Maria Pina [0000-0003-3598-2537], Davey Smith, George [0000-0002-1407-8314], Davies, Gail [0000-0003-1120-7026], Franco, Oscar [0000-0002-4606-4929], Ganna, Andrea [0000-0002-8147-240X], Gaskins, Audrey J [0000-0001-9195-646X], Gieger, Christian [0000-0001-6986-9554], Girotto, Giorgia [0000-0003-4507-6589], Grabe, Hans Jörgen [0000-0003-3684-4208], Gunderson, Erica P [0000-0002-2039-1964], He, Chunyan [0000-0001-9443-4368], Hoffmann, Eva R [0000-0002-2588-0652], Homuth, Georg [0000-0001-6839-0605], Hottenga, Jouke Jan [0000-0002-5668-2368], Hyppӧnen, Elina [0000-0003-3670-9399], Ikram, M Arfan [0000-0003-0372-8585], Jansen, Rick [0000-0002-3333-6737], Johannesson, Magnus [0000-0001-8759-6393], Kamali, Zoha [0000-0001-6492-5887], Kavousi, Maryam [0000-0001-5976-6519], Kifley, Annette [0000-0002-3764-4905], Kiiskinen, Tuomo [0000-0002-6306-8227], Kraft, Peter [0000-0002-4472-8103], Langenberg, Claudia [0000-0002-5017-7344], Lind, Penelope A [0000-0002-3887-2598], Luan, Jian'an [0000-0003-3137-6337], Magnusson, Patrik KE [0000-0002-7315-7899], Mahajan, Anubha [0000-0001-5585-3420], Mbarek, Hamdi [0000-0002-1108-0371], Metspalu, Andres [0000-0002-3718-796X], Milani, Lili [0000-0002-5323-3102], Møllegaard, Stine [0000-0001-5676-2248], Morgan, Anna [0000-0001-6290-445X], van der Most, Peter J [0000-0001-8450-3518], Nauck, Matthias [0000-0002-6678-7964], Nolte, Ilja M [0000-0001-5047-4077], Noordam, Raymond [0000-0001-7801-809X], Peters, Annette [0000-0001-6645-0985], Peyser, Patricia A [0000-0002-9717-8459], Pribisalic, Ajka [0000-0002-3725-3728], Rietveld, Cornelius A [0000-0003-4053-1861], Ring, Susan M [0000-0003-3103-9330], Smith, Jennifer A [0000-0002-3575-5468], Stankovic, Stasa [0000-0002-6602-1379], Teumer, Alexander [0000-0002-8309-094X], Thurik, A Roy [0000-0002-0242-6908], Timpson, Nicholas J [0000-0002-7141-9189], Uitterlinden, André G [0000-0002-7276-3387], Waldenberger, Melanie [0000-0003-0583-5093], Wareham, Nicholas J [0000-0003-1422-2993], Weir, David R [0000-0002-1661-2402], Zhao, Wei [0000-0001-7388-0692], Zhao, Yajie [0000-0002-2747-0219], Snieder, Harold [0000-0003-1949-2298], den Hoed, Marcel [0000-0001-8081-428X], Ong, Ken K [0000-0003-4689-7530], Mills, Melinda C [0000-0003-1704-0001], Perry, John RB [0000-0001-6483-3771], and Apollo - University of Cambridge Repository

Subjects
Aging, Fertility, Reproduction, Humans, Female, Menopause, Selection, Genetic, FOS: Medical biotechnology, Child
Abstract

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Published
2023

2. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour

Author

Mills, Melinda C, Tropf, Felix C, Brazel, David M, van Zuydam, Natalie, Vaez, Ahmad, eQTLGen Consortium, BIOS Consortium, Human Reproductive Behaviour Consortium, Pers, Tune H, Snieder, Harold, Perry, John RB, Ong, Ken K, den Hoed, Marcel, Barban, Nicola, Day, Felix R, Mills, Melinda C [0000-0003-1704-0001], Tropf, Felix C [0000-0003-2445-515X], Brazel, David M [0000-0001-5361-2498], Vaez, Ahmad [0000-0001-9048-3795], Pers, Tune H [0000-0003-0207-4831], Snieder, Harold [0000-0003-1949-2298], Perry, John RB [0000-0001-6483-3771], Ong, Ken K [0000-0003-4689-7530], den Hoed, Marcel [0000-0001-8081-428X], Barban, Nicola [0000-0002-4362-4652], Day, Felix R [0000-0003-3789-7651], and Apollo - University of Cambridge Repository

Subjects
Male, Adolescent, Reproduction, Age Factors, Coitus, Parturition, Humans, Female, Polymorphism, Single Nucleotide, Genetic Association Studies
Abstract

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

Published
2021

3. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Anderson, Christopher D, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie L M, Tanislav, Christian, Tatlisumak, Turgut, Chong, Michael, Taylor, Kent D, Thijs, Vincent N S, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Adams, Hieab H H, Wassertheil-Smoller, Sylvia, Wilson, James G, Wiggins, Kerri L, Yang, Qiong, Yusuf, Salim, Consortium, AFGen, Epidemiology, Cohorts for Heart and Aging Research in Genomic, Pressure, International Genomics of Blood, Consortium, INVENT, STARNET, Ago, Tetsuro, Bis, Joshua C, Pastinen, Tomi, Ruusalepp, Arno, Schadt, Eric E, Koplev, Simon, Björkegren, Johan L M, Codoni, Veronica, Civelek, Mete, Smith, Nicholas L, Trégouët, David A, Almgren, Peter, Christophersen, Ingrid E, Roselli, Carolina, Lubitz, Steven A, Ellinor, Patrick T, Tai, E Shyong, Kooner, Jaspal S, Kato, Norihiro, He, Jiang, van der Harst, Pim, Elliott, Paul, Amouyel, Philippe, Chambers, John C, Takeuchi, Fumihiko, Johnson, Andrew D, Group, BioBank Japan Cooperative Hospital, Consortium, COMPASS, Consortium, EPIC-CVD, Consortium, EPIC-InterAct, Consortium, International Stroke Genetics, Consortium, METASTROKE, Consortium, Neurology Working Group of the CHARGE, Ay, Hakan, Network, NINDS Stroke Genetics, Study, UK Young Lacunar DNA, Consortium, MEGASTROKE, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Longstreth, W. T., Rolfs, Arndt, Bartz, Traci M, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Benavente, Oscar R, Fornage, Myriam, Markus, Hugh S, Howson, Joanna M M, Kamatani, Yoichiro, Debette, Stephanie, Dichgans, Martin, Traylor, Matthew, Sargurupremraj, Muralidharan, Bevan, Steve, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei-Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul I W, DeStefano, Anita L, Hoed, Marcel den, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I, Ikram, M Arfan, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei-Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O'Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu-Ching, Choi, Seung Hoan, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean-François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, den Hoed, Marcel, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Liu, Yong Mei, Lopez, Oscar L, Makoto, Hirata, Martinez-Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller-Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Peddareddygari, Leema Reddy, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba-Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti-Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano-Tárraga, Carolina, Stanne, Tara, Stine, O Colin, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres-Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles D A, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, 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), Pathology, Epidemiology, Radiology & Nuclear Medicine, Cardiovascular Centre (CVC), Universitat de Barcelona, Traylor, Matthew [0000-0001-6624-8621], Okada, Yukinori [0000-0002-0311-8472], Rutten-Jacobs, Loes [0000-0003-3223-885X], van der Laan, Sander W [0000-0001-6888-1404], Adams, Hieab HH [0000-0003-3687-2508], Almgren, Peter [0000-0002-0473-0241], Amouyel, Philippe [0000-0001-9088-234X], Correa, Adolfo [0000-0002-9501-600X], Cruchaga, Carlos [0000-0002-0276-2899], den Hoed, Marcel [0000-0001-8081-428X], Gustafsson, Stefan [0000-0001-5894-0351], Havulinna, Aki S [0000-0002-4787-8959], Ikram, M Arfan [0000-0003-0372-8585], Jukema, J Wouter [0000-0002-3246-8359], Kanai, Masahiro [0000-0001-5165-4408], Lewis, Cathryn M [0000-0002-8249-8476], Lin, Wei-Yu [0000-0002-9267-7988], Magnusson, Patrik K [0000-0002-7315-7899], Pulit, Sara L [0000-0002-2502-3669], Wiggins, Kerri L [0000-0003-2749-1279], Yang, Qiong [0000-0002-3658-1375], Schadt, Eric E [0000-0002-7892-8808], Koplev, Simon [0000-0002-8586-5614], Civelek, Mete [0000-0002-8141-0284], Trégouët, David A [0000-0001-9084-7800], Christophersen, Ingrid E [0000-0002-6141-4712], Roselli, Carolina [0000-0001-5267-6756], Ellinor, Patrick T [0000-0002-2067-0533], van der Harst, Pim [0000-0002-2713-686X], Elliott, Paul [0000-0002-7511-5684], Takeuchi, Fumihiko [0000-0003-3185-5661], Jern, Christina [0000-0002-7531-2354], Saleheen, Danish [0000-0001-6193-020X], Kamatani, Yoichiro [0000-0001-8748-5597], Dichgans, Martin [0000-0002-0654-387X], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, COMPASS Consortium, Linkage disequilibrium, Candidate gene, UK Young Lacunar DNA Study, Genome-wide association study, SEPIA, Linkage Disequilibrium, Epigenesis, Genetic, classification [Stroke], International Stroke Genetics Consortium (ISGC), 0302 clinical medicine, INDEL Mutation, HEMORRHAGIC STROKE, Risk Factors, Pleiotropy, Databases, Genetic, Neurology Working Group of the CHARGE Consortium, WHITE-MATTER HYPERINTENSITIES, Gene Regulatory Networks, Stroke, Genetics & Heredity, Genetics, International Genomics of Blood Pressure (iGEN-BP) Consortium, physiopathology [Stroke], AFGen Consortium, 11 Medical And Health Sciences, Genomics, 3. Good health, [MEGASTROKE Consortium], ISCHEMIC-STROKE, VINTAGE, genetics [Stroke], CORONARY-ARTERY-DISEASE, Medical genetics, Female, EPIC-InterAct Consortium, MEGASTROKE Consortium, Life Sciences & Biomedicine, Gens, medicine.medical_specialty, SUSCEPTIBILITY LOCI, STARNET, INVENT Consortium, SMALL-VESSEL DISEASE, Biology, Polymorphism, Single Nucleotide, EPIC-CVD Consortium, Article, Chromosomes, HUMAN GENETIC-VARIATION, NINDS Stroke Genetics Network (SiGN), 03 medical and health sciences, ddc:570, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Science & Technology, Models, Genetic, COMPLEX TRAITS, Computational Biology, 06 Biological Sciences, medicine.disease, METASTROKE Consortium, Human genetics, Cromosomes, BioBank Japan Cooperative Hospital Group, Genòmica, 030104 developmental biology, Genes, Genetic Loci, ATRIAL-FIBRILLATION, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, SUDDEN CARDIAC DEATH, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke sub-types. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Published
2018

4. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Ilaria, Gandin, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth JF, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thomas, Mitchell, Braxton D, Munzel, Thomas, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcus, and Ferrucci, Luigi

Subjects
Male, Human Genome, Atrial Function, Cardiovascular, Linkage Disequilibrium, Electrophysiological Phenomena, Electrocardiography, Heart Disease, Risk Factors, Mutation, Atrioventricular Node, Genetics, Humans, 2.1 Biological and endogenous factors, Female, Missense, Aetiology, Genome-Wide Association Study, Biotechnology
Abstract

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

Published
2018

5. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei-Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I, Ikram, M Arfan, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei-Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O'Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, and Sale, Michele M

Subjects
Male, COMPASS Consortium, MEGASTROKE Consortium, NINDS Stroke Genetics Network, UK Young Lacunar DNA Study, INVENT Consortium, STARNET, Cardiovascular, Medical and Health Sciences, Polymorphism, Single Nucleotide, EPIC-CVD Consortium, International Stroke Genetics Consortium, Linkage Disequilibrium, Epigenesis, Genetic, Databases, Genetic, INDEL Mutation, Models, Clinical Research, Risk Factors, Databases, Genetic, Neurology Working Group of the CHARGE Consortium, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Gene Regulatory Networks, Polymorphism, Aetiology, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, International Genomics of Blood Pressure (iGEN-BP) Consortium, Models, Genetic, Human Genome, AFGen Consortium, Computational Biology, Single Nucleotide, Biological Sciences, METASTROKE Consortium, Brain Disorders, BioBank Japan Cooperative Hospital Group, Stroke, Genetic Loci, Female, EPIC-InterAct Consortium, Epigenesis, Developmental Biology, Genome-Wide Association Study
Abstract

© 2018 The Author(s). Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Published
2018

6. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults

Author

Graff, Mariaelisa, Scott, Robert A, Justice, Anne E, Young, Kristin L, Feitosa, Mary F, Barata, Llilda, Winkler, Thomas W, Chu, Audrey Y, Mahajan, Anubha, Hadley, David, Xue, Luting, Workalemahu, Tsegaselassie, Heard-Costa, Nancy L, den Hoed, Marcel, Ahluwalia, Tarunveer S, Qi, Qibin, Ngwa, Julius S, Renström, Frida, Quaye, Lydia, Eicher, John D, Hayes, James E, Cornelis, Marilyn, Kutalik, Zoltan, Lim, Elise, Luan, Jian'an, Huffman, Jennifer E, Zhang, Weihua, Zhao, Wei, Griffin, Paula J, Haller, Toomas, Ahmad, Shafqat, Marques-Vidal, Pedro M, Bien, Stephanie, Yengo, Loic, Teumer, Alexander, Smith, Albert Vernon, Kumari, Meena, Harder, Marie Neergaard, Justesen, Johanne Marie, Kleber, Marcus E, Hollensted, Mette, Lohman, Kurt, Rivera, Natalia V, Whitfield, John B, Zhao, Jing Hua, Stringham, Heather M, Lyytikäinen, Leo-Pekka, Huppertz, Charlotte, Willemsen, Gonneke, Peyrot, Wouter J, Wu, Ying, Kristiansson, Kati, Demirkan, Ayse, Fornage, Myriam, Hassinen, Maija, Bielak, Lawrence F, Cadby, Gemma, Tanaka, Toshiko, Mägi, Reedik, van der Most, Peter J, Jackson, Anne U, Bragg-Gresham, Jennifer L, Vitart, Veronique, Marten, Jonathan, Navarro, Pau, Bellis, Claire, Pasko, Dorota, Johansson, Åsa, Snitker, Søren, Cheng, Yu-Ching, Eriksson, Joel, Lim, Unhee, Aadahl, Mette, Adair, Linda S, Amin, Najaf, Balkau, Beverley, Auvinen, Juha, Beilby, John, Bergman, Richard N, Bergmann, Sven, Bertoni, Alain G, Blangero, John, Bonnefond, Amélie, Bonnycastle, Lori L, Borja, Judith B, Brage, Søren, Busonero, Fabio, Buyske, Steve, Campbell, Harry, Chines, Peter S, Collins, Francis S, Corre, Tanguy, Smith, George Davey, Delgado, Graciela E, Dueker, Nicole, Dörr, Marcus, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tõnu, Faul, Jessica D, and Edwards, Todd L

Subjects
Male, Epigenomics, Genotype, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Cardiovascular, Oral and gastrointestinal, Body Mass Index, PAGE Consortium, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Obesity, Aetiology, Exercise, Metabolic and endocrine, Adiposity, Nutrition, Cancer, Waist-Hip Ratio, Prevention, Human Genome, Stroke, CHARGE Consortium, Female, EPIC-InterAct Consortium, Waist Circumference, Genome-Wide Association Study, Developmental Biology
Abstract

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Published
2017

7. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niels, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian'an, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inês, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, CVD50 consortium, Cupples, L Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G, Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jørgensen, Marit E, Jukema, J Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D, Key, Timothy J, Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T, Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L, Morris, Andrew P, Muir, Kenneth, Müller-Nurasyid, Martina, Munroe, Patricia B, Navarro, Carmen, Nielsen, Sune F, Nilsson, Peter M, Nordestgaard, Børge G, Packard, Chris J, Palli, Domenico, Panico, Salvatore, Peloso, Gina M, Perola, Markus, Peters, Annette, Poole, Christopher J, Quirós, J Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María-José, Sattar, Naveed, Sharp, Stephen J, Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A, Thompson, Deborah J, and Trompet, Stella

Subjects
Serotonin, Genotype, CHARGE consortium, Dipeptidyl Peptidase 4, Clinical Trials and Supportive Activities, Coronary Disease, Cardiovascular, Medical and Health Sciences, Glucagon-Like Peptide-1 Receptor, Sodium-Glucose Transporter 1, Clinical Research, Receptors, Genetics, Diabetes Mellitus, 2.1 Biological and endogenous factors, Humans, Obesity, 5-HT2C, Aetiology, Cannabinoid, Heart Disease - Coronary Heart Disease, Metabolic and endocrine, Alleles, Nutrition, CHD Exome+ Consortium, Human Genome, Diabetes, Alzheimer’s Disease Genetics Consortium, GERAD_EC Consortium, Neurology Working Group of the Cohorts for Heart, Biological Sciences, CB2, CARDIOGRAM Exome Consortium, CVD50 consortium, Aging Research in Genomic Epidemiology, Heart Disease, Good Health and Well Being, 5.1 Pharmaceuticals, EPIC-InterAct, Development of treatments and therapeutic interventions, European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease, Somatostatin, Type 2, Pancreatic Cancer Cohort Consortium, Receptor
Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

Published
2016

8. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour

Author

Mills, Melinda C, Tropf, Felix C, Brazel, David M, Van Zuydam, Natalie, Vaez, Ahmad, EQTLGen Consortium, BIOS Consortium, Human Reproductive Behaviour Consortium, Pers, Tune H, Snieder, Harold, Perry, John RB, Ong, Ken K, Den Hoed, Marcel, Barban, Nicola, and Day, Felix R

Subjects
Male, Adolescent, Reproduction, Age Factors, Coitus, Parturition, Humans, Female, FOS: Medical biotechnology, Polymorphism, Single Nucleotide, Genetic Association Studies, 3. Good health
Abstract

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

9. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, Van Der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei-Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, De Bakker, Paul IW, DeStefano, Anita L, Den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I, Ikram, M Arfan, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei-Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O'Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, Van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil-Smoller, Sylvia, Wilson, James G, Wiggins, Kerri L, Yang, Qiong, Yusuf, Salim, AFGen Consortium, Cohorts For Heart And Aging Research In Genomic Epidemiology (CHARGE) Consortium, International Genomics Of Blood Pressure (IGEN-BP) Consortium, INVENT Consortium, STARNET, Bis, Joshua C, Pastinen, Tomi, Ruusalepp, Arno, Schadt, Eric E, Koplev, Simon, Björkegren, Johan LM, Codoni, Veronica, Civelek, Mete, Smith, Nicholas L, Trégouët, David A, Christophersen, Ingrid E, Roselli, Carolina, Lubitz, Steven A, Ellinor, Patrick T, Tai, E Shyong, Kooner, Jaspal S, Kato, Norihiro, He, Jiang, Van Der Harst, Pim, Elliott, Paul, Chambers, John C, Takeuchi, Fumihiko, Johnson, Andrew D, BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium (ISGC), METASTROKE Consortium, Neurology Working Group Of The CHARGE Consortium, NINDS Stroke Genetics Network (SiGN), UK Young Lacunar DNA Study, MEGASTROKE Consortium, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Longstreth, WT, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Subjects
Male, Models, Genetic, Computational Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 3. Good health, Epigenesis, Genetic, Stroke, INDEL Mutation, Genetic Loci, Risk Factors, Databases, Genetic, Humans, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

10. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Author

Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J., Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn C., Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer S., Bartz, Traci M., Bentley, Amy R., Bielak, Lawrence F., Chong, Mike, Chu, Audrey Y., Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole D., Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary F., Gieger, Christian, Graff, Mariaelisa, Hall, Leanne M., Haller, Toomas, Hartwig, Fernando P., Hillis, David A., Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne U., Johansson, Åsa, Jørgensen, Anja Moltke, Kaakinen, Marika A., Karlsson, Robert, Kerr, Kathleen F., Kim, Boram, Koolhaas, Chantal M., Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope A., Lorentzon, Mattias, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Metzendorf, Christoph, Monroe, Kristine R., Pacolet, Alexander, Pérusse, Louis, Pool, Rene, Richmond, Rebecca C., Rivera, Natalia V., Robiou-du-Pont, Sebastien, Schraut, Katharina E., Schulz, Christina-Alexandra, Stringham, Heather M., Tanaka, Toshiko, Teumer, Alexander, Turman, Constance, van der Most, Peter J., Vanmunster, Mathias, van Rooij, Frank J. A., van Vliet-Ostaptchouk, Jana V., Zhang, Xiaoshuai, Zhao, Jing-Hua, Zhao, Wei, Balkhiyarova, Zhanna, Balslev-Harder, Marie N., Baumeister, Sebastian E., Beilby, John, Blangero, John, Boomsma, Dorret I., Brage, Søren Karl, Braund, Peter S., Brody, Jennifer A., Bruinenberg, Marcel, Ekelund, Ulf, Liu, Ching-Ti, Cole, John W., Collins, Francis S., Cupples, L. Adrienne, Esko, Tõnu, Enroth, Stefan, Faul, Jessica D., Fernandez-Rhodes, Lindsay, Fohner, Alison E., Franco, Oscar H., Galesloot, Tessel E., Gordon, Scott D., Grarup, Niels, Hartman, Catharina A., Heiss, Gerardo, Hui, Jennie, Illig, Thomas, Jago, Russell, James, Alan, Joshi, Peter K., Jung, Taeyeong, Kähönen, Mika, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Kolcic, Ivana, Kraft, Peter P., Kuusisto, Johanna, Launer, Lenore J., Li, Aihua, Linneberg, Allan, Luan, Jian’an, Vidal, Pedro Marques, Medland, Sarah E., Milaneschi, Yuri, Moscati, Arden, Musk, Bill, Nelson, Christopher P., Nolte, Ilja M., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Power, Christine, Raitakari, Olli T., Reedik, Mägi, Reiner, Alex P., Ridker, Paul M., Rudan, Igor, Ryan, Kathy, Sarzynski, Mark A., Scott, Laura J., Scott, Robert A., Sidney, Stephen, Siggeirsdottir, Kristin, Smith, Albert V., Smith, Jennifer A., Sonestedt, Emily, Strøm, Marin, Tai, E. Shyong, Teo, Koon K., Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Uitterlinden, Andre G., Vangipurapu, Jagadish, van Schoor, Natasja, Völker, Uwe, Willemsen, Gonneke, Williams, Kayleen, Wong, Quenna, Xu, Huichun, Young, Kristin L., Yuan, Jian Min, Zillikens, M. Carola, Zonderman, Alan B., Ameur, Adam, Bandinelli, Stefania, Bis, Joshua C., Boehnke, Michael, Bouchard, Claude, Chasman, Daniel I., Smith, George Davey, de Geus, Eco J. C., Deldicque, Louise, Dörr, Marcus, Evans, Michele K., Ferrucci, Luigi, Fornage, Myriam, Fox, Caroline, Garland, Theodore, Gudnason, Vilmundur, Gyllensten, Ulf, Hansen, Torben, Hayward, Caroline, Horta, Bernardo L., Hyppönen, Elina, Jarvelin, Marjo-Riitta, Johnson, W. Craig, Kardia, Sharon L. R., Kiemeney, Lambertus A., Laakso, Markku, Langenberg, Claudia, Lehtimäki, Terho, Marchand, Loic Le, Alizadeh, Behrooz Z., Boezen, H. Marike, Franke, Lude, Swertz, Morris, Wijmenga, Tjitske Nienke, van der Harst, Pim, Navis, Gerjan, Rots, Marianne, Wolffenbuttel, Bruce H. R., Magnusson, Patrik K. E., Martin, Nicholas G., Melbye, Mads, Metspalu, Andres, Meyre, David, North, Kari E., Ohlsson, Claes, Oldehinkel, Albertine J., Orho-Melander, Marju, Pare, Guillaume, Park, Taesung, Pedersen, Oluf, Penninx, Brenda W. J. H., Pers, Tune H., Polasek, Ozren, Prokopenko, Inga, Rotimi, Charles N., Samani, Nilesh J., Sim, Xueling, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Timpson, Nicholas J., van Dam, Rob M., van der Velde, Nathalie, van Duijn, Cornelia M., Vollenweider, Peter, Völzke, Henry, Voortman, Trudy, Waeber, Gérard, Wareham, Nicholas J., Weir, David R., Wichmann, Heinz-Erich, Wilson, James F., Hevener, Andrea L., Krook, Anna, Zierath, Juleen R., Thomis, Martine A. I., Loos, Ruth J. F., Hoed, Marcel den, Epidemiology, Internal Medicine, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J, Moore, Tim, Hyppönen, Elina, den Hoed, Marcel, Lifelines Cohort Study, Alizadeh, B.Z., Boezen, H.M., Franke, L., Swertz, M., Wijmenga, C., van der Harst, P., Navis, G., Rots, M., Wolffenbuttel, BHR, Wang, Zhe [0000-0002-8046-4969], Emmerich, Andrew [0000-0002-0908-9924], Pillon, Nicolas J [0000-0003-1107-9490], Moore, Tim [0000-0003-4250-3370], Ameur, Adam [0000-0001-6085-6749], Bis, Joshua C [0000-0002-3409-1110], Boehnke, Michael [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Chasman, Daniel I [0000-0003-3357-0862], Smith, George Davey [0000-0002-1407-8314], de Geus, Eco JC [0000-0001-6022-2666], Dörr, Marcus [0000-0001-7471-475X], Ferrucci, Luigi [0000-0002-6273-1613], Fornage, Myriam [0000-0003-0677-8158], Garland, Theodore [0000-0002-7916-3552], Gyllensten, Ulf [0000-0002-6316-3355], Hansen, Torben [0000-0001-8748-3831], Horta, Bernardo L [0000-0001-9843-412X], Hyppönen, Elina [0000-0003-3670-9399], Johnson, W Craig [0000-0002-3161-3753], Kiemeney, Lambertus A [0000-0002-2368-1326], Laakso, Markku [0000-0002-3394-7749], Langenberg, Claudia [0000-0002-5017-7344], Lehtimäki, Terho [0000-0002-2555-4427], Magnusson, Patrik KE [0000-0002-7315-7899], Martin, Nicholas G [0000-0003-4069-8020], Melbye, Mads [0000-0001-8264-6785], Metspalu, Andres [0000-0002-3718-796X], Meyre, David [0000-0003-4850-7444], North, Kari E [0000-0002-8903-0366], Ohlsson, Claes [0000-0002-9633-2805], Oldehinkel, Albertine J [0000-0003-3925-3913], Orho-Melander, Marju [0000-0002-3578-2503], Pare, Guillaume [0000-0002-6795-4760], Park, Taesung [0000-0002-8294-590X], Pedersen, Oluf [0000-0002-3321-3972], Pers, Tune H [0000-0003-0207-4831], Polasek, Ozren [0000-0002-5765-1862], Prokopenko, Inga [0000-0003-1624-7457], Rotimi, Charles N [0000-0001-5759-053X], Sim, Xueling [0000-0002-1233-7642], Snieder, Harold [0000-0003-1949-2298], Sørensen, Thorkild IA [0000-0003-4821-430X], Spector, Tim D [0000-0002-9795-0365], Timpson, Nicholas J [0000-0002-7141-9189], Voortman, Trudy [0000-0003-2830-6813], Waeber, Gérard [0000-0003-4193-788X], Wareham, Nicholas J [0000-0003-1422-2993], Weir, David R [0000-0002-1661-2402], Wilson, James F [0000-0001-5751-9178], Krook, Anna [0000-0002-0891-0258], Zierath, Juleen R [0000-0001-6891-7497], Thomis, Martine AI [0000-0001-9093-2191], Loos, Ruth JF [0000-0002-8532-5087], Hoed, Marcel den [0000-0001-8081-428X], Apollo - University of Cambridge Repository, Center for Liver, Digestive and Metabolic Diseases (CLDM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Geriatrics, AMS - Ageing & Vitality, APH - Aging & Later Life, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, and AMS - Sports

Subjects
Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], 631/208/205/2138, 610 Medicine & health, heritability, Actinin/genetics, Cross-Sectional Studies, Exercise/physiology, Genome-Wide Association Study, Humans, Leisure Activities, Sedentary Behavior, apolipoprotein-e genotype, Lifelines Cohort Study, 360 Social problems & social services, 692/308/575, Genetics, Actinin, Exercise, Medicinsk genetik, exercise, APOLIPOPROTEIN-E GENOTYPE, LD SCORE REGRESSION, GENE-EXPRESSION, EXERCISE, COMPLEX, PERFORMANCE, GWAS, HERITABILITY, MORTALITY, FITNESS, 360 Soziale Probleme, Sozialdienste, 692/308/2056, article, gwas, gene-expression, mortality, 3142 Public health care science, environmental and occupational health, fitness, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], LD score regression, 3111 Biomedicine, 610 Medizin und Gesundheit, Medical Genetics, complex, performance
Abstract

Funder: Kjell och Märta Beijers Stiftelse (Kjell and Marta Beijer Foundation); doi: https://doi.org/10.13039/501100006353, Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Published
2022
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11. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Nicola D. Kerrison, Carlos González, Mark Walker, Adam S. Butterworth, Martina Müller-Nurasyid, Mark I. McCarthy, Jarmo Virtamo, Nilesh J. Samani, Daniel F. Freitag, Jennifer Wessel, Inês Barroso, Jette Bork-Jensen, Marit E. Jørgensen, Torben Hansen, Nita G. Forouhi, Jennifer A. Smith, Peter Vollenweider, Douglas F. Easton, Heiner Boeing, Helena M. Earl, Laufey T. Amundadottir, Annette Peters, Ingrid B. Borecki, L. Adrienne Cupples, Li Li, Josée Dupuis, Sara Benlloch Garcia, J. Wouter Jukema, Shuai Wang, Veikko Salomaa, Jukka Kontto, Timothy J. Key, Yuning Chen, Sune F. Nielsen, Robin Young, Jing Hua Zhao, Andrew P. Morris, Larraitz Arriola, Claudia Langenberg, Joshua C. Bis, Nisa M. Maruthur, Ele Ferrannini, Joanna M. M. Howson, Marcel den Hoed, Jeanette Erdmann, Rosalind A. Eeles, Daphne L. van der A, Panos Deloukas, Eric Boerwinkle, Sara M. Willems, Elio Riboli, Markku Laakso, Gina M. Peloso, Muriel J. Caslake, Nadia Slimani, Zsofia Kote-Jarai, Paul W. Franks, EPIC-InterAct, Dominique Arveiler, Sarah Bowden, Janet A. Dunn, Jan-Håkan Jansson, Carlos Cruchaga, Audrey Y. Chu, James S. Pankow, Rudolf Kaaks, Jerome I. Rotter, Jaspal S. Kooner, Ailith Pirie, Johanna Kuusisto, Hanieh Yaghootkar, Niels Grarup, Danish Saleheen, Thomas Foltynie, Jean Abraham, Stefan Blankenberg, Mark O. Goodarzi, Markus Perola, Olov Rolandsson, Chris J. Packard, Praveen Surendran, Allan Linneberg, Beverley Balkau, Christopher J. Poole, Frank Kee, Carmen Navarro, Nicholas J. Wareham, Oluf Pedersen, Heribert Schunkert, Domenico Palli, Patricia B. Munroe, Sven J. van der Lee, Chunyu Liu, Rebecca Sims, Georg Ehret, Michael Boehnke, Stephen J. Sharp, Peter M. Nilsson, Salvatore Panico, Børge G. Nordestgaard, Aldi T. Kraja, Sara Grioni, Sekar Kathiresan, Dawn M. Waterworth, Francesco Gianfagna, Jacek Czajkowski, Naveed Sattar, Margaret G. Ehm, Christopher J. Gillson, Karen L. Mohlke, Stella Trompet, John Danesh, Carlotta Sacerdote, Gaëlle Marenne, Jian'an Luan, Timothy M. Frayling, J. Ramón Quirós, Iciar Aviles-Olmos, Robert A. Scott, Yvonne T. van der Schouw, Jennifer L. Aponte, María José Sánchez, Deborah J. Thompson, Klaudia Walter, James B. Meigs, Tibor V. Varga, Kari Kuulasmaa, Torben Jørgensen, Rosario Tumino, Kyriaki Michailidou, Kenneth Muir, Philippe Amouyel, Ian Ford, Aurelio Barricarte, Stephen O'Rahilly, Ali Amin Al Olama, Louise Hiller, Alena Stančáková, Carlos Caldas, Jean Ferrières, Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niel, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian'An, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inê, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork Jensen, Jette, Bowden, Sarah, Caldas, Carlo, Caslake, Muriel, Cupples, L. Adrienne, Cruchaga, Carlo, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thoma, Ford, Ian, Forouhi, Nita G, Gianfagna, Francesco, Gonzalez, Carlo, Grioni, Sara, Hiller, Louise, Jansson, Jan Håkan, Jørgensen, Marit E, Jukema, J. Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D, Key, Timothy J, Kontto, Jukka, Kote Jarai, Zsofia, Kraja, Aldi T, Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L, Morris, Andrew P, Muir, Kenneth, Müller Nurasyid, Martina, Munroe, Patricia B, Navarro, Carmen, Nielsen, Sune F, Nilsson, Peter M, Nordestgaard, Børge G, Packard, Chris J, Palli, Domenico, Panico, Salvatore, Peloso, Gina M, Perola, Marku, Peters, Annette, Poole, Christopher J, Quirós, J. Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María José, Sattar, Naveed, Sharp, Stephen J, Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A, Thompson, Deborah J, Trompet, Stella, Tumino, Rosario, van der A, Daphne L, van der Schouw, Yvonne T, Virtamo, Jarmo, Walker, Mark, Walter, Klaudia, Abraham, Jean E, Amundadottir, Laufey T, Aponte, Jennifer L, Butterworth, Adam S, Dupuis, Josée, Easton, Douglas F, Eeles, Rosalind A, Erdmann, Jeanette, Franks, Paul W, Frayling, Timothy M, Hansen, Torben, Howson, Joanna M. M, Jørgensen, Torben, Kooner, Jaspal, Laakso, Markku, Langenberg, Claudia, Mccarthy, Mark I, Pankow, James S, Pedersen, Oluf, Riboli, Elio, Rotter, Jerome I, Saleheen, Danish, Samani, Nilesh J, Schunkert, Heribert, Vollenweider, Peter, O'Rahilly, Stephen, Deloukas, Pano, Danesh, John, Goodarzi, Mark O, Kathiresan, Sekar, Meigs, James B, Ehm, Margaret G, Wareham, Nicholas J, Waterworth, Dawn M., Surgery, Epidemiology, Ehret, Georg Benedikt, Surendran, Praveen [0000-0002-4911-6077], Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Caldas, Carlos [0000-0003-3547-1489], Earl, Helena [0000-0003-1549-8094], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Thompson, Deborah [0000-0003-1465-5799], Abraham, Jean [0000-0003-0688-4807], Butterworth, Adam [0000-0002-6915-9015], Easton, Douglas [0000-0003-2444-3247], Howson, Joanna [0000-0001-7618-0050], Langenberg, Claudia [0000-0002-5017-7344], O'Rahilly, Stephen [0000-0003-2199-4449], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
Type 2/genetics, 0301 basic medicine, Somatostatin/genetics, Heart disease, Epidemiology, CHARGE consortium, Obesity/genetics, RECEPTOR AGONIST LIXISENATIDE, Coronary Disease, Type 2 diabetes, Research & Experimental Medicine, Bioinformatics, PLACEBO-CONTROLLED TRIAL, Receptor, Cannabinoid, CB2, DOUBLE-BLIND, Dipeptidyl Peptidase 4/genetics, 0302 clinical medicine, ONCE-DAILY LIXISENATIDE, Receptors, Receptor, Serotonin, 5-HT2C, Receptors, Somatostatin, Exome sequencing, GLUCAGON-LIKE PEPTIDE-1, CHD Exome+ Consortium, Neurology Working Group of the Cohorts for Heart, General Medicine, 11 Medical And Health Sciences, RANDOMIZED CONTROLLED-TRIAL, 3. Good health, Coronary Disease/genetics, 5-HT2C/genetics, CVD50 consortium, Drug development, Medicine, Research & Experimental, EPIC-InterAct, Public Health, Life Sciences & Biomedicine, INCRETIN-BASED THERAPIES, Receptor, Serotonin, RM, European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD), Genotype, Dipeptidyl Peptidase 4, CB2/genetics, TYPE-2 DIABETES-MELLITUS, 030209 endocrinology & metabolism, Article, Glucagon-Like Peptide-1 Receptor, 03 medical and health sciences, Sodium-Glucose Transporter 1, BETA-CELL FUNCTION, Diabetes mellitus, Diabetes Mellitus, Journal Article, medicine, Humans, Sodium-Glucose Transporter 1/genetics, Obesity, Cannabinoid, Alleles, Science & Technology, business.industry, Alzheimer’s Disease Genetics Consortium, Glucagon-Like Peptide-1 Receptor/genetics, GERAD_EC Consortium, Cell Biology, 06 Biological Sciences, medicine.disease, R1, Human genetics, CARDIOGRAM Exome Consortium, Clinical trial, Minor allele frequency, BODY-MASS INDEX, 030104 developmental biology, Diabetes Mellitus, Type 2, Aging Research in Genomic Epidemiology (CHARGE), business, RC, Pancreatic Cancer Cohort Consortium
Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11, 806 individuals by targeted exome sequencing and follow-up in 39, 979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved.

Published
2016

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