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

Karlsson, R.; Biroli, P.; Kong, E.; Meddens, S.F.W.; Wedow, R.; Fontana, M.A.; Lebreton, M.; Tino, S.P.; Abdellaoui, A.; Hammerschlag, A.R.; Nivard, M.G.; Okbay, A.; Rietveld, C.A.; Timshel, P.N.; Trzaskowski, M.; Vlaming, R.; Zünd, C.L.; Bao, Y.; Buzdugan, L.; Caplin, A.H.; Chen, C.-Y.; Eibich, P.; Fontanillas, P.; Gonzalez, J.R.; Joshi, P.K.; Karhunen, V.; Kleinman, A.; Levin, R.Z.; Lill, C.M.; Meddens, G.A.; Muntané, G.; Sanchez-Roige, S.; Rooij, F.J.; Taskesen, E.; Wu, Y.; Zhang, F.; Agee, M.; Alipanahi, B.; Bell, R.K.; Bryc, K.; Elson, S.L.; Furlotte, N.A.; Huber, K.E.; Litterman, N.K.; McCreight, J.C.; McIntyre, M.H.; Mountain, J.L.; Northover, C.A.M.; Pitts, S.J.; Sathirapongsasuti, J.F.; Sazonova, O.V.; Shelton, J.F.; Shringarpure, S.; Tian, C.; Tung, J.Y.; Vacic, V.; Wilson, C.H.; Agbessi, M.; Ahsan, H.; Alves, I.; Andiappan, A.; Awadalla, P.; Battle, A.; Beutner, F.; Jan, M.; Boomsma, D.I.; Christiansen, M.; Claringbould, A.; Deelen, P.; Esko, T.; Favé, M.-J.; Franke, L.; Frayling, T.; Gharib, S.A.; Gibson, G.; Heijmans, B.; Hemani, G.; Jansen, R.; Kähönen, M.; Kalnapenkis, A.; Kasela, S.; Kettunen, J.; Kim, Y.; Kirsten, H.; Kovacs, P.; Krohn, K.; Kronberg-Guzman, J.; Kukushkina, V.; Kutalik, Z.; Lee, B.; Lehtimäki, T.; Loeffler, M.; Marigorta, U.M.; Metspalu, A.; Milani, L.; Montgomery, G.W.; Müller-Nurasyid, M.; Nauck, M.; Penninx, B.; Perola, M.; Pervjakova, N.; Pierce, B.; Powell, J.; Prokisch, H.; Psaty, B.M.; Raitakari, O.; Ring, S.; Ripatti, S.; Rotzchke, O.; Rüeger, S.; Saha, A.; Scholz, M.; Schramm, K.; Seppälä, I.; Stumvoll, M.; Sullivan, P.; Hoen, P.-B.; Teumer, A.; Thiery, J.; Tong, L.; Tönjes, A.; Dongen, J.; Meurs, J.; Verlouw, J.; Visscher, P.M.; Völker, U.; Võsa, U.; Westra, H.-J.; Yaghootkar, Hanieh; Yang, J.; Zeng, B.; Beauchamp, J.P.; Lee, J.J.; Pers, T.H.; Turley, P.; Chen, G.-B.; Emilsson, V.; Oskarsson, S.; Pickrell, J.K.; Thom, K.; de, R.; Ahluwalia, T.S.; Bacelis, J.; Baumbach, C.; Bjornsdottir, G.; Brandsma, J.H.; Concas, M.P.; Derringer, J.; Galesloot, T.E.; Girotto, G.; Gupta, R.; Hall, L.M.; Harris, S.E.; Hofer, E.; Horikoshi, M.; Huffman, J.E.; Kaasik, K.; Kalafati, I.P.; Kong, A.; Lahti, J.; Lee, S.J.; de, C.; Lind, P.A.; Lindgren, K.-O.; Liu, T.; Mangino, M.; Marten, J.; Mihailov, E.; Miller, M.B.; Most, P.J.; Oldmeadow, C.; Payton, A.; Peyrot, W.J.; Qian, Y.; Rueedi, R.; Salvi, E.; Schmidt, B.; Schraut, K.E.; Shi, J.; Smith, A.V.; Poot, R.A.; Pourcain, B.S.; Thorleifsson, G.; Verweij, N.; Vuckovic, D.; Wellmann, J.; Zhao, W.; Zhu, Z.; Alizadeh, B.Z.; Amin, N.; Bakshi, A.; Baumeister, S.E.; Biino, G.; Bønnelykke, K.; Boyle, P.A.; Campbell, H.; Cappuccio, F.P.; Davies, G.; De, J.-E.; Deloukas, P.; Demuth, I.; Ding, J.; Eisele, L.; Eklund, N.; Evans, D.M.; Faul, J.D.; Feitosa, M.F.; Forstner, A.J.; Gandin, I.; Gunnarsson, B.; Halldórsson, B.V.; Harris, T.B.; Heath, A.C.; Hocking, L.J.; Holliday, E.G.; Homuth, G.; Horan, M.A.; Hottenga, J.-J.; de, P.L.; Jugessur, A.; Kaakinen, M.A.; Kanoni, S.; Keltigangas-Järvinen, L.; Kiemeney, L.A.L.M.; Kolcic, I.; Koskinen, S.; Kraja, A.T.; Kroh, M.; Latvala, A.; Launer, L.J.; Levinson, D.F.; Lichtenstein, P.; Lichtner, P.; Liewald, D.C.M.; Loukola, A.; Madden, P.A.; Mägi, R.; Mäki-Opas, T.; Marioni, R.E.; Marques-Vidal, P.; McMahon, G.; Meisinger, C.; Meitinger, T.; Milaneschi, Y.; Myhre, R.; Nelson, C.P.; Nyholt, D.R.; Ollier, W.E.R.; Palotie, A.; Paternoster, L.; Pedersen, N.L.; Petrovic, K.E.; Porteous, D.J.; Räikkönen, K.; Robino, A.; Rostapshova, O.; Rudan, I.; Rustichini, A.; Salomaa, V.; Sanders, A.R.; Sarin, A.-P.; Schmidt, H.; Scott, R.J.; Smith, B.H.; Smith, J.A.; Staessen, J.A.; Steinhagen-Thiessen, E.; Strauch, K.; Terracciano, A.; Tobin, M.D.; Ulivi, S.; Vaccargiu, S.; Quaye, L.; Venturini, C.; Vinkhuyzen, A.A.E.; Völzke, H.; Vonk, J.M.; Vozzi, D.; Waage, J.; Ware, E.B.; Willemsen, G.; Attia, J.R.; Bennett, D.A.; Berger, K.; Bertram, L.; Bisgaard, H.; Borecki, I.B.; Bültmann, U.; Chabris, C.F.; Cucca, F.; Cusi, D.; Deary, I.J.; Dedoussis, G.V.; Duijn, C.M.; Eriksson, J.G.; Franke, B.; Gasparini, P.; Gejman, P.V.; Gieger, C.; Grabe, H.-J.; Gratten, J.; Groenen, P.J.F.; Gudnason, V.; Harst, P.; Hayward, C.; Hinds, D.A.; Hoffmann, W.; Hyppönen, E.; Iacono, W.G.; Jacobsson, B.; Järvelin, M.-R.; Jöckel, K.-H.; Kaprio, J.; Kardia, S.L.R.; Lehrer, S.F.; Magnusson, P.K.E.; Martin, N.G.; McGue, M.; Pendleton, N.; Pirastu, N.; Pirastu, M.; Polasek, O.; Posthuma, D.; Power, C.; Province, M.A.; Samani, N.J.; Schlessinger, D.; Schmidt, R.; Sørensen, T.I.A.; Spector, T.D.; Stefansson, K.; Thorsteinsdottir, U.; Thurik, A.R.; Timpson, N.J.; Tiemeier, H.; Uitterlinden, A.G.; Vitart, V.; Vollenweider, P.; Weir, D.R.; Wilson, J.F.; Wright, A.F.; Conley, D.C.; Krueger, R.F.; Smith, G.D.; Hofman, A.; Laibson, D.I.; Medland, S.E.; Meyer, M.N.; Johannesson, M.; Koellinger, P.D.; Cesarini, D.; Benjamin, D.J.; Auton, A.; Boardman, J.D.; Clark, D.W.; Conlin, A.; Dolan, C.C.; Fischbacher, U.; Harris, K.M.; Hasler, G.; Ikram, M.A.; Jain, S.; Kessler, R.C.; Kooyman, M.; MacKillop, J.; Männikkö, M.; Morcillo-Suarez, C.; McQueen, M.B.; Schmidt, K.M.; Smart, M.C.; Sutter, M.; White, J.; Wit, H.; Fehr, E.; Kumari, M.; Navarro, A.; Palmer, A.A.; Schunk, D.; Stein, M.B.; Svento, R.; Timmers, P.R.H.J.; Ursano, R.J.; Wagner, G.G.

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

journal contribution

posted on 2024-07-25, 15:48 authored by R. Karlsson, P. Biroli, E. Kong, S.F.W. Meddens, R. Wedow, M.A. Fontana, M. Lebreton, S.P. Tino, A. Abdellaoui, A.R. Hammerschlag, M.G. Nivard, A. Okbay, C.A. Rietveld, P.N. Timshel, M. Trzaskowski, R. Vlaming, C.L. Zünd, Y. Bao, L. Buzdugan, A.H. Caplin, C.-Y. Chen, P. Eibich, P. Fontanillas, J.R. Gonzalez, P.K. Joshi, V. Karhunen, A. Kleinman, R.Z. Levin, C.M. Lill, G.A. Meddens, G. Muntané, S. Sanchez-Roige, F.J. Rooij, E. Taskesen, Y. Wu, F. Zhang, M. Agee, B. Alipanahi, R.K. Bell, K. Bryc, S.L. Elson, N.A. Furlotte, K.E. Huber, N.K. Litterman, J.C. McCreight, M.H. McIntyre, J.L. Mountain, C.A.M. Northover, S.J. Pitts, J.F. Sathirapongsasuti, O.V. Sazonova, J.F. Shelton, S. Shringarpure, C. Tian, J.Y. Tung, V. Vacic, C.H. Wilson, M. Agbessi, H. Ahsan, I. Alves, A. Andiappan, P. Awadalla, A. Battle, F. Beutner, M. Jan, D.I. Boomsma, M. Christiansen, A. Claringbould, P. Deelen, T. Esko, M.-J. Favé, L. Franke, T. Frayling, S.A. Gharib, G. Gibson, B. Heijmans, G. Hemani, R. Jansen, M. Kähönen, A. Kalnapenkis, S. Kasela, J. Kettunen, Y. Kim, H. Kirsten, P. Kovacs, K. Krohn, J. Kronberg-Guzman, V. Kukushkina, Z. Kutalik, B. Lee, T. Lehtimäki, M. Loeffler, U.M. Marigorta, A. Metspalu, L. Milani, G.W. Montgomery, M. Müller-Nurasyid, M. Nauck, B. Penninx, M. Perola, N. Pervjakova, B. Pierce, J. Powell, H. Prokisch, B.M. Psaty, O. Raitakari, S. Ring, S. Ripatti, O. Rotzchke, S. Rüeger, A. Saha, M. Scholz, K. Schramm, I. Seppälä, M. Stumvoll, P. Sullivan, P.-B. Hoen, A. Teumer, J. Thiery, L. Tong, A. Tönjes, J. Dongen, J. Meurs, J. Verlouw, P.M. Visscher, U. Völker, U. Võsa, H.-J. Westra, Hanieh YaghootkarHanieh Yaghootkar, J. Yang, B. Zeng, J.P. Beauchamp, J.J. Lee, T.H. Pers, P. Turley, G.-B. Chen, V. Emilsson, S. Oskarsson, J.K. Pickrell, K. Thom, R. de, T.S. Ahluwalia, J. Bacelis, C. Baumbach, G. Bjornsdottir, J.H. Brandsma, M.P. Concas, J. Derringer, T.E. Galesloot, G. Girotto, R. Gupta, L.M. Hall, S.E. Harris, E. Hofer, M. Horikoshi, J.E. Huffman, K. Kaasik, I.P. Kalafati, A. Kong, J. Lahti, S.J. Lee, C. de, P.A. Lind, K.-O. Lindgren, T. Liu, M. Mangino, J. Marten, E. Mihailov, M.B. Miller, P.J. Most, C. Oldmeadow, A. Payton, W.J. Peyrot, Y. Qian, R. Rueedi, E. Salvi, B. Schmidt, K.E. Schraut, J. Shi, A.V. Smith, R.A. Poot, B.S. Pourcain, G. Thorleifsson, N. Verweij, D. Vuckovic, J. Wellmann, W. Zhao, Z. Zhu, B.Z. Alizadeh, N. Amin, A. Bakshi, S.E. Baumeister, G. Biino, K. Bønnelykke, P.A. Boyle, H. Campbell, F.P. Cappuccio, G. Davies, J.-E. De, P. Deloukas, I. Demuth, J. Ding, L. Eisele, N. Eklund, D.M. Evans, J.D. Faul, M.F. Feitosa, A.J. Forstner, I. Gandin, B. Gunnarsson, B.V. Halldórsson, T.B. Harris, A.C. Heath, L.J. Hocking, E.G. Holliday, G. Homuth, M.A. Horan, J.-J. Hottenga, P.L. de, A. Jugessur, M.A. Kaakinen, S. Kanoni, L. Keltigangas-Järvinen, L.A.L.M. Kiemeney, I. Kolcic, S. Koskinen, A.T. Kraja, M. Kroh, A. Latvala, L.J. Launer, D.F. Levinson, P. Lichtenstein, P. Lichtner, D.C.M. Liewald, A. Loukola, P.A. Madden, R. Mägi, T. Mäki-Opas, R.E. Marioni, P. Marques-Vidal, G. McMahon, C. Meisinger, T. Meitinger, Y. Milaneschi, R. Myhre, C.P. Nelson, D.R. Nyholt, W.E.R. Ollier, A. Palotie, L. Paternoster, N.L. Pedersen, K.E. Petrovic, D.J. Porteous, K. Räikkönen, A. Robino, O. Rostapshova, I. Rudan, A. Rustichini, V. Salomaa, A.R. Sanders, A.-P. Sarin, H. Schmidt, R.J. Scott, B.H. Smith, J.A. Smith, J.A. Staessen, E. Steinhagen-Thiessen, K. Strauch, A. Terracciano, M.D. Tobin, S. Ulivi, S. Vaccargiu, L. Quaye, C. Venturini, A.A.E. Vinkhuyzen, H. Völzke, J.M. Vonk, D. Vozzi, J. Waage, E.B. Ware, G. Willemsen, J.R. Attia, D.A. Bennett, K. Berger, L. Bertram, H. Bisgaard, I.B. Borecki, U. Bültmann, C.F. Chabris, F. Cucca, D. Cusi, I.J. Deary, G.V. Dedoussis, C.M. Duijn, J.G. Eriksson, B. Franke, P. Gasparini, P.V. Gejman, C. Gieger, H.-J. Grabe, J. Gratten, P.J.F. Groenen, V. Gudnason, P. Harst, C. Hayward, D.A. Hinds, W. Hoffmann, E. Hyppönen, W.G. Iacono, B. Jacobsson, M.-R. Järvelin, K.-H. Jöckel, J. Kaprio, S.L.R. Kardia, S.F. Lehrer, P.K.E. Magnusson, N.G. Martin, M. McGue, N. Pendleton, N. Pirastu, M. Pirastu, O. Polasek, D. Posthuma, C. Power, M.A. Province, N.J. Samani, D. Schlessinger, R. Schmidt, T.I.A. Sørensen, T.D. Spector, K. Stefansson, U. Thorsteinsdottir, A.R. Thurik, N.J. Timpson, H. Tiemeier, A.G. Uitterlinden, V. Vitart, P. Vollenweider, D.R. Weir, J.F. Wilson, A.F. Wright, D.C. Conley, R.F. Krueger, G.D. Smith, A. Hofman, D.I. Laibson, S.E. Medland, M.N. Meyer, M. Johannesson, P.D. Koellinger, D. Cesarini, D.J. Benjamin, A. Auton, J.D. Boardman, D.W. Clark, A. Conlin, C.C. Dolan, U. Fischbacher, K.M. Harris, G. Hasler, M.A. Ikram, S. Jain, R.C. Kessler, M. Kooyman, J. MacKillop, M. Männikkö, C. Morcillo-Suarez, M.B. McQueen, K.M. Schmidt, M.C. Smart, M. Sutter, J. White, H. Wit, E. Fehr, M. Kumari, A. Navarro, A.A. Palmer, D. Schunk, M.B. Stein, R. Svento, P.R.H.J. Timmers, R.J. Ursano, G.G. Wagner

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated (∣r̂ g∣ ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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School of Chemistry (Research Outputs)

Publication Title

Nature Genetics

Volume

51

Issue

2

Pages/Article Number

245-257

Publisher

Nature Research

External DOI

https://www.doi.org/10.1038/s41588-018-0309-3

ISSN

10614036

Date Accepted

2018-11-07

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

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