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2. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

Author

Sherr, Elliott, Mukherjee, Pratik, Nagarajan, Srikantan, Marco, Elysa, Zufferey, F, Sherr, EH, Beckmann, ND, Hanson, E, Maillard, AM, Hippolyte, L, Macé, A, Ferrari, C, Kutalik, Z, and Andrieux, J

Abstract

Background The recurrent ~ 600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural

Published
2012

5. Meta-analysis of genome-wide association studies of anxiety disorders

Author

Otowa, T, Hek, K, Lee, M, Byrne, E M, Mirza, S S, Nivard, M G, Bigdeli, T, Aggen, S H, Adkins, D, Wolen, A, Fanous, A, Keller, M C, Castelao, E, Kutalik, Z, der Auwera, S V, Homuth, G, Nauck, M, Teumer, A, Milaneschi, Y, Hottenga, J-J, Direk, N, Hofman, A, Uitterlinden, A, Mulder, C L, Henders, A K, Medland, S E, Gordon, S, Heath, A C, Madden, P A F, Pergadia, M L, van der Most, P J, Nolte, I M, van Oort, F V A, Hartman, C A, Oldehinkel, A J, Preisig, M, Grabe, H J, Middeldorp, C M, Penninx, B W J H, Boomsma, D, Martin, N G, Montgomery, G, Maher, B S, van den Oord, E J, Wray, N R, Tiemeier, H, and Hettema, J M

Published
2016
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7. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Author

Wang, Zhe, Emmerich, A., Pillon, N.J., Moore, T., Hemerich, D., Cornelis, M.C., Mazzaferro, E., Broos, S., Ahluwalia, T.S., Bartz, T.M., Bentley, A.R., Bielak, L.F., Chong, M., Chu, A.Y., Berry, D., Dorajoo, R., Dueker, N.D., Kasbohm, E., Feenstra, B., Feitosa, M.F., Gieger, C., Graff, M, Hall, L.M., Haller, T., Hartwig, F.P., Hillis, D.A., Huikari, V., Heard-Costa, N., Holzapfel, C., Jackson, A.U., Johansson, Å., Jørgensen, A.M., Kaakinen, M.A., Karlsson, R., Kerr, K.F., Kim, Boram, Koolhaas, C.M., Kutalik, Z., Lagou, V., Lind, P.A., Lorentzon, M., Lyytikäinen, L.P., Mangino, M., Metzendorf, C., Monroe, K.R., Pacolet, A., Pérusse, L., Pool, R., Richmond, R.C., Rivera, N.V., Robiou-du-Pont, S., Schraut, K.E., Schulz, C.A., Stringham, H.M., Tanaka, T., Teumer, A., Turman, C., Most, P.J. van der, Vanmunster, M., Rooij, F.J. van, Vliet-Ostaptchouk, J.V. Van, Zhang, Xiaoshuai, Zhao, J.H., Zhao, W, Balkhiyarova, Z., Balslev-Harder, M.N., Baumeister, S.E., Beilby, J., Blangero, J., Boomsma, D.I., Brage, S., Braund, P.S., Brody, J.A., Bruinenberg, M., Ekelund, U., Liu, C.T., Cole, J.W., Collins, F.S., Cupples, L.A., Esko, T., Enroth, S., Faul, J.D., Fernandez-Rhodes, L., Fohner, A.E., Franco, O.H., Galesloot, T.E., Gordon, S.D.S., Grarup, N., Hartman, C.A., Heiss, G., Hui, J., Illig, T., Jago, R., James, A., Joshi, P.K., Jung, T., Kähönen, M., Kilpeläinen, T.O., Koh, W.P., Kolcic, I., Kiemeney, L.A.L.M., Loos, R.J.F., Hoed, Marcel Den, Wang, Zhe, Emmerich, A., Pillon, N.J., Moore, T., Hemerich, D., Cornelis, M.C., Mazzaferro, E., Broos, S., Ahluwalia, T.S., Bartz, T.M., Bentley, A.R., Bielak, L.F., Chong, M., Chu, A.Y., Berry, D., Dorajoo, R., Dueker, N.D., Kasbohm, E., Feenstra, B., Feitosa, M.F., Gieger, C., Graff, M, Hall, L.M., Haller, T., Hartwig, F.P., Hillis, D.A., Huikari, V., Heard-Costa, N., Holzapfel, C., Jackson, A.U., Johansson, Å., Jørgensen, A.M., Kaakinen, M.A., Karlsson, R., Kerr, K.F., Kim, Boram, Koolhaas, C.M., Kutalik, Z., Lagou, V., Lind, P.A., Lorentzon, M., Lyytikäinen, L.P., Mangino, M., Metzendorf, C., Monroe, K.R., Pacolet, A., Pérusse, L., Pool, R., Richmond, R.C., Rivera, N.V., Robiou-du-Pont, S., Schraut, K.E., Schulz, C.A., Stringham, H.M., Tanaka, T., Teumer, A., Turman, C., Most, P.J. van der, Vanmunster, M., Rooij, F.J. van, Vliet-Ostaptchouk, J.V. Van, Zhang, Xiaoshuai, Zhao, J.H., Zhao, W, Balkhiyarova, Z., Balslev-Harder, M.N., Baumeister, S.E., Beilby, J., Blangero, J., Boomsma, D.I., Brage, S., Braund, P.S., Brody, J.A., Bruinenberg, M., Ekelund, U., Liu, C.T., Cole, J.W., Collins, F.S., Cupples, L.A., Esko, T., Enroth, S., Faul, J.D., Fernandez-Rhodes, L., Fohner, A.E., Franco, O.H., Galesloot, T.E., Gordon, S.D.S., Grarup, N., Hartman, C.A., Heiss, G., Hui, J., Illig, T., Jago, R., James, A., Joshi, P.K., Jung, T., Kähönen, M., Kilpeläinen, T.O., Koh, W.P., Kolcic, I., Kiemeney, L.A.L.M., Loos, R.J.F., and Hoed, Marcel Den

Abstract

Contains fulltext : 282313.pdf (Publisher’s version ) (Open Access), 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 II(A) 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

8. Gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis.

Author

Pistis, G, Vázquez-Bourgon, J, Fournier, M, Jenni, R, Cleusix, M, Papiol, S, Smart, SE, Pardiñas, AF, Walters, JTR, MacCabe, JH, Kutalik, Z, Conus, P, Crespo-Facorro, B, Q Do, K, Pistis, G, Vázquez-Bourgon, J, Fournier, M, Jenni, R, Cleusix, M, Papiol, S, Smart, SE, Pardiñas, AF, Walters, JTR, MacCabe, JH, Kutalik, Z, Conus, P, Crespo-Facorro, B, and Q Do, K

Abstract

Polygenic risk prediction remains an important aim of genetic association studies. Currently, the predictive power of schizophrenia polygenic risk scores (PRSs) is not large enough to allow highly accurate discrimination between cases and controls and thus is not adequate for clinical integration. Since PRSs are rarely used to reveal biological functions or to validate candidate pathways, to fill this gap, we investigated whether their predictive ability could be improved by building genome-wide (GW-PRSs) and pathway-specific PRSs, using distance- or expression quantitative trait loci (eQTLs)- based mapping between genetic variants and genes. We focused on five pathways (glutamate, oxidative stress, GABA/interneurons, neuroimmune/neuroinflammation and myelin) which belong to a critical hub of schizophrenia pathophysiology, centred on redox dysregulation/oxidative stress. Analyses were first performed in the Lausanne Treatment and Early Intervention in Psychosis Program (TIPP) study (n = 340, cases/controls: 208/132), a sample of first-episode of psychosis patients and matched controls, and then validated in an independent study, the epidemiological and longitudinal intervention program of First-Episode Psychosis in Cantabria (PAFIP) (n = 352, 224/128). Our results highlighted two main findings. First, GW-PRSs for schizophrenia were significantly associated with early psychosis status. Second, oxidative stress was the only significantly associated pathway that showed an enrichment in both the TIPP (p = 0.03) and PAFIP samples (p = 0.002), and exclusively when gene-variant linking was done using eQTLs. The results suggest that the predictive accuracy of polygenic risk scores could be improved with the inclusion of information from functional annotations, and through a focus on specific pathways, emphasizing the need to build and study functionally informed risk scores.

Published
2022

9. A saturated map of common genetic variants associated with human height

Author

Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, A, Kovacs, P, Kraaijeveld, A, Kraft, P, Krauss, RM, Kumari, M, Kutalik, Z, Laakso, M, Lange, LA, Langenberg, C, Launer, LJ, Le Marchand, L, Lee, H, Lee, NR, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, D, Metspalu, A, Mitchell, BD, Mitchell, P, Mook-Kanamori, DO, Morris, AD, Mucci, LA, Munroe, PB, Nalls, MA, Nazarian, S, Nelson, AE, Neville, MJ, Newton-Cheh, C, Nielsen, CS, Nothen, MM, Ohlsson, C, Oldehinkel, AJ, Orozco, L, Pahkala, K, Pajukanta, P, Palmer, CNA, Parra, EJ, Pattaro, C, Pedersen, O, Pennell, CE, Penninx, BWJH, Perusse, L, Peters, A, Peyser, PA, Porteous, DJ, Posthuma, D, Power, C, Pramstaller, PP, Province, MA, Qi, Q, Qu, J, Rader, DJ, Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, Hirschhorn, JN, Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, A, Kovacs, P, Kraaijeveld, A, Kraft, P, Krauss, RM, Kumari, M, Kutalik, Z, Laakso, M, Lange, LA, Langenberg, C, Launer, LJ, Le Marchand, L, Lee, H, Lee, NR, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, D, Metspalu, A, Mitchell, BD, Mitchell, P, Mook-Kanamori, DO, Morris, AD, Mucci, LA, Munroe, PB, Nalls, MA, Nazarian, S, Nelson, AE, Neville, MJ, Newton-Cheh, C, Nielsen, CS, Nothen, MM, Ohlsson, C, Oldehinkel, AJ, Orozco, L, Pahkala, K, Pajukanta, P, Palmer, CNA, Parra, EJ, Pattaro, C, Pedersen, O, Pennell, CE, Penninx, BWJH, Perusse, L, Peters, A, Peyser, PA, Porteous, DJ, Posthuma, D, Power, C, Pramstaller, PP, Province, MA, Qi, Q, Qu, J, Rader, DJ, Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, and Hirschhorn, JN

Abstract

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Published
2022

10. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

Author

Cornelis, M C, Byrne, E M, Esko, T, Nalls, M A, Ganna, A, Paynter, N, Monda, K L, Amin, N, Fischer, K, Renstrom, F, Ngwa, J S, Huikari, V, Cavadino, A, Nolte, I M, Teumer, A, Yu, K, Marques-Vidal, P, Rawal, R, Manichaikul, A, Wojczynski, M K, Vink, J M, Zhao, J H, Burlutsky, G, Lahti, J, Mikkilä, V, Lemaitre, R N, Eriksson, J, Musani, S K, Tanaka, T, Geller, F, Luan, J, Hui, J, Mägi, R, Dimitriou, M, Garcia, M E, Ho, W-K, Wright, M J, Rose, L M, Magnusson, P K E, Pedersen, N L, Couper, D, Oostra, B A, Hofman, A, Ikram, M A, Tiemeier, H W, Uitterlinden, A G, van Rooij, F J A, Barroso, I, Johansson, I, Xue, L, Kaakinen, M, Milani, L, Power, C, Snieder, H, Stolk, R P, Baumeister, S E, Biffar, R, Gu, F, Bastardot, F, Kutalik, Z, Jacobs, Jr, D R, Forouhi, N G, Mihailov, E, Lind, L, Lindgren, C, Michaëlsson, K, Morris, A, Jensen, M, Khaw, K-T, Luben, R N, Wang, J J, Männistö, S, Perälä, M-M, Kähönen, M, Lehtimäki, T, Viikari, J, Mozaffarian, D, Mukamal, K, Psaty, B M, Döring, A, Heath, A C, Montgomery, G W, Dahmen, N, Carithers, T, Tucker, K L, Ferrucci, L, Boyd, H A, Melbye, M, Treur, J L, Mellström, D, Hottenga, J J, Prokopenko, I, Tönjes, A, Deloukas, P, Kanoni, S, Lorentzon, M, Houston, D K, Liu, Y, Danesh, J, Rasheed, A, Mason, M A, Zonderman, A B, Franke, L, Kristal, B S, Karjalainen, J, Reed, D R, Westra, H-J, Evans, M K, Saleheen, D, Harris, T B, Dedoussis, G, Curhan, G, Stumvoll, M, Beilby, J, Pasquale, L R, Feenstra, B, Bandinelli, S, Ordovas, J M, Chan, A T, Peters, U, Ohlsson, C, Gieger, C, Martin, N G, Waldenberger, M, Siscovick, D S, Raitakari, O, Eriksson, J G, Mitchell, P, Hunter, D J, Kraft, P, Rimm, E B, Boomsma, D I, Borecki, I B, Loos, R J F, Wareham, N J, Vollenweider, P, Caporaso, N, Grabe, H J, Neuhouser, M L, Wolffenbuttel, B H R, Hu, F B, Hyppönen, E, Järvelin, M-R, Cupples, L A, Franks, P W, Ridker, P M, van Duijn, C M, Heiss, G, Metspalu, A, North, K E, Ingelsson, E, Nettleton, J A, van Dam, R M, and Chasman, D I

Published
2015
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11. The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia Predisposition in Chromosome 16p11.2 Autism Individuals

Author

Giannuzzi, G., Schmidt, P. J., Porcu, E., Willemin, G., Munson, K. M., Nuttle, X., Earl, R., Chrast, J., Hoekzema, K., Risso, D., Mannik, K., De Nittis, P., Baratz, E. D., Attanasio, C., Martin, S., Jacquemont, S., Bottani, A., Gerard, M., Weber, S., Jacquette, A., Lesne, F., Isidor, B., Le Caignec, C., Nizon, M., Vincent-Delorme, C., Gilbert-Dussardier, B., Curro`, A., Renieri, A., Giachino, D., Brusco, A., Herault, Y., Gao, X., Philpott, C. C., Bernier, R. A., Kutalik, Z., Fleming, M. D., Eichler, E. E., Reymond, A., Chercheur indépendant, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Weill Medical College of Cornell University [New York], University of Tartu, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Christian Albrechts University, Department of Psychiatry and Behavioral Sciences, Department of Medical Genetics, Université de Lausanne (UNIL), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), and Université de Lausanne (UNIL)-Université de Lausanne (UNIL)

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Chromosome Disorders, 0302 clinical medicine, Chromosome Duplication, Gene duplication, Homeostasis, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), 2. Zero hunger, Genetics, iron deficiency anemia, medicine.diagnostic_test, Microcytosis, Anemia, Iron deficiency, 3. Good health, BOLA2, Phenotype, medicine.anatomical_structure, Serum iron, Female, Chromosome Deletion, Heterozygote, DNA Copy Number Variations, Genotype, 16p11.2 copy number variants, Iron, Biology, Article, 03 medical and health sciences, human evolution, gene duplication, human-specific segmental duplications, medicine, Animals, Humans, Autistic Disorder, [SDV.GEN]Life Sciences [q-bio]/Genetics, Proteins, medicine.disease, Red blood cell, 030104 developmental biology, Iron-deficiency anemia, Hemoglobin, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery
Abstract

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4–BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4–BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e−7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2(+/−) and Bola2(−/−) animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency.

Published
2019

13. Limited evidence for blood eQTLs in human sexual dimorphism

Author

Porcu, E., Claringbould, A., Weihs, A., Lepik, K., Richardson, T.G., Völker, U., Santoni, F.A., Teumer, A., Franke, L., Reymond, A., Kutalik, Z., Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and BIOS Consortium

Subjects
Male, Sex Characteristics, OBJECTIVES, VARIANT, Quantitative Trait Loci, ROTTERDAM, BIOBANK, Polymorphism, Single Nucleotide, Female, Genome-Wide Association Study/methods, Humans, Transcriptome, RESOURCE, OBESITY, GWAS, INTEGRATION, TRAITS, GENE-EXPRESSION, Genome-Wide Association Study
Abstract

Background: The genetic underpinning of sexual dimorphism is very poorly understood. The prevalence of many diseases differs between men and women, which could be in part caused by sex-specific genetic effects. Nevertheless, only a few published genome-wide association studies (GWAS) were performed separately in each sex. The reported enrichment of expression quantitative trait loci (eQTLs) among GWAS-associated SNPs suggests a potential role of sex-specific eQTLs in the sex-specific genetic mechanism underlying complex traits. Methods: To explore this scenario, we combined sex-specific whole blood RNA-seq eQTL data from 3447 European individuals included in BIOS Consortium and GWAS data from UK Biobank. Next, to test the presence of sex-biased causal effect of gene expression on complex traits, we performed sex-specific transcriptome-wide Mendelian randomization (TWMR) analyses on the two most sexually dimorphic traits, waist-to-hip ratio (WHR) and testosterone levels. Finally, we performed power analysis to calculate the GWAS sample size needed to observe sex-specific trait associations driven by sex-biased eQTLs. Results: Among 9 million SNP-gene pairs showing sex-combined associations, we found 18 genes with significant sex-biased cis-eQTLs (FDR 5%). Our phenome-wide association study of the 18 top sex-biased eQTLs on >700 traits unraveled that these eQTLs do not systematically translate into detectable sex-biased trait-associations. In addition, we observed that sex-specific causal effects of gene expression on complex traits are not driven by sex-specific eQTLs. Power analyses using real eQTL- and causal-effect sizes showed that millions of samples would be necessary to observe sex-biased trait associations that are fully driven by sex-biased cis-eQTLs. Compensatory effects may further hamper their detection. Conclusions: Our results suggest that sex-specific eQTLs in whole blood do not translate to detectable sex-specific trait associations of complex diseases, and vice versa that the observed sex-specific trait associations cannot be explained by sex-specific eQTLs.

Published
2021

15. Assessment of network module identification across complex diseases

Author

Choobdar, S, Ahsen, M, Crawford, J, Tomasoni, M, Fang, T, Lamparter, D, Lin, J, Hescott, B, Hu, X, Mercer, J, Natoli, T, Narayan, R, Aicheler, F, Amoroso, N, Arenas, A, Azhagesan, K, Baker, A, Banf, M, Batzoglou, S, Baudot, A, Bellotti, R, Bergmann, S, Boroevich, K, Brun, C, Cai, S, Caldera, M, Calderone, A, Cesareni, G, Chen, W, Chichester, C, Cowen, L, Cui, H, Dao, P, De Domenico, M, Dhroso, A, Didier, G, Divine, M, del Sol, A, Feng, X, Flores-Canales, J, Fortunato, S, Gitter, A, Gorska, A, Guan, Y, Guenoche, A, Gomez, S, Hamza, H, Hartmann, A, He, S, Heijs, A, Heinrich, J, Hu, Y, Huang, X, Hughitt, V, Jeon, M, Jeub, L, Johnson, N, Joo, K, Joung, I, Jung, S, Kalko, S, Kamola, P, Kang, J, Kaveelerdpotjana, B, Kim, M, Kim, Y, Kohlbacher, O, Korkin, D, Krzysztof, K, Kunji, K, Kutalik, Z, Lage, K, Lang-Brown, S, Le, T, Lee, J, Lee, S, Li, D, Li, J, Liu, L, Loizou, A, Luo, Z, Lysenko, A, Ma, T, Mall, R, Marbach, D, Mattia, T, Medvedovic, M, Menche, J, Micarelli, E, Monaco, A, Muller, F, Narykov, O, Norman, T, Park, S, Perfetto, L, Perrin, D, Pirro, S, Przytycka, T, Qian, X, Raman, K, Ramazzotti, D, Ramsahai, E, Ravindran, B, Rennert, P, Saez-Rodriguez, J, Scharfe, C, Sharan, R, Shi, N, Shin, W, Shu, H, Sinha, H, Slonim, D, Spinelli, L, Srinivasan, S, Subramanian, A, Suver, C, Szklarczyk, D, Tangaro, S, Thiagarajan, S, Tichit, L, Tiede, T, Tripathi, B, Tsherniak, A, Tsunoda, T, Turei, D, Ullah, E, Vahedi, G, Valdeolivas, A, Vivek, J, von Mering, C, Waagmeester, A, Wang, B, Wang, Y, Weir, B, White, S, Winkler, S, Xu, K, Xu, T, Yan, C, Yang, L, Yu, K, Yu, X, Zaffaroni, G, Zaslavskiy, M, Zeng, T, Zhang, J, Zhang, L, Zhang, W, Zhang, X, Zhou, X, Zhou, J, Zhu, H, Zhu, J, Zuccon, G, Stolovitzky, G, Choobdar S., Ahsen M. E., Crawford J., Tomasoni M., Fang T., Lamparter D., Lin J., Hescott B., Hu X., Mercer J., Natoli T., Narayan R., Aicheler F., Amoroso N., Arenas A., Azhagesan K., Baker A., Banf M., Batzoglou S., Baudot A., Bellotti R., Bergmann S., Boroevich K. A., Brun C., Cai S., Caldera M., Calderone A., Cesareni G., Chen W., Chichester C., Cowen L., Cui H., Dao P., De Domenico M., Dhroso A., Didier G., Divine M., del Sol A., Feng X., Flores-Canales J. C., Fortunato S., Gitter A., Gorska A., Guan Y., Guenoche A., Gomez S., Hamza H., Hartmann A., He S., Heijs A., Heinrich J., Hu Y., Huang X., Hughitt V. K., Jeon M., Jeub L., Johnson N. T., Joo K., Joung I. S., Jung S., Kalko S. G., Kamola P. J., Kang J., Kaveelerdpotjana B., Kim M., Kim Y. -A., Kohlbacher O., Korkin D., Krzysztof K., Kunji K., Kutalik Z., Lage K., Lang-Brown S., Le T. D., Lee J., Lee S., Li D., Li J., Liu L., Loizou A., Luo Z., Lysenko A., Ma T., Mall R., Marbach D., Mattia T., Medvedovic M., Menche J., Micarelli E., Monaco A., Muller F., Narykov O., Norman T., Park S., Perfetto L., Perrin D., Pirro S., Przytycka T. M., Qian X., Raman K., Ramazzotti D., Ramsahai E., Ravindran B., Rennert P., Saez-Rodriguez J., Scharfe C., Sharan R., Shi N., Shin W., Shu H., Sinha H., Slonim D. K., Spinelli L., Srinivasan S., Subramanian A., Suver C., Szklarczyk D., Tangaro S., Thiagarajan S., Tichit L., Tiede T., Tripathi B., Tsherniak A., Tsunoda T., Turei D., Ullah E., Vahedi G., Valdeolivas A., Vivek J., von Mering C., Waagmeester A., Wang B., Wang Y., Weir B. A., White S., Winkler S., Xu K., Xu T., Yan C., Yang L., Yu K., Yu X., Zaffaroni G., Zaslavskiy M., Zeng T., Zhang J. D., Zhang L., Zhang W., Zhang X., Zhang J., Zhou X., Zhou J., Zhu H., Zhu J., Zuccon G., Stolovitzky G., Cowen L. J., Choobdar, S, Ahsen, M, Crawford, J, Tomasoni, M, Fang, T, Lamparter, D, Lin, J, Hescott, B, Hu, X, Mercer, J, Natoli, T, Narayan, R, Aicheler, F, Amoroso, N, Arenas, A, Azhagesan, K, Baker, A, Banf, M, Batzoglou, S, Baudot, A, Bellotti, R, Bergmann, S, Boroevich, K, Brun, C, Cai, S, Caldera, M, Calderone, A, Cesareni, G, Chen, W, Chichester, C, Cowen, L, Cui, H, Dao, P, De Domenico, M, Dhroso, A, Didier, G, Divine, M, del Sol, A, Feng, X, Flores-Canales, J, Fortunato, S, Gitter, A, Gorska, A, Guan, Y, Guenoche, A, Gomez, S, Hamza, H, Hartmann, A, He, S, Heijs, A, Heinrich, J, Hu, Y, Huang, X, Hughitt, V, Jeon, M, Jeub, L, Johnson, N, Joo, K, Joung, I, Jung, S, Kalko, S, Kamola, P, Kang, J, Kaveelerdpotjana, B, Kim, M, Kim, Y, Kohlbacher, O, Korkin, D, Krzysztof, K, Kunji, K, Kutalik, Z, Lage, K, Lang-Brown, S, Le, T, Lee, J, Lee, S, Li, D, Li, J, Liu, L, Loizou, A, Luo, Z, Lysenko, A, Ma, T, Mall, R, Marbach, D, Mattia, T, Medvedovic, M, Menche, J, Micarelli, E, Monaco, A, Muller, F, Narykov, O, Norman, T, Park, S, Perfetto, L, Perrin, D, Pirro, S, Przytycka, T, Qian, X, Raman, K, Ramazzotti, D, Ramsahai, E, Ravindran, B, Rennert, P, Saez-Rodriguez, J, Scharfe, C, Sharan, R, Shi, N, Shin, W, Shu, H, Sinha, H, Slonim, D, Spinelli, L, Srinivasan, S, Subramanian, A, Suver, C, Szklarczyk, D, Tangaro, S, Thiagarajan, S, Tichit, L, Tiede, T, Tripathi, B, Tsherniak, A, Tsunoda, T, Turei, D, Ullah, E, Vahedi, G, Valdeolivas, A, Vivek, J, von Mering, C, Waagmeester, A, Wang, B, Wang, Y, Weir, B, White, S, Winkler, S, Xu, K, Xu, T, Yan, C, Yang, L, Yu, K, Yu, X, Zaffaroni, G, Zaslavskiy, M, Zeng, T, Zhang, J, Zhang, L, Zhang, W, Zhang, X, Zhou, X, Zhou, J, Zhu, H, Zhu, J, Zuccon, G, Stolovitzky, G, Choobdar S., Ahsen M. E., Crawford J., Tomasoni M., Fang T., Lamparter D., Lin J., Hescott B., Hu X., Mercer J., Natoli T., Narayan R., Aicheler F., Amoroso N., Arenas A., Azhagesan K., Baker A., Banf M., Batzoglou S., Baudot A., Bellotti R., Bergmann S., Boroevich K. A., Brun C., Cai S., Caldera M., Calderone A., Cesareni G., Chen W., Chichester C., Cowen L., Cui H., Dao P., De Domenico M., Dhroso A., Didier G., Divine M., del Sol A., Feng X., Flores-Canales J. C., Fortunato S., Gitter A., Gorska A., Guan Y., Guenoche A., Gomez S., Hamza H., Hartmann A., He S., Heijs A., Heinrich J., Hu Y., Huang X., Hughitt V. K., Jeon M., Jeub L., Johnson N. T., Joo K., Joung I. S., Jung S., Kalko S. G., Kamola P. J., Kang J., Kaveelerdpotjana B., Kim M., Kim Y. -A., Kohlbacher O., Korkin D., Krzysztof K., Kunji K., Kutalik Z., Lage K., Lang-Brown S., Le T. D., Lee J., Lee S., Li D., Li J., Liu L., Loizou A., Luo Z., Lysenko A., Ma T., Mall R., Marbach D., Mattia T., Medvedovic M., Menche J., Micarelli E., Monaco A., Muller F., Narykov O., Norman T., Park S., Perfetto L., Perrin D., Pirro S., Przytycka T. M., Qian X., Raman K., Ramazzotti D., Ramsahai E., Ravindran B., Rennert P., Saez-Rodriguez J., Scharfe C., Sharan R., Shi N., Shin W., Shu H., Sinha H., Slonim D. K., Spinelli L., Srinivasan S., Subramanian A., Suver C., Szklarczyk D., Tangaro S., Thiagarajan S., Tichit L., Tiede T., Tripathi B., Tsherniak A., Tsunoda T., Turei D., Ullah E., Vahedi G., Valdeolivas A., Vivek J., von Mering C., Waagmeester A., Wang B., Wang Y., Weir B. A., White S., Winkler S., Xu K., Xu T., Yan C., Yang L., Yu K., Yu X., Zaffaroni G., Zaslavskiy M., Zeng T., Zhang J. D., Zhang L., Zhang W., Zhang X., Zhang J., Zhou X., Zhou J., Zhu H., Zhu J., Zuccon G., Stolovitzky G., and Cowen L. J.

Abstract

Many bioinformatics methods have been proposed for reducing the complexity of large gene or protein networks into relevant subnetworks or modules. Yet, how such methods compare to each other in terms of their ability to identify disease-relevant modules in different types of network remains poorly understood. We launched the ‘Disease Module Identification DREAM Challenge’, an open competition to comprehensively assess module identification methods across diverse protein–protein interaction, signaling, gene co-expression, homology and cancer-gene networks. Predicted network modules were tested for association with complex traits and diseases using a unique collection of 180 genome-wide association studies. Our robust assessment of 75 module identification methods reveals top-performing algorithms, which recover complementary trait-associated modules. We find that most of these modules correspond to core disease-relevant pathways, which often comprise therapeutic targets. This community challenge establishes biologically interpretable benchmarks, tools and guidelines for molecular network analysis to study human disease biology.

Published
2019

16. Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults A 2-Sample Mendelian Randomization Study

Author

Choi, K.W., Chen, C.Y., Stein, M.B., Klimentidis, Y.C., Wang, M.J., Koenen, K.C., Smoller, J.W., Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Agerbo, E., Air, T., Andlauer, T.F.M., Bacanu, S.A., Baekvad-Hansen, M., Beekman, A.T.F., Bigdeli, T.B., Binder, E.B., Blackwood, D.H.R., Bryois, J., Buttenschon, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Hvarregaard, J., Christensen, J.H., Clarke, T.K., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, F.F.H., Finucane, H.K., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hall, L.S., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Ising, M., Jansen, R., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W., Krogh, J., Kutalik, Z., Li, Y.H., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Marchini, J., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., O'Reilly, P.F., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Saeed, S., Schoevers, R., Schulte, E.C., Shen, L., Shi, J.X., Shyn, S.I., Sigurdsson, E., Sinnamon, G.C.B., Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Auwera, S. van der, Hemert, A.M. van, Viktorin, A., Visscher, P.M., Wang, Y.P., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.L.S., Yang, J., Zhang, F.T., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., Geus, E.J.C. de, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.Q.S., Lucae, S., Madden, P.A.F., Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Mors, O., Mortensen, P.B., Nordentoft, M., Nothen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, B.W.J.H., Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Stefansson, K., Tiemeier, H., Uher, R., Volzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Breen, G., Borglum, A.D., Sullivan, P.F., Major Depressive Disorder Working, Epidemiology, Internal Medicine, Child and Adolescent Psychiatry / Psychology, Psychiatry, Biological Psychology, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, and Adult Psychiatry

Subjects
Adult, DISORDER, medicine.medical_specialty, Genome-wide association study, EXERCISE, CAUSALITY, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, PEOPLE, Internal medicine, Accelerometry, Mendelian randomization, SCHIZOPHRENIA, Humans, Medicine, ANXIETY, Exercise, RISK, Depressive Disorder, Major, business.industry, Case-control study, SEDENTARY BEHAVIOR, Mendelian Randomization Analysis, Odds ratio, ASSOCIATION, Protective Factors, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Sample size determination, Case-Control Studies, Meta-analysis, Major depressive disorder, Self Report, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Importance: Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity.Objective: To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference.Design, Setting, and Participants: This 2-sample mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes-self-reported (n = 377 234) and objective accelerometer-based (n = 91 084)-and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in diverse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR-Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018.Main Outcomes and Measures: MDD and physical activity.Results: GWAS summary data were available for a combined sample size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [OR], 0.74 for MDD per 1-SD increase in mean acceleration; 95% CI, 0.59-0.92; P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (β = -0.08 in mean acceleration per MDD vs control status; 95% CI, -0.47 to 0.32; P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity; 95% CI, 0.57-3.37; P = .48), or between MDD and self-reported activity (β = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status; 95% CI, -0.008 to 0.05; P = .15).Conclusions and Relevance: Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed-but not self-reported-physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression.

Published
2019

19. Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Author

Ahluwalia, T.S., Prins, B.P., Abdollahi, M., Armstrong, N.J., Aslibekyan, S., Bain, L., Jefferis, B., Baumert, J., Beekman, M., Ben-Shlomo, Y., Bis, J.C., Mitchell, B.D., Geus, E. de, Delgado, G.E., Marek, D., Eriksson, J., Kajantie, E., Kanoni, S., Kemp, J.P., Lu, C., Marioni, R.E., McLachlan, S., Milaneschi, Y., Nolte, I.M., Petrelis, A.M., Porcu, E., Sabater-Lleal, M., Naderi, E., Seppala, I., Shah, T., Singhal, G., Standl, M., Teumer, A., Thalamuthu, A., Thiering, E., Trompet, S., Ballantyne, C.M., Benjamin, E.J., Casas, J.P., Toben, C., Dedoussis, G., Deelen, J., Durda, P., Engmann, J., Feitosa, M.F., Grallert, H., Hammarstedt, A., Harris, S.E., Homuth, G., Hottenga, J.J., Jalkanen, S., Jamshidi, Y., Jawahar, M.C., Jess, T., Kivimaki, M., Kleber, M.E., Lahti, J., Liu, Y., Marques-Vidal, P., Mellstrom, D., Mooijaart, S.P., Muller-Nurasyid, M., Penninx, B., Revez, J.A., Rossing, P., Raikkonen, K., Sattar, N., Scharnagl, H., Sennblad, B., Silveira, A., St Pourcain, B., Timpson, N.J., Trollor, J., Dongen, J. van, Heemst, D. van, Visvikis-Siest, S., Vollenweider, P., Volker, U., Waldenberger, M., Willemsen, G., Zabaneh, D., Morris, R.W., Arnett, D.K., Baune, B.T., Boomsma, D.I., Chang, Y.P.C., Deary, I.J., Deloukas, P., Eriksson, J.G., Evans, D.M., Ferreira, M.A., Gaunt, T., Gudnason, V., Hamsten, A., Heinrich, J., Hingorani, A., Humphries, S.E., Jukema, J.W., Koenig, W., Kumari, M., Kutalik, Z., Lawlor, D.A., Lehtimaki, T., Marz, W., Mather, K.A., Naitza, S., Nauck, M., Ohlsson, C., Price, J.F., Raitakari, O., Rice, K., Sachdev, P.S., Slagboom, E., Sorensen, T.I.A., Spector, T., Stacey, D., Stathopoulou, M.G., Tanaka, T., Wannamethee, S.G., Whincup, P., Rotter, J.I., Dehghan, A., Boerwinkle, E., Psaty, B.M., Snieder, H., Alizadeh, B.Z., and CHARGE Inflammation Working Grp

Abstract

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (n(discovery)=52654 and n(replication)=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (P-combined=1.8x10(-11)), HLA-DRB1/DRB5 rs660895 on Chr6p21 (P-combined=1.5x10(-10)) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (P-combined=1.2x10(-122)). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Published
2021

20. Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci

Author

Ahluwalia, TS, Prins, BP, Abdollahi, M, Armstrong, NJ, Aslibekyan, S, Bain, L, Jefferis, B, Baumert, J, Beekman, M, Ben-Shlomo, Y, Bis, JC, Mitchell, BD, de Geus, E, Delgado, GE, Marek, D, Eriksson, J, Kajantie, E, Kanoni, S, Kemp, JP, Lu, C, Marioni, RE, McLachlan, S, Milaneschi, Y, Nolte, IM, Petrelis, AM, Porcu, E, Sabater-Lleal, M, Naderi, E, Seppälä, I, Shah, T, Singhal, G, Standl, M, Teumer, A, Thalamuthu, A, Thiering, E, Trompet, S, Ballantyne, CM, Benjamin, EJ, Casas, JP, Toben, C, Dedoussis, G, Deelen, J, Durda, P, Engmann, J, Feitosa, MF, Grallert, H, Hammarstedt, A, Harris, SE, Homuth, G, Hottenga, J-J, Jalkanen, S, Jamshidi, Y, Jawahar, MC, Jess, T, Kivimaki, M, Kleber, ME, Lahti, J, Liu, Y, Marques-Vidal, P, Mellström, D, Mooijaart, SP, Müller-Nurasyid, M, Penninx, B, Revez, JA, Rossing, P, Räikkönen, K, Sattar, N, Scharnagl, H, Sennblad, B, Silveira, A, Pourcain, BS, Timpson, NJ, Trollor, J, CHARGE Inflammation Working Group, van Dongen, J, Van Heemst, D, Visvikis-Siest, S, Vollenweider, P, Völker, U, Waldenberger, M, Willemsen, G, Zabaneh, D, Morris, RW, Arnett, DK, Baune, BT, Boomsma, DI, Chang, Y-PC, Deary, IJ, Deloukas, P, Eriksson, JG, Evans, DM, Ferreira, MA, Gaunt, T, Gudnason, V, Hamsten, A, Heinrich, J, Hingorani, A, Humphries, SE, Jukema, JW, Koeing, W, Kumari, M, Kutalik, Z, Lawlor, DA, Lehtimäki, T, März, W, Mather, K, Naitza, S, Nauck, M, Ohlsson, C, Price, JF, Raitakari, O, Rice, K, Sachdev, PS, Slagboom, E, Sørensen, TIA, Spector, T, Stacey, D, Stathopoulou, MG, Tanaka, T, Wannamethee, SG, Whincup, P, Rotter, JI, Dehghan, A, Boerwinkle, E, Psaty, BM, Snieder, H, and Alizadeh, BZ

Abstract

Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Published
2021

21. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Author

Vosa, U. (Urmo), Claringbould, A. (Annique), Westra, H.-J. (Harm-Jan), Bonder, M. J. (Marc Jan), Deelen, P. (Patrick), Zeng, B. (Biao), Kirsten, H. (Holger), Saha, A. (Ashis), Kreuzhuber, R. (Roman), Yazar, S. (Seyhan), Brugge, H. (Harm), Oelen, R. (Roy), de Vries, D. H. (Dylan H.), van der Wijst, M. G. (Monique G. P.), Kasela, S. (Silva), Pervjakova, N. (Natalia), Alves, I. (Isabel), Fave, M.-J. (Marie-Julie), Agbessi, M. (Mawusse), Christiansen, M. W. (Mark W.), Jansen, R. (Rick), Seppala, I. (Ilkka), Tong, L. (Lin), Teumer, A. (Alexander), Schramm, K. (Katharina), Hemani, G. (Gibran), Verlouw, J. (Joost), Yaghootkar, H. (Hanieh), Flitman, R. S. (Reyhan Sonmez), Brown, A. (Andrew), Kukushkina, V. (Viktorija), Kalnapenkis, A. (Anette), Rueger, S. (Sina), Porcu, E. (Eleonora), Kronberg, J. (Jaanika), Kettunen, J. (Johannes), Lee, B. (Bernett), Zhang, F. (Futao), Qi, T. (Ting), Hernandez, J. A. (Jose Alquicira), Arindrarto, W. (Wibowo), Beutner, F. (Frank), Dmitrieva, J. (Julia), Elansary, M. (Mahmoud), Fairfax, B. P. (Benjamin P.), Georges, M. (Michel), Heijmans, B. T. (Bastiaan T.), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Kim, Y. (Yungil), Knight, J. C. (Julian C.), Kovacs, P. (Peter), Krohn, K. (Knut), Li, S. (Shuang), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Momozawa, Y. (Yukihide), Mueller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. G. (Michel G.), Penninx, B. W. (Brenda W. J. H.), Pritchard, J. K. (Jonathan K.), Raitakari, O. T. (Olli T.), Rotzschke, O. (Olaf), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Thiery, J. (Joachim), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), Veldink, J. H. (Jan H.), Voelker, U. (Uwe), Warmerdam, R. (Robert), Wijmenga, C. (Cisca), Swertz, M. (Morris), Andiappan, A. (Anand), Montgomery, G. W. (Grant W.), Ripatti, S. (Samuli), Perola, M. (Markus), Kutalik, Z. (Zoltan), Dermitzakis, E. (Emmanouil), Bergmann, S. (Sven), Frayling, T. (Timothy), van Meurs, J. (Joyce), Prokisch, H. (Holger), Ahsan, H. (Habibul), Pierce, B. L. (Brandon L.), Lehtimaki, T. (Terho), Boomsma, D. I. (Dorret, I), Psaty, B. M. (Bruce M.), Gharib, S. A. (Sina A.), Awadalla, P. (Philip), Milani, L. (Lili), Ouwehand, W. H. (Willem H.), Downes, K. (Kate), Stegle, O. (Oliver), Battle, A. (Alexis), Visscher, P. M. (Peter M.), Yang, J. (Jian), Scholz, M. (Markus), Powell, J. (Joseph), Gibson, G. (Greg), Esko, T. (Tonu), and Franke, L. (Lude)

Abstract

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.

Published
2021

22. Genetic insights into biological mechanisms governing human ovarian ageing.

Author

Ruth K.S., Day F.R., Hussain J., Martinez-Marchal A., Aiken C.E., Azad A., Thompson D.J., Knoblochova L., Abe H., Tarry-Adkins J.L., Gonzalez J.M., Fontanillas P., Claringbould A., Bakker O.B., Sulem P., Walters R.G., Terao C., Turon S., Horikoshi M., Lin K., Onland-Moret N.C., Sankar A., Hertz E.P.T., Timshel P.N., Shukla V., Borup R., Olsen K.W., Aguilera P., Ferrer-Roda M., Huang Y., Stankovic S., Timmers P.R.H.J., Ahearn T.U., Alizadeh B.Z., Naderi E., Andrulis I.L., Arnold A.M., Aronson K.J., Augustinsson A., Bandinelli S., Barbieri C.M., Beaumont R.N., Becher H., Beckmann M.W., Benonisdottir S., Bergmann S., Bochud M., Boerwinkle E., Bojesen S.E., Bolla M.K., Boomsma D.I., Bowker N., Brody J.A., Broer L., Buring J.E., Campbell A., Campbell H., Castelao J.E., Catamo E., Chanock S.J., Chenevix-Trench G., Ciullo M., Corre T., Couch F.J., Cox A., Crisponi L., Cross S.S., Cucca F., Czene K., Smith G.D., de Geus E.J.C.N., de Mutsert R., De Vivo I., Demerath E.W., Dennis J., Dunning A.M., Dwek M., Eriksson M., Esko T., Fasching P.A., Faul J.D., Ferrucci L., Franceschini N., Frayling T.M., Gago-Dominguez M., Mezzavilla M., Garcia-Closas M., Gieger C., Giles G.G., Grallert H., Gudbjartsson D.F., Gudnason V., Guenel P., Haiman C.A., Hakansson N., Hall P., Hayward C., He C., He W., Heiss G., Hoffding M.K., Hopper J.L., Hottenga J.J., Hu F., Hunter D., Ikram M.A., Jackson R.D., Joaquim M.D.R., John E.M., Joshi P.K., Karasik D., Kardia S.L.R., Kartsonaki C., Karlsson R., Kitahara C.M., Kolcic I., Kooperberg C., Kraft P., Kurian A.W., Kutalik Z., La Bianca M., LaChance G., Langenberg C., Launer L.J., Laven J.S.E., Lawlor D.A., Le Marchand L., Li J., Lindblom A., Lindstrom S., Lindstrom T., Linet M., Liu Y.M., Liu S., Luan J., Magi R., Magnusson P.K.E., Mangino M., Mannermaa A., Marco B., Marten J., Martin N.G., Mbarek H., McKnight B., Medland S.E., Meisinger C., Meitinger T., Menni C., Metspalu A., Milani L., Milne R.L., Montgomery G.W., Mook-Kanamori D.O., Mulas A., Mulligan A.M., Nalls M.A., Newman A., Noordam R., Nutile T., Nyholt D.R., Olshan A.F., Olsson H., Painter J.N., Patel A.V., Pedersen N.L., Perjakova N., Peters A., Peters U., Pharoah P.D.P., Polasek O., Porcu E., Psaty B.M., Rahman I., Rennert G., Rennert H.S., Ridker P.M., Ring S.M., Robino A., Rose L.M., Rosendaal F.R., Rossouw J., Rudan I., Rueedi R., Ruggiero D., Sala C.F., Saloustros E., Sandler D.P., Sanna S., Sawyer E.J., Sarnowski C., Schlessinger D., Schmidt M.K., Schoemaker M.J., Schraut K.E., Scott C., Shekari S., Shrikhande A., Smith A.V., Smith B.H., Smith J.A., Sorice R., Southey M.C., Spector T.D., Spinelli J.J., Stampfer M., Stockl D., van Meurs J.B.J., Strauch K., Styrkarsdottir U., Swerdlow A.J., Tanaka T., Teras L.R., Teumer A., Thorsteinsdottir U., Timpson N.J., Toniolo D., Traglia M., Troester M.A., Truong T., Tyrrell J., Uitterlinden A.G., Ulivi S., Vachon C.M., Vitart V., Volker U., Vollenweider P., Volzke H., Wang Q., Wareham N.J., Weinberg C.R., Weir D.R., Wilcox A.N., van Dijk K.W., Willemsen G., Wilson J.F., Wolffenbuttel B.H.R., Wolk A., Wood A.R., Zhao W., Zygmunt M., Chen Z., Li L., Franke L., Burgess S., Deelen P., Pers T.H., Grondahl M.L., Andersen C.Y., Pujol A., Lopez-Contreras A.J., Daniel J.A., Stefansson K., Chang-Claude J., van der Schouw Y.T., Lunetta K.L., Chasman D.I., Easton D.F., Visser J.A., Ozanne S.E., Namekawa S.H., Solc P., Murabito J.M., Ong K.K., Hoffmann E.R., Murray A., Roig I., Perry J.R.B., Ruth K.S., Day F.R., Hussain J., Martinez-Marchal A., Aiken C.E., Azad A., Thompson D.J., Knoblochova L., Abe H., Tarry-Adkins J.L., Gonzalez J.M., Fontanillas P., Claringbould A., Bakker O.B., Sulem P., Walters R.G., Terao C., Turon S., Horikoshi M., Lin K., Onland-Moret N.C., Sankar A., Hertz E.P.T., Timshel P.N., Shukla V., Borup R., Olsen K.W., Aguilera P., Ferrer-Roda M., Huang Y., Stankovic S., Timmers P.R.H.J., Ahearn T.U., Alizadeh B.Z., Naderi E., Andrulis I.L., Arnold A.M., Aronson K.J., Augustinsson A., Bandinelli S., Barbieri C.M., Beaumont R.N., Becher H., Beckmann M.W., Benonisdottir S., Bergmann S., Bochud M., Boerwinkle E., Bojesen S.E., Bolla M.K., Boomsma D.I., Bowker N., Brody J.A., Broer L., Buring J.E., Campbell A., Campbell H., Castelao J.E., Catamo E., Chanock S.J., Chenevix-Trench G., Ciullo M., Corre T., Couch F.J., Cox A., Crisponi L., Cross S.S., Cucca F., Czene K., Smith G.D., de Geus E.J.C.N., de Mutsert R., De Vivo I., Demerath E.W., Dennis J., Dunning A.M., Dwek M., Eriksson M., Esko T., Fasching P.A., Faul J.D., Ferrucci L., Franceschini N., Frayling T.M., Gago-Dominguez M., Mezzavilla M., Garcia-Closas M., Gieger C., Giles G.G., Grallert H., Gudbjartsson D.F., Gudnason V., Guenel P., Haiman C.A., Hakansson N., Hall P., Hayward C., He C., He W., Heiss G., Hoffding M.K., Hopper J.L., Hottenga J.J., Hu F., Hunter D., Ikram M.A., Jackson R.D., Joaquim M.D.R., John E.M., Joshi P.K., Karasik D., Kardia S.L.R., Kartsonaki C., Karlsson R., Kitahara C.M., Kolcic I., Kooperberg C., Kraft P., Kurian A.W., Kutalik Z., La Bianca M., LaChance G., Langenberg C., Launer L.J., Laven J.S.E., Lawlor D.A., Le Marchand L., Li J., Lindblom A., Lindstrom S., Lindstrom T., Linet M., Liu Y.M., Liu S., Luan J., Magi R., Magnusson P.K.E., Mangino M., Mannermaa A., Marco B., Marten J., Martin N.G., Mbarek H., McKnight B., Medland S.E., Meisinger C., Meitinger T., Menni C., Metspalu A., Milani L., Milne R.L., Montgomery G.W., Mook-Kanamori D.O., Mulas A., Mulligan A.M., Nalls M.A., Newman A., Noordam R., Nutile T., Nyholt D.R., Olshan A.F., Olsson H., Painter J.N., Patel A.V., Pedersen N.L., Perjakova N., Peters A., Peters U., Pharoah P.D.P., Polasek O., Porcu E., Psaty B.M., Rahman I., Rennert G., Rennert H.S., Ridker P.M., Ring S.M., Robino A., Rose L.M., Rosendaal F.R., Rossouw J., Rudan I., Rueedi R., Ruggiero D., Sala C.F., Saloustros E., Sandler D.P., Sanna S., Sawyer E.J., Sarnowski C., Schlessinger D., Schmidt M.K., Schoemaker M.J., Schraut K.E., Scott C., Shekari S., Shrikhande A., Smith A.V., Smith B.H., Smith J.A., Sorice R., Southey M.C., Spector T.D., Spinelli J.J., Stampfer M., Stockl D., van Meurs J.B.J., Strauch K., Styrkarsdottir U., Swerdlow A.J., Tanaka T., Teras L.R., Teumer A., Thorsteinsdottir U., Timpson N.J., Toniolo D., Traglia M., Troester M.A., Truong T., Tyrrell J., Uitterlinden A.G., Ulivi S., Vachon C.M., Vitart V., Volker U., Vollenweider P., Volzke H., Wang Q., Wareham N.J., Weinberg C.R., Weir D.R., Wilcox A.N., van Dijk K.W., Willemsen G., Wilson J.F., Wolffenbuttel B.H.R., Wolk A., Wood A.R., Zhao W., Zygmunt M., Chen Z., Li L., Franke L., Burgess S., Deelen P., Pers T.H., Grondahl M.L., Andersen C.Y., Pujol A., Lopez-Contreras A.J., Daniel J.A., Stefansson K., Chang-Claude J., van der Schouw Y.T., Lunetta K.L., Chasman D.I., Easton D.F., Visser J.A., Ozanne S.E., Namekawa S.H., Solc P., Murabito J.M., Ong K.K., Hoffmann E.R., Murray A., Roig I., and Perry J.R.B.

Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.Copyright © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

Published
2021

23. Genetic insights into biological mechanisms governing human ovarian ageing

Author

Ruth, KS, Day, FR, Hussain, J, Martinez-Marchal, A, Aiken, CE, Azad, A, Thompson, DJ, Knoblochova, L, Abe, H, Tarry-Adkins, JL, Gonzalez, JM, Fontanillas, P, Claringbould, A, Bakker, OB, Sulem, P, Walters, RG, Terao, C, Turon, S, Horikoshi, M, Lin, K, Onland-Moret, NC, Sankar, A, Hertz, EPT, Timshel, PN, Shukla, V, Borup, R, Olsen, KW, Aguilera, P, Ferrer-Roda, M, Huang, Y, Stankovic, S, Timmers, PRHJ, Ahearn, TU, Alizadeh, BZ, Naderi, E, Andrulis, IL, Arnold, AM, Aronson, KJ, Augustinsson, A, Bandinelli, S, Barbieri, CM, Beaumont, RN, Becher, H, Beckmann, MW, Benonisdottir, S, Bergmann, S, Bochud, M, Boerwinkle, E, Bojesen, SE, Bolla, MK, Boomsma, DI, Bowker, N, Brody, JA, Broer, L, Buring, JE, Campbell, A, Campbell, H, Castelao, JE, Catamo, E, Chanock, SJ, Chenevix-Trench, G, Ciullo, M, Corre, T, Couch, FJ, Cox, A, Crisponi, L, Cross, SS, Cucca, F, Czene, K, Smith, GD, de Geus, EJCN, de Mutsert, R, De Vivo, I, Demerath, EW, Dennis, J, Dunning, AM, Dwek, M, Eriksson, M, Esko, T, Fasching, PA, Faul, JD, Ferrucci, L, Franceschini, N, Frayling, TM, Gago-Dominguez, M, Mezzavilla, M, Garcia-Closas, M, Gieger, C, Giles, GG, Grallert, H, Gudbjartsson, DF, Gudnason, V, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hayward, C, He, C, He, W, Heiss, G, Hoffding, MK, Hopper, JL, Hottenga, JJ, Hu, F, Hunter, D, Ikram, MA, Jackson, RD, Joaquim, MDR, John, EM, Joshi, PK, Karasik, D, Kardia, SLR, Kartsonaki, C, Karlsson, R, Kitahara, CM, Kolcic, I, Kooperberg, C, Kraft, P, Kurian, AW, Kutalik, Z, La Bianca, M, LaChance, G, Langenberg, C, Launer, LJ, Laven, JSE, Lawlor, DA, Le Marchand, L, Li, J, Lindblom, A, Lindstrom, S, Lindstrom, T, Linet, M, Liu, Y, Liu, S, Luan, J, Magi, R, Magnusson, PKE, Mangino, M, Mannermaa, A, Marco, B, Marten, J, Martin, NG, Mbarek, H, McKnight, B, Medland, SE, Meisinger, C, Meitinger, T, Menni, C, Metspalu, A, Milani, L, Milne, RL, Montgomery, GW, Mook-Kanamori, DO, Mulas, A, Mulligan, AM, Murray, A, Nalls, MA, Newman, A, Noordam, R, Nutile, T, Nyholt, DR, Olshan, AF, Olsson, H, Painter, JN, Patel, AV, Pedersen, NL, Perjakova, N, Peters, A, Peters, U, Pharoah, PDP, Polasek, O, Porcu, E, Psaty, BM, Rahman, I, Rennert, G, Rennert, HS, Ridker, PM, Ring, SM, Robino, A, Rose, LM, Rosendaal, FR, Rossouw, J, Rudan, I, Rueedi, R, Ruggiero, D, Sala, CF, Saloustros, E, Sandler, DP, Sanna, S, Sawyer, EJ, Sarnowski, C, Schlessinger, D, Schmidt, MK, Schoemaker, MJ, Schraut, KE, Scott, C, Shekari, S, Shrikhande, A, Smith, AV, Smith, BH, Smith, JA, Sorice, R, Southey, MC, Spector, TD, Spinelli, JJ, Stampfer, M, Stoeckl, D, van Meurs, JBJ, Strauch, K, Styrkarsdottir, U, Swerdlow, AJ, Tanaka, T, Teras, LR, Teumer, A, thorsteinsdottir, U, Timpson, NJ, Toniolo, D, Traglia, M, Troester, MA, Truong, T, Tyrrell, J, Uitterlinden, AG, Ulivi, S, Vachon, CM, Vitart, V, Voelker, U, Vollenweider, P, Voelzke, H, Wang, Q, Wareham, NJ, Weinberg, CR, Weir, DR, Wilcox, AN, van Dijk, KW, Willemsen, G, Wilson, JF, Wolffenbuttel, BHR, Wolk, A, Wood, AR, Zhao, W, Zygmunt, M, Chen, Z, Li, L, Franke, L, Burgess, S, Deelen, P, Pers, TH, Grondahl, ML, Andersen, CY, Pujol, A, Lopez-Contreras, AJ, Daniel, JA, Stefansson, K, Chang-Claude, J, van der Schouw, YT, Lunetta, KL, Chasman, DI, Easton, DF, Visser, JA, Ozanne, SE, Namekawa, SH, Solc, P, Murabito, JM, Ong, KK, Hoffmann, ER, Roig, I, Perry, JRB, Ruth, KS, Day, FR, Hussain, J, Martinez-Marchal, A, Aiken, CE, Azad, A, Thompson, DJ, Knoblochova, L, Abe, H, Tarry-Adkins, JL, Gonzalez, JM, Fontanillas, P, Claringbould, A, Bakker, OB, Sulem, P, Walters, RG, Terao, C, Turon, S, Horikoshi, M, Lin, K, Onland-Moret, NC, Sankar, A, Hertz, EPT, Timshel, PN, Shukla, V, Borup, R, Olsen, KW, Aguilera, P, Ferrer-Roda, M, Huang, Y, Stankovic, S, Timmers, PRHJ, Ahearn, TU, Alizadeh, BZ, Naderi, E, Andrulis, IL, Arnold, AM, Aronson, KJ, Augustinsson, A, Bandinelli, S, Barbieri, CM, Beaumont, RN, Becher, H, Beckmann, MW, Benonisdottir, S, Bergmann, S, Bochud, M, Boerwinkle, E, Bojesen, SE, Bolla, MK, Boomsma, DI, Bowker, N, Brody, JA, Broer, L, Buring, JE, Campbell, A, Campbell, H, Castelao, JE, Catamo, E, Chanock, SJ, Chenevix-Trench, G, Ciullo, M, Corre, T, Couch, FJ, Cox, A, Crisponi, L, Cross, SS, Cucca, F, Czene, K, Smith, GD, de Geus, EJCN, de Mutsert, R, De Vivo, I, Demerath, EW, Dennis, J, Dunning, AM, Dwek, M, Eriksson, M, Esko, T, Fasching, PA, Faul, JD, Ferrucci, L, Franceschini, N, Frayling, TM, Gago-Dominguez, M, Mezzavilla, M, Garcia-Closas, M, Gieger, C, Giles, GG, Grallert, H, Gudbjartsson, DF, Gudnason, V, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hayward, C, He, C, He, W, Heiss, G, Hoffding, MK, Hopper, JL, Hottenga, JJ, Hu, F, Hunter, D, Ikram, MA, Jackson, RD, Joaquim, MDR, John, EM, Joshi, PK, Karasik, D, Kardia, SLR, Kartsonaki, C, Karlsson, R, Kitahara, CM, Kolcic, I, Kooperberg, C, Kraft, P, Kurian, AW, Kutalik, Z, La Bianca, M, LaChance, G, Langenberg, C, Launer, LJ, Laven, JSE, Lawlor, DA, Le Marchand, L, Li, J, Lindblom, A, Lindstrom, S, Lindstrom, T, Linet, M, Liu, Y, Liu, S, Luan, J, Magi, R, Magnusson, PKE, Mangino, M, Mannermaa, A, Marco, B, Marten, J, Martin, NG, Mbarek, H, McKnight, B, Medland, SE, Meisinger, C, Meitinger, T, Menni, C, Metspalu, A, Milani, L, Milne, RL, Montgomery, GW, Mook-Kanamori, DO, Mulas, A, Mulligan, AM, Murray, A, Nalls, MA, Newman, A, Noordam, R, Nutile, T, Nyholt, DR, Olshan, AF, Olsson, H, Painter, JN, Patel, AV, Pedersen, NL, Perjakova, N, Peters, A, Peters, U, Pharoah, PDP, Polasek, O, Porcu, E, Psaty, BM, Rahman, I, Rennert, G, Rennert, HS, Ridker, PM, Ring, SM, Robino, A, Rose, LM, Rosendaal, FR, Rossouw, J, Rudan, I, Rueedi, R, Ruggiero, D, Sala, CF, Saloustros, E, Sandler, DP, Sanna, S, Sawyer, EJ, Sarnowski, C, Schlessinger, D, Schmidt, MK, Schoemaker, MJ, Schraut, KE, Scott, C, Shekari, S, Shrikhande, A, Smith, AV, Smith, BH, Smith, JA, Sorice, R, Southey, MC, Spector, TD, Spinelli, JJ, Stampfer, M, Stoeckl, D, van Meurs, JBJ, Strauch, K, Styrkarsdottir, U, Swerdlow, AJ, Tanaka, T, Teras, LR, Teumer, A, thorsteinsdottir, U, Timpson, NJ, Toniolo, D, Traglia, M, Troester, MA, Truong, T, Tyrrell, J, Uitterlinden, AG, Ulivi, S, Vachon, CM, Vitart, V, Voelker, U, Vollenweider, P, Voelzke, H, Wang, Q, Wareham, NJ, Weinberg, CR, Weir, DR, Wilcox, AN, van Dijk, KW, Willemsen, G, Wilson, JF, Wolffenbuttel, BHR, Wolk, A, Wood, AR, Zhao, W, Zygmunt, M, Chen, Z, Li, L, Franke, L, Burgess, S, Deelen, P, Pers, TH, Grondahl, ML, Andersen, CY, Pujol, A, Lopez-Contreras, AJ, Daniel, JA, Stefansson, K, Chang-Claude, J, van der Schouw, YT, Lunetta, KL, Chasman, DI, Easton, DF, Visser, JA, Ozanne, SE, Namekawa, SH, Solc, P, Murabito, JM, Ong, KK, Hoffmann, ER, Roig, I, and Perry, JRB

Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Published
2021

24. Correction: Socio-economic position as a moderator of cardiometabolic outcomes in patients receiving psychotropic treatment associated with weight gain: results from a prospective 12-month inception cohort study and a large population-based cohort.

Author

Dubath, C, Gholam-Rezaee, M, Sjaarda, J, Levier, A, Saigi-Morgui, N, Delacrétaz, A, Glatard, A, Panczak, R, Correll, CU, Solida, A, Plessen, KJ, von Gunten, A, Kutalik, Z, Conus, P, Eap, CB, Dubath, C, Gholam-Rezaee, M, Sjaarda, J, Levier, A, Saigi-Morgui, N, Delacrétaz, A, Glatard, A, Panczak, R, Correll, CU, Solida, A, Plessen, KJ, von Gunten, A, Kutalik, Z, Conus, P, and Eap, CB

Published
2021

25. Socio-economic position as a moderator of cardiometabolic outcomes in patients receiving psychotropic treatment associated with weight gain: results from a prospective 12-month inception cohort study and a large population-based cohort

Author

Dubath, C, Gholam-Rezaee, M, Sjaarda, J, Levier, A, Saigi-Morgui, N, Delacretaz, A, Glatard, A, Panczak, R, Correll, CU, Solida, A, Plessen, KJ, von Gunten, A, Kutalik, Z, Conus, P, Eap, CB, Dubath, C, Gholam-Rezaee, M, Sjaarda, J, Levier, A, Saigi-Morgui, N, Delacretaz, A, Glatard, A, Panczak, R, Correll, CU, Solida, A, Plessen, KJ, von Gunten, A, Kutalik, Z, Conus, P, and Eap, CB

Abstract

Weight gain and metabolic complications are major adverse effects of many psychotropic drugs. We aimed to understand how socio-economic status (SES), defined as the Swiss socio-economic position (SSEP), is associated with cardiometabolic parameters after initiation of psychotropic medications known to induce weight gain. Cardiometabolic parameters were collected in two Swiss cohorts following the prescription of psychotropic medications. The SSEP integrated neighborhood-based income, education, occupation, and housing condition. The results were then validated in an independent replication sample (UKBiobank), using educational attainment (EA) as a proxy for SES. Adult patients with a low SSEP had a higher risk of developing metabolic syndrome over one year versus patients with a high SSEP (Hazard ratio (95% CI) = 3.1 (1.5-6.5), n = 366). During the first 6 months of follow-up, a significant negative association between SSEP and body mass index (BMI), weight change, and waist circumference change was observed (25 ≤ age < 65, n = 526), which was particularly important in adults receiving medications with the highest risk of weight gain, with a BMI difference of 0.86 kg/m2 between patients with low versus high SSEP (95% CI: 0.03-1.70, n = 99). Eventually, a causal effect of EA on BMI was revealed using Mendelian randomization in the UKBiobank, which was notably strong in high-risk medication users (beta: -0.47 SD EA per 1 SD BMI; 95% CI: -0.46 to -0.27, n = 11,314). An additional aspect of personalized medicine was highlighted, suggesting the patients' SES represents a significant risk factor. Particular attention should be paid to patients with low SES when initiating high cardiometabolic risk psychotropic medications.

Published
2021

26. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), Willer, C. J. (Cristen J.), Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), and Willer, C. J. (Cristen J.)

Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4‐23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

Published
2021

27. The trans-ancestral genomic architecture of glycemic traits

Author

Chen, J. (Ji), Spracklen, C. N. (Cassandra N.), Marenne, G. (Gaelle), Varshney, A. (Arushi), Corbin, L. J. (Laura J.), Luan, J. (Jian'an), Willems, S. M. (Sara M.), Wu, Y. (Ying), Zhang, X. (Xiaoshuai), Horikoshi, M. (Momoko), Boutin, T. S. (Thibaud S.), Magi, R. (Reedik), Waage, J. (Johannes), Li-Gao, R. (Ruifang), Chan, K. H. (Kei Hang Katie), Yao, J. (Jie), Anasanti, M. D. (Mila D.), Chu, A. Y. (Audrey Y.), Claringbould, A. (Annique), Heikkinen, J. (Jani), Hong, J. (Jaeyoung), Hottenga, J.-J. (Jouke-Jan), Huo, S. (Shaofeng), Kaakinen, M. A. (Marika A.), Louie, T. (Tin), Maerz, W. (Winfried), Moreno-Macias, H. (Hortensia), Ndungu, A. (Anne), Nelson, S. C. (Sarah C.), Nolte, I. M. (Ilja M.), North, K. E. (Kari E.), Raulerson, C. K. (Chelsea K.), Ray, D. (Debashree), Rohde, R. (Rebecca), Rybin, D. (Denis), Schurmann, C. (Claudia), Sim, X. (Xueling), Southam, L. (Lorraine), Stewart, I. D. (Isobel D.), Wang, C. A. (Carol A.), Wang, Y. (Yujie), Wu, P. (Peitao), Zhang, W. (Weihua), Ahluwalia, T. S. (Tarunveer S.), Appel, E. V. (Emil V. R.), Bielak, L. F. (Lawrence F.), Brody, J. A. (Jennifer A.), Burtt, N. P. (Noel P.), Cabrera, C. P. (Claudia P.), Cade, B. E. (Brian E.), Chai, J. F. (Jin Fang), Chai, X. (Xiaoran), Chang, L.-C. (Li-Ching), Chen, C.-H. (Chien-Hsiun), Chen, B. H. (Brian H.), Chitrala, K. N. (Kumaraswamy Naidu), Chiu, Y.-F. (Yen-Feng), de Haan, H. G. (Hugoline G.), Delgado, G. E. (Graciela E.), Demirkan, A. (Ayse), Duan, Q. (Qing), Engmann, J. (Jorgen), Fatumo, S. A. (Segun A.), Gayan, J. (Javier), Giulianini, F. (Franco), Gong, J. H. (Jung Ho), Gustafsson, S. (Stefan), Hai, Y. (Yang), Hartwig, F. P. (Fernando P.), He, J. (Jing), Heianza, Y. (Yoriko), Huang, T. (Tao), Huerta-Chagoya, A. (Alicia), Hwang, M. Y. (Mi Yeong), Jensen, R. A. (Richard A.), Kawaguchi, T. (Takahisa), Kentistou, K. A. (Katherine A.), Kim, Y. J. (Young Jin), Kleber, M. E. (Marcus E.), Kooner, I. K. (Ishminder K.), Lai, S. (Shuiqing), Lange, L. A. (Leslie A.), Langefeld, C. D. (Carl D.), Lauzon, M. (Marie), Li, M. (Man), Ligthart, S. (Symen), Liu, J. (Jun), Loh, M. (Marie), Long, J. (Jirong), Lyssenko, V. (Valeriya), Mangino, M. (Massimo), Marzi, C. (Carola), Montasser, M. E. (May E.), Nag, A. (Abhishek), Nakatochi, M. (Masahiro), Noce, D. (Damia), Noordam, R. (Raymond), Pistis, G. (Giorgio), Preuss, M. (Michael), Raffield, L. (Laura), Rasmussen-Torvik, L. J. (Laura J.), Rich, S. S. (Stephen S.), Robertson, N. R. (Neil R.), Rueedi, R. (Rico), Ryan, K. (Kathleen), Sanna, S. (Serena), Saxena, R. (Richa), Schraut, K. E. (Katharina E.), Sennblad, B. (Bengt), Setoh, K. (Kazuya), Smith, A. V. (Albert V.), Sparso, T. (Thomas), Strawbridge, R. J. (Rona J.), Takeuchi, F. (Fumihiko), Tan, J. (Jingyi), Trompet, S. (Stella), van den Akker, E. (Erik), van der Most, P. J. (Peter J.), Verweij, N. (Niek), Vogel, M. (Mandy), Wang, H. (Heming), Wang, C. (Chaolong), Wang, N. (Nan), Warren, H. R. (Helen R.), Wen, W. (Wanqing), Wilsgaard, T. (Tom), Wong, A. (Andrew), Wood, A. R. (Andrew R.), Xie, T. (Tian), Zafarmand, M. H. (Mohammad Hadi), Zhao, J.-H. (Jing-Hua), Zhao, W. (Wei), Amin, N. (Najaf), Arzumanyan, Z. (Zorayr), Astrup, A. (Arne), Bakker, S. J. (Stephan J. L.), Baldassarre, D. (Damiano), Beekman, M. (Marian), Bergman, R. N. (Richard N.), Bertoni, A. (Alain), Blueher, M. (Matthias), Bonnycastle, L. L. (Lori L.), Bornstein, S. R. (Stefan R.), Bowden, D. W. (Donald W.), Cai, Q. (Qiuyin), Campbell, A. (Archie), Campbell, H. (Harry), Chang, Y. C. (Yi Cheng), de Geus, E. J. (Eco J. C.), Dehghan, A. (Abbas), Du, S. (Shufa), Eiriksdottir, G. (Gudny), Farmaki, A. E. (Aliki Eleni), Franberg, M. (Mattias), Fuchsberger, C. (Christian), Gao, Y. (Yutang), Gjesing, A. P. (Anette P.), Goel, A. (Anuj), Han, S. (Sohee), Hartman, C. A. (Catharina A.), Herder, C. (Christian), Hicks, A. A. (Andrew A.), Hsieh, C.-H. (Chang-Hsun), Hsueh, W. A. (Willa A.), Ichihara, S. (Sahoko), Igase, M. (Michiya), Ikram, M. A. (M. Arfan), Johnson, W. C. (W. Craig), Jorgensen, M. E. (Marit E.), Joshi, P. K. (Peter K.), Kalyani, R. R. (Rita R.), Kandeel, F. R. (Fouad R.), Katsuya, T. (Tomohiro), Khor, C. C. (Chiea Chuen), Kiess, W. (Wieland), Kolcic, I. (Ivana), Kuulasmaa, T. (Teemu), Kuusisto, J. (Johanna), Lall, K. (Kristi), Lam, K. (Kelvin), Lawlor, D. A. (Deborah A.), Lee, N. R. (Nanette R.), Lemaitre, R. N. (Rozenn N.), Li, H. (Honglan), Lin, S.-Y. (Shih-Yi), Lindstrom, J. (Jaana), Linneberg, A. (Allan), Liu, J. (Jianjun), Lorenzo, C. (Carlos), Matsubara, T. (Tatsuaki), Matsuda, F. (Fumihiko), Mingrone, G. (Geltrude), Mooijaart, S. (Simon), Moon, S. (Sanghoon), Nabika, T. (Toru), Nadkarni, G. N. (Girish N.), Nadler, J. L. (Jerry L.), Nelis, M. (Mari), Neville, M. J. (Matt J.), Norris, J. M. (Jill M.), Ohyagi, Y. (Yasumasa), Peters, A. (Annette), Peyser, P. A. (Patricia A.), Polasek, O. (Ozren), Qi, Q. (Qibin), Raven, D. (Dennis), Reilly, D. F. (Dermot F.), Reiner, A. (Alex), Rivideneira, F. (Fernando), Roll, K. (Kathryn), Rudan, I. (Igor), Sabanayagam, C. (Charumathi), Sandow, K. (Kevin), Sattar, N. (Naveed), Schuermann, A. (Annette), Shi, J. (Jinxiu), Stringham, H. M. (Heather M.), Taylor, K. D. (Kent D.), Teslovich, T. M. (Tanya M.), Thuesen, B. (Betina), Timmers, P. R. (Paul R. H. J.), Tremoli, E. (Elena), Tsai, M. Y. (Michael Y.), Uitterlinden, A. (Andre), van Dam, R. M. (Rob M.), van Heemst, D. (Diana), van Hylckama Vlieg, A. (Astrid), van Vliet-Ostaptchouk, J. V. (Jana V.), Vangipurapu, J. (Jagadish), Vestergaard, H. (Henrik), Wang, T. (Tao), Willems van Dijk, K. (Ko), Zemunik, T. (Tatijana), Abecasis, G. R. (Goncalo R.), Adair, L. S. (Linda S.), Aguilar-Salinas, C. A. (Carlos Alberto), Alarcon-Riquelme, M. E. (Marta E.), An, P. (Ping), Aviles-Santa, L. (Larissa), Becker, D. M. (Diane M.), Beilin, L. J. (Lawrence J.), Bergmann, S. (Sven), Bisgaard, H. (Hans), Black, C. (Corri), Boehnke, M. (Michael), Boerwinkle, E. (Eric), Boehm, B. O. (Bernhard O.), Bonnelykke, K. (Klaus), Boomsma, D. I. (D. I.), Bottinger, E. P. (Erwin P.), Buchanan, T. A. (Thomas A.), Canouil, M. (Mickael), Caulfield, M. J. (Mark J.), Chambers, J. C. (John C.), Chasman, D. I. (Daniel I.), Chen, Y. I. (Yii-Der Ida), Cheng, C.-Y. (Ching-Yu), Collins, F. S. (Francis S.), Correa, A. (Adolfo), Cucca, F. (Francesco), de Silva, H. J. (H. Janaka), Dedoussis, G. (George), Elmstahl, S. (Solve), Evans, M. K. (Michele K.), Ferrannini, E. (Ele), Ferrucci, L. (Luigi), Florez, J. C. (Jose C.), Franks, P. W. (Paul W.), Frayling, T. M. (Timothy M.), Froguel, P. (Philippe), Gigante, B. (Bruna), Goodarzi, M. O. (Mark O.), Gordon-Larsen, P. (Penny), Grallert, H. (Harald), Grarup, N. (Niels), Grimsgaard, S. (Sameline), Groop, L. (Leif), Gudnason, V. (Vilmundur), Guo, X. (Xiuqing), Hamsten, A. (Anders), Hansen, T. (Torben), Hayward, C. (Caroline), Heckbert, S. R. (Susan R.), Horta, B. L. (Bernardo L.), Huang, W. (Wei), Ingelsson, E. (Erik), James, P. S. (Pankow S.), Järvelin, M.-R. (Marjo-Ritta), Jonas, J. B. (Jost B.), Jukema, J. W. (J. Wouter), Kaleebu, P. (Pontiano), Kaplan, R. (Robert), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Keinanen-Kiukaanniemi, S. M. (Sirkka M.), Kim, B.-J. (Bong-Jo), Kivimaki, M. (Mika), Koistinen, H. A. (Heikki A.), Kooner, J. S. (Jaspal S.), Koerner, A. (Antje), Kovacs, P. (Peter), Kuh, D. (Diana), Kumari, M. (Meena), Kutalik, Z. (Zoltan), Laakso, M. (Markku), Lakka, T. A. (Timo A.), Launer, L. J. (Lenore J.), Leander, K. (Karin), Li, H. (Huaixing), Lin, X. (Xu), Lind, L. (Lars), Lindgren, C. (Cecilia), Liu, S. (Simin), Loos, R. J. (Ruth J. F.), Magnusson, P. K. (Patrik K. E.), Mahajan, A. (Anubha), Metspalu, A. (Andres), Mook-Kanamori, D. O. (Dennis O.), Mori, T. A. (Trevor A.), Munroe, P. B. (Patricia B.), Njolstad, I. (Inger), O'Connell, J. R. (Jeffrey R.), Oldehinkel, A. J. (Albertine J.), Ong, K. K. (Ken K.), Padmanabhan, S. (Sandosh), Palmer, C. N. (Colin N. A.), Palmer, N. D. (Nicholette D.), Pedersen, O. (Oluf), Pennell, C. E. (Craig E.), Porteous, D. J. (David J.), Pramstaller, P. P. (Peter P.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Qi, L. (Lu), Raffel, L. J. (Leslie J.), Rauramaa, R. (Rainer), Redline, S. (Susan), Ridker, P. M. (Paul M.), Rosendaal, F. R. (Frits R.), Saaristo, T. E. (Timo E.), Sandhu, M. (Manjinder), Saramies, J. (Jouko), Schneiderman, N. (Neil), Schwarz, P. (Peter), Scott, L. J. (Laura J.), Selvin, E. (Elizabeth), Sever, P. (Peter), Shu, X.-o. (Xiao-ou), Slagboom, P. E. (P. Eline), Small, K. S. (Kerrin S.), Smith, B. H. (Blair H.), Snieder, H. (Harold), Sofer, T. (Tamar), Sorensen, T. I. (Thorkild I. A.), Spector, T. D. (Tim D.), Stanton, A. (Alice), Steves, C. J. (Claire J.), Stumvoll, M. (Michael), Sun, L. (Liang), Tabara, Y. (Yasuharu), Tai, E. S. (E. Shyong), Timpson, N. J. (Nicholas J.), Tonjes, A. (Anke), Tuomilehto, J. (Jaakko), Tusie, T. (Teresa), Uusitupa, M. (Matti), van der Harst, P. (Pim), van Duijn, C. (Cornelia), Vitart, V. (Veronique), Vollenweider, P. (Peter), Vrijkotte, T. G. (Tanja G. M.), Wagenknecht, L. E. (Lynne E.), Walker, M. (Mark), Wang, Y. X. (Ya X.), Wareham, N. J. (Nick J.), Watanabe, R. M. (Richard M.), Watkins, H. (Hugh), Wei, W. B. (Wen B.), Wickremasinghe, A. R. (Ananda R.), Willemsen, G. (Gonneke), Wilson, J. F. (James F.), Wong, T.-Y. (Tien-Yin), Wu, J.-Y. (Jer-Yuarn), Xiang, A. H. (Anny H.), Yanek, L. R. (Lisa R.), Yengo, L. (Loic), Yokota, M. (Mitsuhiro), Zeggini, E. (Eleftheria), Zheng, W. (Wei), Zonderman, A. B. (Alan B.), Rotter, J. I. (Jerome I.), Gloyn, A. L. (Anna L.), McCarthy, M. I. (Mark I.), Dupuis, J. (Josee), Meigs, J. B. (James B.), Scott, R. A. (Robert A.), Prokopenko, I. (Inga), Leong, A. (Aaron), Liu, C.-T. (Ching-Ti), Parker, S. C. (Stephen C. J.), Mohlke, K. L. (Karen L.), Langenberg, C. (Claudia), Wheeler, E. (Eleanor), Morris, A. P. (Andrew P.), Barroso, I. (Ines), Chen, J. (Ji), Spracklen, C. N. (Cassandra N.), Marenne, G. (Gaelle), Varshney, A. (Arushi), Corbin, L. J. (Laura J.), Luan, J. (Jian'an), Willems, S. M. (Sara M.), Wu, Y. (Ying), Zhang, X. (Xiaoshuai), Horikoshi, M. (Momoko), Boutin, T. S. (Thibaud S.), Magi, R. (Reedik), Waage, J. (Johannes), Li-Gao, R. (Ruifang), Chan, K. H. (Kei Hang Katie), Yao, J. (Jie), Anasanti, M. D. (Mila D.), Chu, A. Y. (Audrey Y.), Claringbould, A. (Annique), Heikkinen, J. (Jani), Hong, J. (Jaeyoung), Hottenga, J.-J. (Jouke-Jan), Huo, S. (Shaofeng), Kaakinen, M. A. (Marika A.), Louie, T. (Tin), Maerz, W. (Winfried), Moreno-Macias, H. (Hortensia), Ndungu, A. (Anne), Nelson, S. C. (Sarah C.), Nolte, I. M. (Ilja M.), North, K. E. (Kari E.), Raulerson, C. K. (Chelsea K.), Ray, D. (Debashree), Rohde, R. (Rebecca), Rybin, D. (Denis), Schurmann, C. (Claudia), Sim, X. (Xueling), Southam, L. (Lorraine), Stewart, I. D. (Isobel D.), Wang, C. A. (Carol A.), Wang, Y. (Yujie), Wu, P. (Peitao), Zhang, W. (Weihua), Ahluwalia, T. S. (Tarunveer S.), Appel, E. V. (Emil V. R.), Bielak, L. F. (Lawrence F.), Brody, J. A. (Jennifer A.), Burtt, N. P. (Noel P.), Cabrera, C. P. (Claudia P.), Cade, B. E. (Brian E.), Chai, J. F. (Jin Fang), Chai, X. (Xiaoran), Chang, L.-C. (Li-Ching), Chen, C.-H. (Chien-Hsiun), Chen, B. H. (Brian H.), Chitrala, K. N. (Kumaraswamy Naidu), Chiu, Y.-F. (Yen-Feng), de Haan, H. G. (Hugoline G.), Delgado, G. E. (Graciela E.), Demirkan, A. (Ayse), Duan, Q. (Qing), Engmann, J. (Jorgen), Fatumo, S. A. (Segun A.), Gayan, J. (Javier), Giulianini, F. (Franco), Gong, J. H. (Jung Ho), Gustafsson, S. (Stefan), Hai, Y. (Yang), Hartwig, F. P. (Fernando P.), He, J. (Jing), Heianza, Y. (Yoriko), Huang, T. (Tao), Huerta-Chagoya, A. (Alicia), Hwang, M. Y. (Mi Yeong), Jensen, R. A. (Richard A.), Kawaguchi, T. (Takahisa), Kentistou, K. A. (Katherine A.), Kim, Y. J. (Young Jin), Kleber, M. E. (Marcus E.), Kooner, I. K. (Ishminder K.), Lai, S. (Shuiqing), Lange, L. A. (Leslie A.), Langefeld, C. D. (Carl D.), Lauzon, M. (Marie), Li, M. (Man), Ligthart, S. (Symen), Liu, J. (Jun), Loh, M. (Marie), Long, J. (Jirong), Lyssenko, V. (Valeriya), Mangino, M. (Massimo), Marzi, C. (Carola), Montasser, M. E. (May E.), Nag, A. (Abhishek), Nakatochi, M. (Masahiro), Noce, D. (Damia), Noordam, R. (Raymond), Pistis, G. (Giorgio), Preuss, M. (Michael), Raffield, L. (Laura), Rasmussen-Torvik, L. J. (Laura J.), Rich, S. S. (Stephen S.), Robertson, N. R. (Neil R.), Rueedi, R. (Rico), Ryan, K. (Kathleen), Sanna, S. (Serena), Saxena, R. (Richa), Schraut, K. E. (Katharina E.), Sennblad, B. (Bengt), Setoh, K. (Kazuya), Smith, A. V. (Albert V.), Sparso, T. (Thomas), Strawbridge, R. J. (Rona J.), Takeuchi, F. (Fumihiko), Tan, J. (Jingyi), Trompet, S. (Stella), van den Akker, E. (Erik), van der Most, P. J. (Peter J.), Verweij, N. (Niek), Vogel, M. (Mandy), Wang, H. (Heming), Wang, C. (Chaolong), Wang, N. (Nan), Warren, H. R. (Helen R.), Wen, W. (Wanqing), Wilsgaard, T. (Tom), Wong, A. (Andrew), Wood, A. R. (Andrew R.), Xie, T. (Tian), Zafarmand, M. H. (Mohammad Hadi), Zhao, J.-H. (Jing-Hua), Zhao, W. (Wei), Amin, N. (Najaf), Arzumanyan, Z. (Zorayr), Astrup, A. (Arne), Bakker, S. J. (Stephan J. L.), Baldassarre, D. (Damiano), Beekman, M. (Marian), Bergman, R. N. (Richard N.), Bertoni, A. (Alain), Blueher, M. (Matthias), Bonnycastle, L. L. (Lori L.), Bornstein, S. R. (Stefan R.), Bowden, D. W. (Donald W.), Cai, Q. (Qiuyin), Campbell, A. (Archie), Campbell, H. (Harry), Chang, Y. C. (Yi Cheng), de Geus, E. J. (Eco J. C.), Dehghan, A. (Abbas), Du, S. (Shufa), Eiriksdottir, G. (Gudny), Farmaki, A. E. (Aliki Eleni), Franberg, M. (Mattias), Fuchsberger, C. (Christian), Gao, Y. (Yutang), Gjesing, A. P. (Anette P.), Goel, A. (Anuj), Han, S. (Sohee), Hartman, C. A. (Catharina A.), Herder, C. (Christian), Hicks, A. A. (Andrew A.), Hsieh, C.-H. (Chang-Hsun), Hsueh, W. A. (Willa A.), Ichihara, S. (Sahoko), Igase, M. (Michiya), Ikram, M. A. (M. Arfan), Johnson, W. C. (W. Craig), Jorgensen, M. E. (Marit E.), Joshi, P. K. (Peter K.), Kalyani, R. R. (Rita R.), Kandeel, F. R. (Fouad R.), Katsuya, T. (Tomohiro), Khor, C. C. (Chiea Chuen), Kiess, W. (Wieland), Kolcic, I. (Ivana), Kuulasmaa, T. (Teemu), Kuusisto, J. (Johanna), Lall, K. (Kristi), Lam, K. (Kelvin), Lawlor, D. A. (Deborah A.), Lee, N. R. (Nanette R.), Lemaitre, R. N. (Rozenn N.), Li, H. (Honglan), Lin, S.-Y. (Shih-Yi), Lindstrom, J. (Jaana), Linneberg, A. (Allan), Liu, J. (Jianjun), Lorenzo, C. (Carlos), Matsubara, T. (Tatsuaki), Matsuda, F. (Fumihiko), Mingrone, G. (Geltrude), Mooijaart, S. (Simon), Moon, S. (Sanghoon), Nabika, T. (Toru), Nadkarni, G. N. (Girish N.), Nadler, J. L. (Jerry L.), Nelis, M. (Mari), Neville, M. J. (Matt J.), Norris, J. M. (Jill M.), Ohyagi, Y. (Yasumasa), Peters, A. (Annette), Peyser, P. A. (Patricia A.), Polasek, O. (Ozren), Qi, Q. (Qibin), Raven, D. (Dennis), Reilly, D. F. (Dermot F.), Reiner, A. (Alex), Rivideneira, F. (Fernando), Roll, K. (Kathryn), Rudan, I. (Igor), Sabanayagam, C. (Charumathi), Sandow, K. (Kevin), Sattar, N. (Naveed), Schuermann, A. (Annette), Shi, J. (Jinxiu), Stringham, H. M. (Heather M.), Taylor, K. D. (Kent D.), Teslovich, T. M. (Tanya M.), Thuesen, B. (Betina), Timmers, P. R. (Paul R. H. J.), Tremoli, E. (Elena), Tsai, M. Y. (Michael Y.), Uitterlinden, A. (Andre), van Dam, R. M. (Rob M.), van Heemst, D. (Diana), van Hylckama Vlieg, A. (Astrid), van Vliet-Ostaptchouk, J. V. (Jana V.), Vangipurapu, J. (Jagadish), Vestergaard, H. (Henrik), Wang, T. (Tao), Willems van Dijk, K. (Ko), Zemunik, T. (Tatijana), Abecasis, G. R. (Goncalo R.), Adair, L. S. (Linda S.), Aguilar-Salinas, C. A. (Carlos Alberto), Alarcon-Riquelme, M. E. (Marta E.), An, P. (Ping), Aviles-Santa, L. (Larissa), Becker, D. M. (Diane M.), Beilin, L. J. (Lawrence J.), Bergmann, S. (Sven), Bisgaard, H. (Hans), Black, C. (Corri), Boehnke, M. (Michael), Boerwinkle, E. (Eric), Boehm, B. O. (Bernhard O.), Bonnelykke, K. (Klaus), Boomsma, D. I. (D. I.), Bottinger, E. P. (Erwin P.), Buchanan, T. A. (Thomas A.), Canouil, M. (Mickael), Caulfield, M. J. (Mark J.), Chambers, J. C. (John C.), Chasman, D. I. (Daniel I.), Chen, Y. I. (Yii-Der Ida), Cheng, C.-Y. (Ching-Yu), Collins, F. S. (Francis S.), Correa, A. (Adolfo), Cucca, F. (Francesco), de Silva, H. J. (H. Janaka), Dedoussis, G. (George), Elmstahl, S. (Solve), Evans, M. K. (Michele K.), Ferrannini, E. (Ele), Ferrucci, L. (Luigi), Florez, J. C. (Jose C.), Franks, P. W. (Paul W.), Frayling, T. M. (Timothy M.), Froguel, P. (Philippe), Gigante, B. (Bruna), Goodarzi, M. O. (Mark O.), Gordon-Larsen, P. (Penny), Grallert, H. (Harald), Grarup, N. (Niels), Grimsgaard, S. (Sameline), Groop, L. (Leif), Gudnason, V. (Vilmundur), Guo, X. (Xiuqing), Hamsten, A. (Anders), Hansen, T. (Torben), Hayward, C. (Caroline), Heckbert, S. R. (Susan R.), Horta, B. L. (Bernardo L.), Huang, W. (Wei), Ingelsson, E. (Erik), James, P. S. (Pankow S.), Järvelin, M.-R. (Marjo-Ritta), Jonas, J. B. (Jost B.), Jukema, J. W. (J. Wouter), Kaleebu, P. (Pontiano), Kaplan, R. (Robert), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Keinanen-Kiukaanniemi, S. M. (Sirkka M.), Kim, B.-J. (Bong-Jo), Kivimaki, M. (Mika), Koistinen, H. A. (Heikki A.), Kooner, J. S. (Jaspal S.), Koerner, A. (Antje), Kovacs, P. (Peter), Kuh, D. (Diana), Kumari, M. (Meena), Kutalik, Z. (Zoltan), Laakso, M. (Markku), Lakka, T. A. (Timo A.), Launer, L. J. (Lenore J.), Leander, K. (Karin), Li, H. (Huaixing), Lin, X. (Xu), Lind, L. (Lars), Lindgren, C. (Cecilia), Liu, S. (Simin), Loos, R. J. (Ruth J. F.), Magnusson, P. K. (Patrik K. E.), Mahajan, A. (Anubha), Metspalu, A. (Andres), Mook-Kanamori, D. O. (Dennis O.), Mori, T. A. (Trevor A.), Munroe, P. B. (Patricia B.), Njolstad, I. (Inger), O'Connell, J. R. (Jeffrey R.), Oldehinkel, A. J. (Albertine J.), Ong, K. K. (Ken K.), Padmanabhan, S. (Sandosh), Palmer, C. N. (Colin N. A.), Palmer, N. D. (Nicholette D.), Pedersen, O. (Oluf), Pennell, C. E. (Craig E.), Porteous, D. J. (David J.), Pramstaller, P. P. (Peter P.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Qi, L. (Lu), Raffel, L. J. (Leslie J.), Rauramaa, R. (Rainer), Redline, S. (Susan), Ridker, P. M. (Paul M.), Rosendaal, F. R. (Frits R.), Saaristo, T. E. (Timo E.), Sandhu, M. (Manjinder), Saramies, J. (Jouko), Schneiderman, N. (Neil), Schwarz, P. (Peter), Scott, L. J. (Laura J.), Selvin, E. (Elizabeth), Sever, P. (Peter), Shu, X.-o. (Xiao-ou), Slagboom, P. E. (P. Eline), Small, K. S. (Kerrin S.), Smith, B. H. (Blair H.), Snieder, H. (Harold), Sofer, T. (Tamar), Sorensen, T. I. (Thorkild I. A.), Spector, T. D. (Tim D.), Stanton, A. (Alice), Steves, C. J. (Claire J.), Stumvoll, M. (Michael), Sun, L. (Liang), Tabara, Y. (Yasuharu), Tai, E. S. (E. Shyong), Timpson, N. J. (Nicholas J.), Tonjes, A. (Anke), Tuomilehto, J. (Jaakko), Tusie, T. (Teresa), Uusitupa, M. (Matti), van der Harst, P. (Pim), van Duijn, C. (Cornelia), Vitart, V. (Veronique), Vollenweider, P. (Peter), Vrijkotte, T. G. (Tanja G. M.), Wagenknecht, L. E. (Lynne E.), Walker, M. (Mark), Wang, Y. X. (Ya X.), Wareham, N. J. (Nick J.), Watanabe, R. M. (Richard M.), Watkins, H. (Hugh), Wei, W. B. (Wen B.), Wickremasinghe, A. R. (Ananda R.), Willemsen, G. (Gonneke), Wilson, J. F. (James F.), Wong, T.-Y. (Tien-Yin), Wu, J.-Y. (Jer-Yuarn), Xiang, A. H. (Anny H.), Yanek, L. R. (Lisa R.), Yengo, L. (Loic), Yokota, M. (Mitsuhiro), Zeggini, E. (Eleftheria), Zheng, W. (Wei), Zonderman, A. B. (Alan B.), Rotter, J. I. (Jerome I.), Gloyn, A. L. (Anna L.), McCarthy, M. I. (Mark I.), Dupuis, J. (Josee), Meigs, J. B. (James B.), Scott, R. A. (Robert A.), Prokopenko, I. (Inga), Leong, A. (Aaron), Liu, C.-T. (Ching-Ti), Parker, S. C. (Stephen C. J.), Mohlke, K. L. (Karen L.), Langenberg, C. (Claudia), Wheeler, E. (Eleanor), Morris, A. P. (Andrew P.), and Barroso, I. (Ines)

Abstract

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

Published
2021

28. The trans-ancestral genomic architecture of glycemic traits

Author

Chen, J., Spracklen, C. N., Marenne, G., Varshney, A., Corbin, L. J., Luan, J., Willems, S. M., Wu, Y., Zhang, X., Horikoshi, M., Boutin, T. S., Magi, R., Waage, J., Li-Gao, R., Chan, K. H. K., Yao, J., Anasanti, M. D., Chu, A. Y., Claringbould, A., Heikkinen, J., Hong, J., Hottenga, J. -J., Huo, S., Kaakinen, M. A., Louie, T., Marz, W., Moreno-Macias, H., Ndungu, A., Nelson, S. C., Nolte, I. M., North, K. E., Raulerson, C. K., Ray, D., Rohde, R., Rybin, D., Schurmann, C., Sim, X., Southam, L., Stewart, I. D., Wang, C. A., Wang, Y., Wu, P., Zhang, W., Ahluwalia, T. S., Appel, E. V. R., Bielak, L. F., Brody, J. A., Burtt, N. P., Cabrera, C. P., Cade, B. E., Chai, J. F., Chai, X., Chang, L. -C., Chen, C. -H., Chen, B. H., Chitrala, K. N., Chiu, Y. -F., de Haan, H. G., Delgado, G. E., Demirkan, A., Duan, Q., Engmann, J., Fatumo, S. A., Gayan, J., Giulianini, F., Gong, J. H., Gustafsson, S., Hai, Y., Hartwig, F. P., He, J., Heianza, Y., Huang, T., Huerta-Chagoya, A., Hwang, M. Y., Jensen, R. A., Kawaguchi, T., Kentistou, K. A., Kim, Y. J., Kleber, M. E., Kooner, I. K., Lai, S., Lange, L. A., Langefeld, C. D., Lauzon, M., Li, M., Ligthart, S., Liu, J., Loh, M., Long, J., Lyssenko, V., Mangino, M., Marzi, C., Montasser, M. E., Nag, A., Nakatochi, M., Noce, D., Noordam, R., Pistis, G., Preuss, M., Raffield, L., Rasmussen-Torvik, L. J., Rich, S. S., Robertson, N. R., Rueedi, R., Ryan, K., Sanna, S., Saxena, R., Schraut, K. E., Sennblad, B., Setoh, K., Smith, A. V., Sparso, T., Strawbridge, R. J., Takeuchi, F., Tan, J., Trompet, S., van den Akker, E., van der Most, P. J., Verweij, N., Vogel, M., Wang, H., Wang, Chin Heng, Wang, N., Warren, H. R., Wen, W., Wilsgaard, T., Wong, A., Wood, A. R., Xie, T., Zafarmand, M. H., Zhao, J. -H., Zhao, W., Amin, N., Arzumanyan, Z., Astrup, A., Bakker, S. J. L., Baldassarre, D., Beekman, M., Bergman, R. N., Bertoni, Anna Marta Maria, Bluher, M., Bonnycastle, L. L., Bornstein, S. R., Bowden, D. W., Cai, Q., Campbell, A., Campbell, H., Chang, Y. C., de Geus, E. J. C., Dehghan, A., Du, S., Eiriksdottir, G., Farmaki, A. E., Franberg, M., Fuchsberger, C., Gao, Y., Gjesing, A. P., Goel, A., Han, S., Hartman, C. A., Herder, C., Hicks, A. A., Hsieh, C. -H., Hsueh, W. A., Ichihara, S., Igase, M., Ikram, M. A., Johnson, W. C., Jorgensen, M. E., Joshi, P. K., Kalyani, R. R., Kandeel, F. R., Katsuya, T., Khor, C. C., Kiess, W., Kolcic, I., Kuulasmaa, T., Kuusisto, J., Lall, K., Lam, K., Lawlor, D. A., Lee, N. R., Lemaitre, R. N., Li, H., Lin, S. -Y., Lindstrom, J., Linneberg, A., Lorenzo, C., Matsubara, T., Matsuda, F., Mingrone, Geltrude, Mooijaart, S., Moon, S., Nabika, T., Nadkarni, G. N., Nadler, J. L., Nelis, M., Neville, M. J., Norris, J. M., Ohyagi, Y., Peters, A., Peyser, P. A., Polasek, O., Qi, Q., Raven, D., Reilly, D. F., Reiner, A., Rivideneira, F., Roll, K., Rudan, I., Sabanayagam, C., Sandow, K., Sattar, N., Schurmann, A., Shi, J., Stringham, H. M., Taylor, K. D., Teslovich, T. M., Thuesen, B., Timmers, P. R. H. J., Tremoli, Elena, Tsai, M. Y., Uitterlinden, A., van Dam, R. M., van Heemst, D., van Hylckama Vlieg, A., van Vliet-Ostaptchouk, J. V., Vangipurapu, J., Vestergaard, H., Wang, T., Willems van Dijk, K., Zemunik, T., Abecasis, G. R., Adair, L. S., Aguilar-Salinas, C. A., Alarcon-Riquelme, M. E., An, P., Aviles-Santa, L., Becker, D. M., Beilin, L. J., Bergmann, S., Bisgaard, H., Black, C., Boehnke, M., Boerwinkle, E., Bohm, B. O., Bonnelykke, K., Boomsma, D. I., Bottinger, E. P., Buchanan, T. A., Canouil, M., Caulfield, M. J., Chambers, J. C., Chasman, D. I., Chen, Y. -D. I., Cheng, C. -Y., Collins, F. S., Correa, A., Cucca, F., de Silva, H. J., Dedoussis, G., Elmstahl, S., Evans, M. K., Ferrannini, E., Ferrucci, L., Florez, J. C., Franks, P. W., Frayling, T. M., Froguel, P., Gigante, B., Goodarzi, M. O., Gordon-Larsen, P., Grallert, H., Grarup, N., Grimsgaard, S., Groop, L., Gudnason, V., Guo, X., Hamsten, A., Hansen, T., Hayward, C., Heckbert, S. R., Horta, B. L., Huang, W., Ingelsson, E., James, P. S., Jarvelin, M. -R., Jonas, J. B., Jukema, J. W., Kaleebu, P., Kaplan, R., Kardia, S. L. R., Kato, N., Keinanen-Kiukaanniemi, S. M., Kim, B. -J., Kivimaki, M., Koistinen, H. A., Kooner, J. S., Korner, A., Kovacs, P., Kuh, D., Kumari, M., Kutalik, Z., Laakso, M., Lakka, T. A., Launer, L. J., Leander, K., Lin, X., Lind, L., Lindgren, C., Liu, S., Loos, R. J. F., Magnusson, P. K. E., Mahajan, A., Metspalu, A., Mook-Kanamori, D. O., Mori, T. A., Munroe, P. B., Njolstad, I., O'Connell, J. R., Oldehinkel, A. J., Ong, K. K., Padmanabhan, S., Palmer, C. N. A., Palmer, N. D., Pedersen, O., Pennell, C. E., Porteous, D. J., Pramstaller, P. P., Province, M. A., Psaty, B. M., Qi, L., Raffel, L. J., Rauramaa, R., Redline, S., Ridker, P. M., Rosendaal, F. R., Saaristo, T. E., Sandhu, M., Saramies, J., Schneiderman, N., Schwarz, P., Scott, L. J., Selvin, E., Sever, P., Shu, X. -O., Slagboom, P. E., Small, K. S., Smith, B. H., Snieder, H., Sofer, T., Sorensen, T. I. A., Spector, T. D., Stanton, A., Steves, C. J., Stumvoll, M., Sun, L., Tabara, Y., Tai, E. S., Timpson, N. J., Tonjes, A., Tuomilehto, J., Tusie, T., Uusitupa, M., van der Harst, P., van Duijn, C., Vitart, V., Vollenweider, P., Vrijkotte, T. G. M., Wagenknecht, L. E., Walker, M., Wang, Y. X., Wareham, N. J., Watanabe, R. M., Watkins, H., Wei, W. B., Wickremasinghe, A. R., Willemsen, G., Wilson, J. F., Wong, T. -Y., Wu, J. -Y., Xiang, A. H., Yanek, L. R., Yengo, L., Yokota, M., Zeggini, E., Zheng, W., Zonderman, A. B., Rotter, J. I., Gloyn, A. L., Mccarthy, M. I., Dupuis, J., Meigs, J. B., Scott, R. A., Prokopenko, I., Leong, A., Liu, C. -T., Parker, S. C. J., Mohlke, K. L., Langenberg, C., Wheeler, E., Morris, A. P., Barroso, I., van Willems van Dijk, K., Wang C., Bertoni A. (ORCID:0000-0001-7228-8718), Mingrone G. (ORCID:0000-0003-2021-528X), Tremoli E., Chen, J., Spracklen, C. N., Marenne, G., Varshney, A., Corbin, L. J., Luan, J., Willems, S. M., Wu, Y., Zhang, X., Horikoshi, M., Boutin, T. S., Magi, R., Waage, J., Li-Gao, R., Chan, K. H. K., Yao, J., Anasanti, M. D., Chu, A. Y., Claringbould, A., Heikkinen, J., Hong, J., Hottenga, J. -J., Huo, S., Kaakinen, M. A., Louie, T., Marz, W., Moreno-Macias, H., Ndungu, A., Nelson, S. C., Nolte, I. M., North, K. E., Raulerson, C. K., Ray, D., Rohde, R., Rybin, D., Schurmann, C., Sim, X., Southam, L., Stewart, I. D., Wang, C. A., Wang, Y., Wu, P., Zhang, W., Ahluwalia, T. S., Appel, E. V. R., Bielak, L. F., Brody, J. A., Burtt, N. P., Cabrera, C. P., Cade, B. E., Chai, J. F., Chai, X., Chang, L. -C., Chen, C. -H., Chen, B. H., Chitrala, K. N., Chiu, Y. -F., de Haan, H. G., Delgado, G. E., Demirkan, A., Duan, Q., Engmann, J., Fatumo, S. A., Gayan, J., Giulianini, F., Gong, J. H., Gustafsson, S., Hai, Y., Hartwig, F. P., He, J., Heianza, Y., Huang, T., Huerta-Chagoya, A., Hwang, M. Y., Jensen, R. A., Kawaguchi, T., Kentistou, K. A., Kim, Y. J., Kleber, M. E., Kooner, I. K., Lai, S., Lange, L. A., Langefeld, C. D., Lauzon, M., Li, M., Ligthart, S., Liu, J., Loh, M., Long, J., Lyssenko, V., Mangino, M., Marzi, C., Montasser, M. E., Nag, A., Nakatochi, M., Noce, D., Noordam, R., Pistis, G., Preuss, M., Raffield, L., Rasmussen-Torvik, L. J., Rich, S. S., Robertson, N. R., Rueedi, R., Ryan, K., Sanna, S., Saxena, R., Schraut, K. E., Sennblad, B., Setoh, K., Smith, A. V., Sparso, T., Strawbridge, R. J., Takeuchi, F., Tan, J., Trompet, S., van den Akker, E., van der Most, P. J., Verweij, N., Vogel, M., Wang, H., Wang, Chin Heng, Wang, N., Warren, H. R., Wen, W., Wilsgaard, T., Wong, A., Wood, A. R., Xie, T., Zafarmand, M. H., Zhao, J. -H., Zhao, W., Amin, N., Arzumanyan, Z., Astrup, A., Bakker, S. J. L., Baldassarre, D., Beekman, M., Bergman, R. N., Bertoni, Anna Marta Maria, Bluher, M., Bonnycastle, L. L., Bornstein, S. R., Bowden, D. W., Cai, Q., Campbell, A., Campbell, H., Chang, Y. C., de Geus, E. J. C., Dehghan, A., Du, S., Eiriksdottir, G., Farmaki, A. E., Franberg, M., Fuchsberger, C., Gao, Y., Gjesing, A. P., Goel, A., Han, S., Hartman, C. A., Herder, C., Hicks, A. A., Hsieh, C. -H., Hsueh, W. A., Ichihara, S., Igase, M., Ikram, M. A., Johnson, W. C., Jorgensen, M. E., Joshi, P. K., Kalyani, R. R., Kandeel, F. R., Katsuya, T., Khor, C. C., Kiess, W., Kolcic, I., Kuulasmaa, T., Kuusisto, J., Lall, K., Lam, K., Lawlor, D. A., Lee, N. R., Lemaitre, R. N., Li, H., Lin, S. -Y., Lindstrom, J., Linneberg, A., Lorenzo, C., Matsubara, T., Matsuda, F., Mingrone, Geltrude, Mooijaart, S., Moon, S., Nabika, T., Nadkarni, G. N., Nadler, J. L., Nelis, M., Neville, M. J., Norris, J. M., Ohyagi, Y., Peters, A., Peyser, P. A., Polasek, O., Qi, Q., Raven, D., Reilly, D. F., Reiner, A., Rivideneira, F., Roll, K., Rudan, I., Sabanayagam, C., Sandow, K., Sattar, N., Schurmann, A., Shi, J., Stringham, H. M., Taylor, K. D., Teslovich, T. M., Thuesen, B., Timmers, P. R. H. J., Tremoli, Elena, Tsai, M. Y., Uitterlinden, A., van Dam, R. M., van Heemst, D., van Hylckama Vlieg, A., van Vliet-Ostaptchouk, J. V., Vangipurapu, J., Vestergaard, H., Wang, T., Willems van Dijk, K., Zemunik, T., Abecasis, G. R., Adair, L. S., Aguilar-Salinas, C. A., Alarcon-Riquelme, M. E., An, P., Aviles-Santa, L., Becker, D. M., Beilin, L. J., Bergmann, S., Bisgaard, H., Black, C., Boehnke, M., Boerwinkle, E., Bohm, B. O., Bonnelykke, K., Boomsma, D. I., Bottinger, E. P., Buchanan, T. A., Canouil, M., Caulfield, M. J., Chambers, J. C., Chasman, D. I., Chen, Y. -D. I., Cheng, C. -Y., Collins, F. S., Correa, A., Cucca, F., de Silva, H. J., Dedoussis, G., Elmstahl, S., Evans, M. K., Ferrannini, E., Ferrucci, L., Florez, J. C., Franks, P. W., Frayling, T. M., Froguel, P., Gigante, B., Goodarzi, M. O., Gordon-Larsen, P., Grallert, H., Grarup, N., Grimsgaard, S., Groop, L., Gudnason, V., Guo, X., Hamsten, A., Hansen, T., Hayward, C., Heckbert, S. R., Horta, B. L., Huang, W., Ingelsson, E., James, P. S., Jarvelin, M. -R., Jonas, J. B., Jukema, J. W., Kaleebu, P., Kaplan, R., Kardia, S. L. R., Kato, N., Keinanen-Kiukaanniemi, S. M., Kim, B. -J., Kivimaki, M., Koistinen, H. A., Kooner, J. S., Korner, A., Kovacs, P., Kuh, D., Kumari, M., Kutalik, Z., Laakso, M., Lakka, T. A., Launer, L. J., Leander, K., Lin, X., Lind, L., Lindgren, C., Liu, S., Loos, R. J. F., Magnusson, P. K. E., Mahajan, A., Metspalu, A., Mook-Kanamori, D. O., Mori, T. A., Munroe, P. B., Njolstad, I., O'Connell, J. R., Oldehinkel, A. J., Ong, K. K., Padmanabhan, S., Palmer, C. N. A., Palmer, N. D., Pedersen, O., Pennell, C. E., Porteous, D. J., Pramstaller, P. P., Province, M. A., Psaty, B. M., Qi, L., Raffel, L. J., Rauramaa, R., Redline, S., Ridker, P. M., Rosendaal, F. R., Saaristo, T. E., Sandhu, M., Saramies, J., Schneiderman, N., Schwarz, P., Scott, L. J., Selvin, E., Sever, P., Shu, X. -O., Slagboom, P. E., Small, K. S., Smith, B. H., Snieder, H., Sofer, T., Sorensen, T. I. A., Spector, T. D., Stanton, A., Steves, C. J., Stumvoll, M., Sun, L., Tabara, Y., Tai, E. S., Timpson, N. J., Tonjes, A., Tuomilehto, J., Tusie, T., Uusitupa, M., van der Harst, P., van Duijn, C., Vitart, V., Vollenweider, P., Vrijkotte, T. G. M., Wagenknecht, L. E., Walker, M., Wang, Y. X., Wareham, N. J., Watanabe, R. M., Watkins, H., Wei, W. B., Wickremasinghe, A. R., Willemsen, G., Wilson, J. F., Wong, T. -Y., Wu, J. -Y., Xiang, A. H., Yanek, L. R., Yengo, L., Yokota, M., Zeggini, E., Zheng, W., Zonderman, A. B., Rotter, J. I., Gloyn, A. L., Mccarthy, M. I., Dupuis, J., Meigs, J. B., Scott, R. A., Prokopenko, I., Leong, A., Liu, C. -T., Parker, S. C. J., Mohlke, K. L., Langenberg, C., Wheeler, E., Morris, A. P., Barroso, I., van Willems van Dijk, K., Wang C., Bertoni A. (ORCID:0000-0001-7228-8718), Mingrone G. (ORCID:0000-0003-2021-528X), and Tremoli E.

Abstract

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10−8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

Published
2021

29. Correction: Socio-economic position as a moderator of cardiometabolic outcomes in patients receiving psychotropic treatment associated with weight gain: results from a prospective 12-month inception cohort study and a large population-based cohort.

Author

Dubath, C., Gholam-Rezaee, M., Sjaarda, J., Levier, A., Saigi-Morgui, N., Delacrétaz, A., Glatard, A., Panczak, R., Correll, C.U., Solida, A., Plessen, K.J., von Gunten, A., Kutalik, Z., Conus, P., Eap, C.B., Dubath, C., Gholam-Rezaee, M., Sjaarda, J., Levier, A., Saigi-Morgui, N., Delacrétaz, A., Glatard, A., Panczak, R., Correll, C.U., Solida, A., Plessen, K.J., von Gunten, A., Kutalik, Z., Conus, P., and Eap, C.B.

Published
2021

30. New quality measure for SNP array based CNV detection

Author

Macé, A., Tuke, M.A., Beckmann, J.S., Lin, L., Jacquemont, S., Weedon, M.N., Reymond, A., Kutalik, Z., Macé, A., Tuke, M.A., Beckmann, J.S., Lin, L., Jacquemont, S., Weedon, M.N., Reymond, A., and Kutalik, Z.

Abstract

Motivation: Only a few large systematic studies have evaluated the impact of copy number variants (CNVs) on common diseases. Several million individuals have been genotyped on single nucleotide variation arrays, which could be used for genome-wide CNVs association studies. However, CNV calls remain prone to false positives and only empirical filtering strategies exist in the literature. To overcome this issue, we defined a new quality score (QS) estimating the probability of a CNV called by PennCNV to be confirmed by other software. Results: Out-of-sample comparison showed that the correlation between the consensus CNV status and the QS is twice as high as it is for any previously proposed CNV filters. ROC curves displayed an AUC higher than 0.8 and simulations showed an increase up to 20% in statistical power when using QS in comparison to other filtering strategies. Superior performance was confirmed also for alternative consensus CNV definition and through improving known CNV-trait associations. Availability and Implementation: http://goo.gl/T6yuFM Contact: zoltan.kutalik@unil.ch or aurelien@mace@unil.ch Supplementary information: Supplementary data are available at Bioinformatics online.

Published
2021

31. Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity (Nature Genetics, (2018), 50, 1, (26-41), 10.1038/s41588-017-0011-x)

Author

Turcot, V., Lu, Y., Highland, H. M., Schurmann, C., Justice, A. E., Fine, R. S., Bradfield, J. P., Esko, T., Giri, A., Graff, M., Guo, X., Hendricks, A. E., Karaderi, T., Lempradl, A., Locke, A. E., Mahajan, A., Marouli, E., Sivapalaratnam, S., Young, K. L., Alfred, T., Feitosa, M. F., Masca, N. G. D., Manning, A. K., Medina-Gomez, C., Mudgal, P., M. C. Y., Ng, Reiner, A. P., Vedantam, S., Willems, S. M., Winkler, T. W., Abecasis, G., Aben, K. K., Alam, D. S., Alharthi, S. E., Marchiori, Allison, Amouyel, P., Asselbergs, F. W., Auer, P. L., Balkau, B., Bang, L. E., Barroso, I., Bastarache, L., Benn, M., Bergmann, S., Bielak, L. F., Bluher, M., Boehnke, M., Boeing, H., Boerwinkle, E., Boger, C. A., Bork-Jensen, J., Bots, M. L., Bottinger, E. P., Bowden, D. W., Brandslund, I., Breen, G., Brilliant, M. H., Broer, L., Brumat, M., Burt, A. A., Butterworth, A. S., Campbell, P. T., Cappellani, S., Carey, D. J., Catamo, E., Caulfield, M. J., Chambers, J. C., Chasman, D. I., Chen, Y. -D. I., Chowdhury, R., Christensen, C., Chu, A. Y., Cocca, M., Collins, F. S., Cook, J. P., Corley, J., Galbany, J. C., Cox, A. J., Crosslin, D. S., Cuellar-Partida, G., D'Eustacchio, A., Danesh, J., Davies, G., Bakker, P. I. W., Groot, M. C. H., Mutsert, R., Deary, I. J., Dedoussis, G., Demerath, E. W., Heijer, M., Hollander, A. I., Ruijter, H. M., Dennis, J. G., Denny, J. C., Di Angelantonio, E., Drenos, F., Du, M., Dube, M. -P., Dunning, A. M., Easton, D. F., Edwards, T. L., Ellinghaus, D., Ellinor, P. T., Elliott, P., Evangelou, E., Farmaki, A. -E., Farooqi, I. S., Faul, J. D., Fauser, S., Feng, S., Ferrannini, E., Ferrieres, J., Florez, J. C., Ford, I., Fornage, M., Franco, O. H., Franke, A., Franks, P. W., Friedrich, N., Frikke-Schmidt, R., Galesloot, T. E., Gan, W., Gandin, I., Gasparini, P., Gibson, J., Giedraitis, V., Gjesing, A. P., Gordon-Larsen, P., Gorski, M., Grabe, H. -J., Grant, S. F. A., Grarup, N., Griffiths, H. L., Grove, M. L., Gudnason, V., Gustafsson, S., Haessler, J., Hakonarson, H., Hammerschlag, A. R., Hansen, T., Harris, K. M., Harris, T. B., Hattersley, A. T., Have, C. T., Hayward, C., He, L., Heard-Costa, N. L., Heath, A. C., Heid, I. M., Helgeland, O., Hernesniemi, J., Hewitt, A. W., Holmen, O. L., Hovingh, G. K., Howson, J. M. M., Hu, Y., Huang, P. L., Huffman, J. E., Ikram, M. A., Ingelsson, E., Jackson, A. U., Jansson, J. -H., Jarvik, G. P., Jensen, G. B., Jia, Y., Johansson, S., Jorgensen, M. E., Jorgensen, T., Jukema, J. W., Kahali, B., Kahn, R. S., Kahonen, M., Kamstrup, P. R., Kanoni, S., Kaprio, J., Karaleftheri, M., Kardia, S. L. R., Karpe, F., Kathiresan, S., Kee, F., Kiemeney, L. A., Kim, E., Kitajima, H., Komulainen, P., Kooner, J. S., Kooperberg, C., Korhonen, T., Kovacs, P., Kuivaniemi, H., Kutalik, Z., Kuulasmaa, K., Kuusisto, J., Laakso, M., Lakka, T. A., Lamparter, D., Lange, E. M., Lange, L. A., Langenberg, C., Larson, E. B., Lee, N. R., Lehtimaki, T., Lewis, C. E., Li, H., Li, J., Li-Gao, R., Lin, H., Lin, K. -H., Lin, L. -A., Lin, X., Lind, L., Lindstrom, J., Linneberg, A., Liu, C. -T., Liu, D. J., Liu, Y., K. S., Lo, Lophatananon, A., Lotery, A. J., Loukola, A., Luan, J., Lubitz, S. A., Lyytikainen, L. -P., Mannisto, S., Marenne, G., Mazul, A. L., Mccarthy, M. I., McKean-Cowdin, R., Medland, S. E., Meidtner, K., Milani, L., Mistry, V., Mitchell, P., Mohlke, K. L., Moilanen, L., Moitry, M., Montgomery, G. W., Mook-Kanamori, D. O., Moore, C., Mori, T. A., Morris, A. D., Morris, A. P., Muller-Nurasyid, M., Munroe, P. B., Nalls, M. A., Narisu, N., Nelson, C. P., Neville, M., Nielsen, S. F., Nikus, K., Njolstad, P. R., Nordestgaard, B. G., Nyholt, D. R., O'Connel, J. R., O'Donoghue, M. L., Loohuis, L. M. O., Ophoff, R. A., Owen, K. R., Packard, C. J., Padmanabhan, S., Palmer, C. N. A., Palmer, N. D., Pasterkamp, G., Patel, A. P., Pattie, A., Pedersen, O., Peissig, P. L., Peloso, G. M., Pennell, C. E., Perola, M., Perry, J. A., Perry, J. R. B., Pers, T. H., Person, T. N., Peters, A., Petersen, E. R. B., Peyser, P. A., Pirie, A., Polasek, O., Polderman, T. J., Puolijoki, H., Raitakari, O. T., Rasheed, A., Rauramaa, R., Reilly, D. F., Renstrom, F., Rheinberger, M., Ridker, P. M., Rioux, J. D., Rivas, M. A., Roberts, D. J., Robertson, N. R., Robino, A., Rolandsson, O., Rudan, I., Ruth, K. S., Saleheen, D., Salomaa, V., Samani, N. J., Sapkota, Y., Sattar, N., Schoen, R. E., Schreiner, P. J., Schulze, M. B., Scott, R. A., Segura-Lepe, M. P., Shah, S. H., Sheu, W. H. -H., Sim, X., Slater, A. J., Small, K. S., Smith, A. V., Southam, L., Spector, T. D., Speliotes, E. K., Starr, J. M., Stefansson, K., Steinthorsdottir, V., Stirrups, K. E., Strauch, K., Stringham, H. M., Stumvoll, M., Sun, L., Surendran, P., Swift, A. J., Tada, H., Tansey, K. E., Tardif, J. -C., Taylor, K. D., Teumer, A., Thompson, D. J., Thorleifsson, G., Thorsteinsdottir, U., Thuesen, B. H., Tonjes, A., Tromp, G., Trompet, S., Tsafantakis, E., Tuomilehto, J., Tybjaerg-Hansen, A., Tyrer, J. P., Uher, R., Uitterlinden, A. G., Uusitupa, M., Laan, S. W., Duijn, C. M., Leeuwen, N., van Setten, J., Vanhala, M., Varbo, A., Varga, T. V., Varma, R., Edwards, D. R. V., Vermeulen, S. H., Veronesi, G., Vestergaard, H., Vitart, V., Vogt, T. F., Volker, U., Vuckovic, D., Wagenknecht, L. E., Walker, M., Wallentin, L., Wang, F., Wang, C. A., Wang, S., Wang, Y., Ware, E. B., Wareham, N. J., Warren, H. R., Waterworth, D. M., Wessel, J., White, H. D., Willer, C. J., Wilson, J. G., Witte, D. R., Wood, A. R., Wu, Y., Yaghootkar, H., Yao, J., Yao, P., Yerges-Armstrong, L. M., Young, R., Zeggini, E., Zhan, X., Zhang, W., Zhao, J. H., Zhao, W., Zhou, W., Zondervan, K. T., Rotter, J. I., Pospisilik, J. A., Rivadeneira, F., Borecki, I. B., Deloukas, P., Frayling, T. M., Lettre, G., North, K. E., Lindgren, C. M., Hirschhorn, J. N., Loos, R. J. F., Turcot, V., Lu, Y., Highland, H. M., Schurmann, C., Justice, A. E., Fine, R. S., Bradfield, J. P., Esko, T., Giri, A., Graff, M., Guo, X., Hendricks, A. E., Karaderi, T., Lempradl, A., Locke, A. E., Mahajan, A., Marouli, E., Sivapalaratnam, S., Young, K. L., Alfred, T., Feitosa, M. F., Masca, N. G. D., Manning, A. K., Medina-Gomez, C., Mudgal, P., Ng, M. C. Y., Reiner, A. P., Vedantam, S., Willems, S. M., Winkler, T. W., Abecasis, G., Aben, K. K., Alam, D. S., Alharthi, S. E., Marchiori, Allison, Amouyel, P., Asselbergs, F. W., Auer, P. L., Balkau, B., Bang, L. E., Barroso, I., Bastarache, L., Benn, M., Bergmann, S., Bielak, L. F., Bluher, M., Boehnke, M., Boeing, H., Boerwinkle, E., Boger, C. A., Bork-Jensen, J., Bots, M. L., Bottinger, E. P., Bowden, D. W., Brandslund, I., Breen, G., Brilliant, M. H., Broer, L., Brumat, M., Burt, A. A., Butterworth, A. S., Campbell, P. T., Cappellani, S., Carey, D. J., Catamo, E., Caulfield, M. J., Chambers, J. C., Chasman, D. I., Chen, Y. -D. I., Chowdhury, R., Christensen, C., Chu, A. Y., Cocca, M., Collins, F. S., Cook, J. P., Corley, J., Galbany, J. C., Cox, A. J., Crosslin, D. S., Cuellar-Partida, G., D'Eustacchio, A., Danesh, J., Davies, G., Bakker, P. I. W., Groot, M. C. H., Mutsert, R., Deary, I. J., Dedoussis, G., Demerath, E. W., Heijer, M., Hollander, A. I., Ruijter, H. M., Dennis, J. G., Denny, J. C., Di Angelantonio, E., Drenos, F., Du, M., Dube, M. -P., Dunning, A. M., Easton, D. F., Edwards, T. L., Ellinghaus, D., Ellinor, P. T., Elliott, P., Evangelou, E., Farmaki, A. -E., Farooqi, I. S., Faul, J. D., Fauser, S., Feng, S., Ferrannini, E., Ferrieres, J., Florez, J. C., Ford, I., Fornage, M., Franco, O. H., Franke, A., Franks, P. W., Friedrich, N., Frikke-Schmidt, R., Galesloot, T. E., Gan, W., Gandin, I., Gasparini, P., Gibson, J., Giedraitis, V., Gjesing, A. P., Gordon-Larsen, P., Gorski, M., Grabe, H. -J., Grant, S. F. A., Grarup, N., Griffiths, H. L., Grove, M. L., Gudnason, V., Gustafsson, S., Haessler, J., Hakonarson, H., Hammerschlag, A. R., Hansen, T., Harris, K. M., Harris, T. B., Hattersley, A. T., Have, C. T., Hayward, C., He, L., Heard-Costa, N. L., Heath, A. C., Heid, I. M., Helgeland, O., Hernesniemi, J., Hewitt, A. W., Holmen, O. L., Hovingh, G. K., Howson, J. M. M., Hu, Y., Huang, P. L., Huffman, J. E., Ikram, M. A., Ingelsson, E., Jackson, A. U., Jansson, J. -H., Jarvik, G. P., Jensen, G. B., Jia, Y., Johansson, S., Jorgensen, M. E., Jorgensen, T., Jukema, J. W., Kahali, B., Kahn, R. S., Kahonen, M., Kamstrup, P. R., Kanoni, S., Kaprio, J., Karaleftheri, M., Kardia, S. L. R., Karpe, F., Kathiresan, S., Kee, F., Kiemeney, L. A., Kim, E., Kitajima, H., Komulainen, P., Kooner, J. S., Kooperberg, C., Korhonen, T., Kovacs, P., Kuivaniemi, H., Kutalik, Z., Kuulasmaa, K., Kuusisto, J., Laakso, M., Lakka, T. A., Lamparter, D., Lange, E. M., Lange, L. A., Langenberg, C., Larson, E. B., Lee, N. R., Lehtimaki, T., Lewis, C. E., Li, H., Li, J., Li-Gao, R., Lin, H., Lin, K. -H., Lin, L. -A., Lin, X., Lind, L., Lindstrom, J., Linneberg, A., Liu, C. -T., Liu, D. J., Liu, Y., Lo, K. S., Lophatananon, A., Lotery, A. J., Loukola, A., Luan, J., Lubitz, S. A., Lyytikainen, L. -P., Mannisto, S., Marenne, G., Mazul, A. L., Mccarthy, M. I., McKean-Cowdin, R., Medland, S. E., Meidtner, K., Milani, L., Mistry, V., Mitchell, P., Mohlke, K. L., Moilanen, L., Moitry, M., Montgomery, G. W., Mook-Kanamori, D. O., Moore, C., Mori, T. A., Morris, A. D., Morris, A. P., Muller-Nurasyid, M., Munroe, P. B., Nalls, M. A., Narisu, N., Nelson, C. P., Neville, M., Nielsen, S. F., Nikus, K., Njolstad, P. R., Nordestgaard, B. G., Nyholt, D. R., O'Connel, J. R., O'Donoghue, M. L., Loohuis, L. M. O., Ophoff, R. A., Owen, K. R., Packard, C. J., Padmanabhan, S., Palmer, C. N. A., Palmer, N. D., Pasterkamp, G., Patel, A. P., Pattie, A., Pedersen, O., Peissig, P. L., Peloso, G. M., Pennell, C. E., Perola, M., Perry, J. A., Perry, J. R. B., Pers, T. H., Person, T. N., Peters, A., Petersen, E. R. B., Peyser, P. A., Pirie, A., Polasek, O., Polderman, T. J., Puolijoki, H., Raitakari, O. T., Rasheed, A., Rauramaa, R., Reilly, D. F., Renstrom, F., Rheinberger, M., Ridker, P. M., Rioux, J. D., Rivas, M. A., Roberts, D. J., Robertson, N. R., Robino, A., Rolandsson, O., Rudan, I., Ruth, K. S., Saleheen, D., Salomaa, V., Samani, N. J., Sapkota, Y., Sattar, N., Schoen, R. E., Schreiner, P. J., Schulze, M. B., Scott, R. A., Segura-Lepe, M. P., Shah, S. H., Sheu, W. H. -H., Sim, X., Slater, A. J., Small, K. S., Smith, A. V., Southam, L., Spector, T. D., Speliotes, E. K., Starr, J. M., Stefansson, K., Steinthorsdottir, V., Stirrups, K. E., Strauch, K., Stringham, H. M., Stumvoll, M., Sun, L., Surendran, P., Swift, A. J., Tada, H., Tansey, K. E., Tardif, J. -C., Taylor, K. D., Teumer, A., Thompson, D. J., Thorleifsson, G., Thorsteinsdottir, U., Thuesen, B. H., Tonjes, A., Tromp, G., Trompet, S., Tsafantakis, E., Tuomilehto, J., Tybjaerg-Hansen, A., Tyrer, J. P., Uher, R., Uitterlinden, A. G., Uusitupa, M., Laan, S. W., Duijn, C. M., Leeuwen, N., van Setten, J., Vanhala, M., Varbo, A., Varga, T. V., Varma, R., Edwards, D. R. V., Vermeulen, S. H., Veronesi, G., Vestergaard, H., Vitart, V., Vogt, T. F., Volker, U., Vuckovic, D., Wagenknecht, L. E., Walker, M., Wallentin, L., Wang, F., Wang, C. A., Wang, S., Wang, Y., Ware, E. B., Wareham, N. J., Warren, H. R., Waterworth, D. M., Wessel, J., White, H. D., Willer, C. J., Wilson, J. G., Witte, D. R., Wood, A. R., Wu, Y., Yaghootkar, H., Yao, J., Yao, P., Yerges-Armstrong, L. M., Young, R., Zeggini, E., Zhan, X., Zhang, W., Zhao, J. H., Zhao, W., Zhou, W., Zondervan, K. T., Rotter, J. I., Pospisilik, J. A., Rivadeneira, F., Borecki, I. B., Deloukas, P., Frayling, T. M., Lettre, G., North, K. E., Lindgren, C. M., Hirschhorn, J. N., and Loos, R. J. F.

Subjects
Publisher correction
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

32. Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

Author

Glanville, KP, Coleman, JR, Hanscombe, KB, Euesden, J, Choi, SW, Purves, KL, Breen, G, Air, TM, Andlauer, TFM, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Buttenschon, HN, Colodro-Conde, L, Dannlowski, U, Direk, N, Dunn, EC, Forstner, AJ, de Geus, EJC, Grabe, HJ, Hamilton, SP, Jones, I, Jones, LA, Knowles, JA, Kutalik, Z, Levinson, DF, Lewis, G, Lind, PA, Lucae, S, Magnusson, PK, McGuffin, P, McIntosh, AM, Milaneschi, Y, Mors, O, Mostafavi, S, Mueller-Myhsok, B, Pedersen, NL, Penninx, BWJH, Potash, JB, Preisig, M, Ripke, S, Shi, J, Shyn, S, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, Van der Auwera, S, Weissman, MM, O'Reilly, PF, Lewis, CM, Wray, NR, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Bryois, J, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Dolan, C, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jorgenson, E, Kohane, IS, Kraft, J, Kretzschmar, WW, Li, Y, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milani, L, Mondimore, FM, Montgomery, GW, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Cichon, S, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Li, QS, Madden, PAF, Martin, NG, Metspalu, A, Mortensen, PB, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Perlis, RH, Porteous, DJ, Rietschel, M, Schaefer, C, Schulze, TG, Stefansson, K, Voelzke, H, Werge, T, Borglum, AD, Glanville, KP, Coleman, JR, Hanscombe, KB, Euesden, J, Choi, SW, Purves, KL, Breen, G, Air, TM, Andlauer, TFM, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Buttenschon, HN, Colodro-Conde, L, Dannlowski, U, Direk, N, Dunn, EC, Forstner, AJ, de Geus, EJC, Grabe, HJ, Hamilton, SP, Jones, I, Jones, LA, Knowles, JA, Kutalik, Z, Levinson, DF, Lewis, G, Lind, PA, Lucae, S, Magnusson, PK, McGuffin, P, McIntosh, AM, Milaneschi, Y, Mors, O, Mostafavi, S, Mueller-Myhsok, B, Pedersen, NL, Penninx, BWJH, Potash, JB, Preisig, M, Ripke, S, Shi, J, Shyn, S, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, Van der Auwera, S, Weissman, MM, O'Reilly, PF, Lewis, CM, Wray, NR, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Bryois, J, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Dolan, C, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jorgenson, E, Kohane, IS, Kraft, J, Kretzschmar, WW, Li, Y, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milani, L, Mondimore, FM, Montgomery, GW, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Cichon, S, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Li, QS, Madden, PAF, Martin, NG, Metspalu, A, Mortensen, PB, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Perlis, RH, Porteous, DJ, Rietschel, M, Schaefer, C, Schulze, TG, Stefansson, K, Voelzke, H, Werge, T, and Borglum, AD

Abstract

BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

Published
2020

33. Genetic comorbidity between major depression and cardio-metabolic traits, stratified by age at onset of major depression

Author

Hagenaars, SP, Coleman, JR, Choi, SW, Gaspar, H, Adams, MJ, Howard, DM, Hodgson, K, Traylor, M, Air, TM, Andlauer, TFM, Arolt, V, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Campbell, A, Cearns, M, Czamara, D, Dannlowski, U, Domschke, K, de Geus, EJC, Hamilton, SP, Hayward, C, Hickie, IB, Hottenga, JJ, Ising, M, Jones, I, Jones, L, Kutalik, Z, Lucae, S, Martin, NG, Milaneschi, Y, Mueller-Myhsok, B, Owen, MJ, Padmanabhan, S, Penninx, BWJH, Pistis, G, Porteous, DJ, Preisig, M, Ripke, S, Shyn, S, Sullivan, PF, Whitfield, JB, Wray, NR, McIntosh, AM, Deary, IJ, Breen, G, Lewis, CM, Hagenaars, SP, Coleman, JR, Choi, SW, Gaspar, H, Adams, MJ, Howard, DM, Hodgson, K, Traylor, M, Air, TM, Andlauer, TFM, Arolt, V, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Campbell, A, Cearns, M, Czamara, D, Dannlowski, U, Domschke, K, de Geus, EJC, Hamilton, SP, Hayward, C, Hickie, IB, Hottenga, JJ, Ising, M, Jones, I, Jones, L, Kutalik, Z, Lucae, S, Martin, NG, Milaneschi, Y, Mueller-Myhsok, B, Owen, MJ, Padmanabhan, S, Penninx, BWJH, Pistis, G, Porteous, DJ, Preisig, M, Ripke, S, Shyn, S, Sullivan, PF, Whitfield, JB, Wray, NR, McIntosh, AM, Deary, IJ, Breen, G, and Lewis, CM

Abstract

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

Published
2020

34. Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank

Author

Coleman, JRI, Peyrot, WJ, Purves, KL, Davis, KAS, Rayner, C, Choi, SW, Hubel, C, Gaspar, HA, Kan, C, Van der Auwera, S, Adams, MJ, Lyall, DM, Choi, KW, Dunn, EC, Vassos, E, Danese, A, Maughan, B, Grabe, HJ, Lewis, CM, O'Reilly, PF, McIntosh, AM, Smith, DJ, Wray, NR, Hotopf, M, Eley, TC, Breen, G, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Volzke, H, Weissman, MM, Werge, T, Levinson, DF, Borglum, AD, Sullivan, PF, Coleman, JRI, Peyrot, WJ, Purves, KL, Davis, KAS, Rayner, C, Choi, SW, Hubel, C, Gaspar, HA, Kan, C, Van der Auwera, S, Adams, MJ, Lyall, DM, Choi, KW, Dunn, EC, Vassos, E, Danese, A, Maughan, B, Grabe, HJ, Lewis, CM, O'Reilly, PF, McIntosh, AM, Smith, DJ, Wray, NR, Hotopf, M, Eley, TC, Breen, G, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Volzke, H, Weissman, MM, Werge, T, Levinson, DF, Borglum, AD, and Sullivan, PF

Abstract

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

Published
2020

36. Antibodies against the c-terminus of apoA-1 as predictors of death in the general population but not as therapeutic targets actionable through cognate peptides immunomodulation

Author

Vuilleumier, N, primary, Antiochos, P, additional, Marques Vidal, P, additional, Virzi, J, additional, Pagano, S, additional, Satta, N, additional, Hartley, O, additional, Brandt, K, additional, Burger, F, additional, Montecucco, F, additional, Kutalik, Z, additional, Waeber, G, additional, Mach, F, additional, and Vollenweider, P, additional

Published
2020
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37. Quality control and conduct of genome-wide association meta-analyses

Author

Winkler, T, Day, F, Croteau Chonka, D, Wood, A, Locke, A, Mägi, R, Ferreira, T, Fall, T, Graff, M, Justice, A, Luan, J, Gustafsson, S, Randall, J, Vedantam, S, Workalemahu, T, Kilpeläinen, T, Scherag, A, Esko, T, Kutalik, Z, Heid, I, Loos, R, Abecasis GR, Absher D, Alavere H, Albrecht E, Allen HL, Almgren P, Amin N, Amouyel P, Anderson D, Arnold AM, Arveiler D, Aspelund T, Asselbergs FW, Assimes TL, Atalay M, Attwood AP, Atwood LD, Bakker SJ, Balkau B, Balmforth AJ, Barlassina C, Barroso I, Basart H, Bauer S, Beckmann JS, Beilby JP, Bennett AJ, Ben Shlomo Y, Bergman RN, Bergmann S, Berndt SI, Biffar R, Di Blasio AM, Boehm BO, Boehnke M, Boeing H, Boerwinkle E, Bolton JL, Bonnefond A, Bonnycastle LL, Boomsma DI, Borecki IB, Bornstein SR, Bouatia Naji N, Boucher G, Bragg Gresham JL, BRAMBILLA, PAOLO, Bruinenberg M, Buchanan TA, Buechler C, Cadby G, Campbell H, Caulfield MJ, Cavalcanti Proença C, CESANA, GIANCARLO, Chanock SJ, Chasman DI, Chen YD, Chines PS, Clegg DJ, Coin L, Collins FS, Connell JM, Cookson W, Cooper MN, Croteau Chonka DC, Cupples LA, Cusi D, Day FR, Day IN, Dedoussis GV, Dei M, Deloukas P, Dermitzakis ET, Dimas AS, Dimitriou M, Dixon AL, Dörr M, van Duijn CM, Ebrahim S, Edkins S, Eiriksdottir G, Eisinger K, Eklund N, Elliott P, Erbel R, Erdmann J, Erdos MR, Eriksson JG, Esko T, Estrada K, Evans DM, de Faire U, Fall T, Farrall M, Feitosa MF, Ferrario MM, Ferreira T, Ferrières J, Fischer K, Fisher E, Fowkes G, Fox CS, Franke L, Franks PW, Fraser RM, Frau F, Frayling T, Freimer NB, Froguel P, Fu M, Gaget S, Ganna A, Gejman PV, Gentilini D, Geus EJ, Gieger C, Gigante B, Gjesing AP, Glazer NL, Goddard ME, Goel A, Grallert H, Gräßler J, Grönberg H, Groop LC, Groves CJ, Gudnason V, Guiducci C, Gustafsson S, Gyllensten U, Hall AS, Hall P, Hallmans G, Hamsten A, Hansen T, Haritunians T, Harris TB, van der Harst P, Hartikainen AL, Hassanali N, Hattersley AT, Havulinna AS, Hayward C, Heard Costa NL, Heath AC, Hebebrand J, Heid IM, den Heijer M, Hengstenberg C, Herzig KH, Hicks AA, Hingorani A, Hinney A, Hirschhorn JN, Hofman A, Holmes CC, Homuth G, Hottenga JJ, Hovingh KG, Hu FB, Hu YJ, Huffman JE, Hui J, Huikuri H, Humphries SE, Hung J, Hunt SE, Hunter D, Hveem K, Hyppönen E, Igl W, Illig T, Ingelsson E, Iribarren C, Isomaa B, Jackson AU, Jacobs KB, James AL, Jansson JO, Jarick I, Jarvelin MR, Jöckel KH, Johansson Å, Johnson T, Jolley J, Jørgensen T, Jousilahti P, Jula A, Justice AE, Kaakinen M, Kähönen M, Kajantie E, Kanoni S, Kao WH, Kaplan LM, Kaplan RC, Kaprio J, Kapur K, Karpe F, Kathiresan S, Kee F, Keinanen Kiukaanniemi SM, Ketkar S, Kettunen J, Khaw KT, Kiemeney LA, Kilpeläinen TO, Kinnunen L, Kivimaki M, Kivmaki M, Van der Klauw MM, Kleber ME, Knowles JW, Koenig W, Kolcic I, Kolovou G, König IR, Koskinen S, Kovacs P, Kraft P, Kraja AT, Kristiansson K, KrjutÅjkov K, Kroemer HK, Krohn JP, Krzelj V, Kuh D, Kulzer JR, Kumari M, Kutalik Z, Kuulasmaa K, Kuusisto J, Kvaloy K, Laakso M, Laitinen JH, Lakka TA, Lamina C, Langenberg C, Lantieri O, Lathrop GM, Launer LJ, Lawlor DA, Lawrence RW, Leach IM, Lecoeur C, Lee SH, Lehtimäki T, Leitzmann MF, Lettre G, Levinson DF, Li G, Li S, Liang L, Lin DY, Lind L, Lindgren CM, Lindström J, Liu J, Liuzzi A, Locke AE, Lokki ML, Loley C, Loos RJ, Lorentzon M, Luan J, Luben RN, Ludwig B, Madden PA, Mägi R, Magnusson PK, Mangino M, Manunta P, Marek D, Marre M, Martin NG, März W, Maschio A, Mathieson I, McArdle WL, McCaroll SA, McCarthy A, McCarthy MI, McKnight B, Medina Gomez C, Medland SE, Meitinger T, Metspalu A, van Meurs JB, Meyre D, Midthjell K, Mihailov E, Milani L, Min JL, Moebus S, Moffatt MF, Mohlke KL, Molony C, Monda KL, Montgomery GW, Mooser V, Morken MA, Morris AD, Morris AP, Mühleisen TW, Müller Nurasyid M, Munroe PB, Musk AW, Narisu N, Navis G, Neale BM, Nelis M, Nemesh J, Neville MJ, Ngwa JS, Nicholson G, Nieminen MS, Njølstad I, Nohr EA, Nolte IM, North KE, Nöthen MM, Nyholt DR, O'Connell JR, Ohlsson C, Oldehinkel AJ, van Ommen GJ, Ong KK, Oostra BA, Ouwehand WH, Palmer CN, Palmer LJ, Palotie A, Paré G, Parker AN, Paternoster L, Pawitan Y, Pechlivanis S, Peden JF, Pedersen NL, Pedersen O, Pellikka N, Peltonen L, Penninx B, Perola M, Perry JR, Person T, Peters A, Peters MJ, Pichler I, Pietiläinen KH, Platou CG, Polasek O, Pouta A, Power C, Pramstaller PP, Preuss M, Price JF, Prokopenko I, Province MA, Psaty BM, Purcell S, Pütter C, Qi L, Quertermous T, Radhakrishnan A, Raitakari O, Randall JC, Rauramaa R, Rayner NW, Rehnberg E, Rendon A, Ridderstråle M, Ridker PM, Ripatti S, Rissanen A, Rivadeneira F, Rivolta C, Robertson NR, Rose LM, Rudan I, Saaristo TE, Sager H, Salomaa V, Samani NJ, Sambrook JG, Sanders AR, Sandholt C, Sanna S, Saramies J, Schadt EE, Scherag A, Schipf S, Schlessinger D, Schreiber S, Schunkert H, Schwarz PE, Scott LJ, Shi J, Shin SY, Shuldiner AR, Shungin D, Signorini S, Silander K, Sinisalo J, Skrobek B, Smit JH, Smith AV, Smith GD, Snieder H, Soranzo N, Sørensen TI, Sovio U, Spector TD, Speliotes EK, Stančáková A, Stark K, Stefansson K, Steinthorsdottir V, Stephens JC, Stirrups K, Stolk RP, Strachan DP, Strawbridge RJ, Stringham HM, Stumvoll M, Surakka I, Swift AJ, Syvanen AC, Tammesoo ML, Teder Laving M, Teslovich TM, Teumer A, Theodoraki EV, Thomson B, Thorand B, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tönjes A, Tregouet DA, Tremoli E, Trip MD, Tuomi T, Tuomilehto J, Tyrer J, Uda M, Uitterlinden AG, Usala G, Uusitupa M, Valle TT, Vandenput L, Vatin V, Vedantam S, de Vegt F, Vermeulen SH, Viikari J, Virtamo J, Visscher PM, Vitart V, Van Vliet Ostaptchouk JV, Voight BF, Vollenweider P, Volpato CB, Völzke H, Waeber G, Waite LL, Wallaschofski H, Walters GB, Wang Z, Wareham NJ, Watanabe RM, Watkins H, Weedon MN, Welch R, Weyant RJ, Wheeler E, White CC, Wichmann HE, Widen E, Wild SH, Willemsen G, Willer CJ, Wilsgaard T, Wilson JF, van Wingerden S, Winkelmann BR, Winkler TW, Witte DR, Witteman JC, Wolffenbuttel BH, Wong A, Wood AR, Workalemahu T, Wright AF, Yang J, Yarnell JW, Zgaga L, Zhao JH, Zillikens MC, Zitting P, Zondervan KT, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Winkler, T, Day, F, Croteau Chonka, D, Wood, A, Locke, A, Mägi, R, Ferreira, T, Fall, T, Graff, M, Justice, A, Luan, J, Gustafsson, S, Randall, J, Vedantam, S, Workalemahu, T, Kilpeläinen, T, Scherag, A, Esko, T, Kutalik, Z, Heid, I, Loos, R, Abecasis, G, Absher, D, Alavere, H, Albrecht, E, Allen, H, Almgren, P, Amin, N, Amouyel, P, Anderson, D, Arnold, A, Arveiler, D, Aspelund, T, Asselbergs, F, Assimes, T, Atalay, M, Attwood, A, Atwood, L, Bakker, S, Balkau, B, Balmforth, A, Barlassina, C, Barroso, I, Basart, H, Bauer, S, Beckmann, J, Beilby, J, Bennett, A, Ben Shlomo, Y, Bergman, R, Bergmann, S, Berndt, S, Biffar, R, Di Blasio, A, Boehm, B, Boehnke, M, Boeing, H, Boerwinkle, E, Bolton, J, Bonnefond, A, Bonnycastle, L, Boomsma, D, Borecki, I, Bornstein, S, Bouatia Naji, N, Boucher, G, Bragg Gresham, J, Brambilla, P, Bruinenberg, M, Buchanan, T, Buechler, C, Cadby, G, Campbell, H, Caulfield, M, Cavalcanti Proença, C, Cesana, G, Chanock, S, Chasman, D, Chen, Y, Chines, P, Clegg, D, Coin, L, Collins, F, Connell, J, Cookson, W, Cooper, M, Cupples, L, Cusi, D, Day, I, Dedoussis, G, Dei, M, Deloukas, P, Dermitzakis, E, Dimas, A, Dimitriou, M, Dixon, A, Dörr, M, van Duijn, C, Ebrahim, S, Edkins, S, Eiriksdottir, G, Eisinger, K, Eklund, N, Elliott, P, Erbel, R, Erdmann, J, Erdos, M, Eriksson, J, Estrada, K, Evans, D, de Faire, U, Farrall, M, Feitosa, M, Ferrario, M, Ferrières, J, Fischer, K, Fisher, E, Fowkes, G, Fox, C, Franke, L, Franks, P, Fraser, R, Frau, F, Frayling, T, Freimer, N, Froguel, P, Fu, M, Gaget, S, Ganna, A, Gejman, P, Gentilini, D, Geus, E, Gieger, C, Gigante, B, Gjesing, A, Glazer, N, Goddard, M, Goel, A, Grallert, H, Gräßler, J, Grönberg, H, Groop, L, Groves, C, Gudnason, V, Guiducci, C, Gyllensten, U, Hall, A, Hall, P, Hallmans, G, Hamsten, A, Hansen, T, Haritunians, T, Harris, T, van der Harst, P, Hartikainen, A, Hassanali, N, Hattersley, A, Havulinna, A, Hayward, C, Heard Costa, N, Heath, A, Hebebrand, J, den Heijer, M, Hengstenberg, C, Herzig, K, Hicks, A, Hingorani, A, Hinney, A, Hirschhorn, J, Hofman, A, Holmes, C, Homuth, G, Hottenga, J, Hovingh, K, Hu, F, Hu, Y, Huffman, J, Hui, J, Huikuri, H, Humphries, S, Hung, J, Hunt, S, Hunter, D, Hveem, K, Hyppönen, E, Igl, W, Illig, T, Ingelsson, E, Iribarren, C, Isomaa, B, Jackson, A, Jacobs, K, James, A, Jansson, J, Jarick, I, Jarvelin, M, Jöckel, K, Johansson, Å, Johnson, T, Jolley, J, Jørgensen, T, Jousilahti, P, Jula, A, Kaakinen, M, Kähönen, M, Kajantie, E, Kanoni, S, Kao, W, Kaplan, L, Kaplan, R, Kaprio, J, Kapur, K, Karpe, F, Kathiresan, S, Kee, F, Keinanen Kiukaanniemi, S, Ketkar, S, Kettunen, J, Khaw, K, Kiemeney, L, Kinnunen, L, Kivimaki, M, Kivmaki, M, Van der Klauw, M, Kleber, M, Knowles, J, Koenig, W, Kolcic, I, Kolovou, G, König, I, Koskinen, S, Kovacs, P, Kraft, P, Kraja, A, Kristiansson, K, Krjutåjkov, K, Kroemer, H, Krohn, J, Krzelj, V, Kuh, D, Kulzer, J, Kumari, M, Kuulasmaa, K, Kuusisto, J, Kvaloy, K, Laakso, M, Laitinen, J, Lakka, T, Lamina, C, Langenberg, C, Lantieri, O, Lathrop, G, Launer, L, Lawlor, D, Lawrence, R, Leach, I, Lecoeur, C, Lee, S, Lehtimäki, T, Leitzmann, M, Lettre, G, Levinson, D, Li, G, Li, S, Liang, L, Lin, D, Lind, L, Lindgren, C, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Loley, C, Lorentzon, M, Luben, R, Ludwig, B, Madden, P, Magnusson, P, Mangino, M, Manunta, P, Marek, D, Marre, M, Martin, N, März, W, Maschio, A, Mathieson, I, Mcardle, W, Mccaroll, S, Mccarthy, A, Mccarthy, M, Mcknight, B, Medina Gomez, C, Medland, S, Meitinger, T, Metspalu, A, van Meurs, J, Meyre, D, Midthjell, K, Mihailov, E, Milani, L, Min, J, Moebus, S, Moffatt, M, Mohlke, K, Molony, C, Monda, K, Montgomery, G, Mooser, V, Morken, M, Morris, A, Mühleisen, T, Müller Nurasyid, M, Munroe, P, Musk, A, Narisu, N, Navis, G, Neale, B, Nelis, M, Nemesh, J, Neville, M, Ngwa, J, Nicholson, G, Nieminen, M, Njølstad, I, Nohr, E, Nolte, I, North, K, Nöthen, M, Nyholt, D, O'Connell, J, Ohlsson, C, Oldehinkel, A, van Ommen, G, Ong, K, Oostra, B, Ouwehand, W, Palmer, C, Palmer, L, Palotie, A, Paré, G, Parker, A, Paternoster, L, Pawitan, Y, Pechlivanis, S, Peden, J, Pedersen, N, Pedersen, O, Pellikka, N, Peltonen, L, Penninx, B, Perola, M, Perry, J, Person, T, Peters, A, Peters, M, Pichler, I, Pietiläinen, K, Platou, C, Polasek, O, Pouta, A, Power, C, Pramstaller, P, Preuss, M, Price, J, Prokopenko, I, Province, M, Psaty, B, Purcell, S, Pütter, C, Qi, L, Quertermous, T, Radhakrishnan, A, Raitakari, O, Rauramaa, R, Rayner, N, Rehnberg, E, Rendon, A, Ridderstråle, M, Ridker, P, Ripatti, S, Rissanen, A, Rivadeneira, F, Rivolta, C, Robertson, N, Rose, L, Rudan, I, Saaristo, T, Sager, H, Salomaa, V, Samani, N, Sambrook, J, Sanders, A, Sandholt, C, Sanna, S, Saramies, J, Schadt, E, Schipf, S, Schlessinger, D, Schreiber, S, Schunkert, H, Schwarz, P, Scott, L, Shi, J, Shin, S, Shuldiner, A, Shungin, D, Signorini, S, Silander, K, Sinisalo, J, Skrobek, B, Smit, J, Smith, A, Smith, G, Snieder, H, Soranzo, N, Sørensen, T, Sovio, U, Spector, T, Speliotes, E, Stančáková, A, Stark, K, Stefansson, K, Steinthorsdottir, V, Stephens, J, Stirrups, K, Stolk, R, Strachan, D, Strawbridge, R, Stringham, H, Stumvoll, M, Surakka, I, Swift, A, Syvanen, A, Tammesoo, M, Teder Laving, M, Teslovich, T, Teumer, A, Theodoraki, E, Thomson, B, Thorand, B, Thorleifsson, G, Thorsteinsdottir, U, Timpson, N, Tönjes, A, Tregouet, D, Tremoli, E, Trip, M, Tuomi, T, Tuomilehto, J, Tyrer, J, Uda, M, Uitterlinden, A, Usala, G, Uusitupa, M, Valle, T, Vandenput, L, Vatin, V, de Vegt, F, Vermeulen, S, Viikari, J, Virtamo, J, Visscher, P, Vitart, V, Van Vliet Ostaptchouk, J, Voight, B, Vollenweider, P, Volpato, C, Völzke, H, Waeber, G, Waite, L, Wallaschofski, H, Walters, G, Wang, Z, Wareham, N, Watanabe, R, Watkins, H, Weedon, M, Welch, R, Weyant, R, Wheeler, E, White, C, Wichmann, H, Widen, E, Wild, S, Willemsen, G, 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GD., Snieder, H., Soranzo, N., Sørensen, TI., Sovio, U., Spector, TD., Speliotes, EK., Stančáková, A., Stark, K., Stefansson, K., Steinthorsdottir, V., Stephens, JC., Stirrups, K., Stolk, RP., Strachan, DP., Strawbridge, RJ., Stringham, HM., Stumvoll, M., Surakka, I., Swift, AJ., Syvanen, AC., Tammesoo, ML., Teder-Laving, M., Teslovich, TM., Teumer, A., Theodoraki, EV., Thomson, B., Thorand, B., Thorleifsson, G., Thorsteinsdottir, U., Timpson, NJ., Tönjes, A., Tregouet, DA., Tremoli, E., Trip, MD., Tuomi, T., Tuomilehto, J., Tyrer, J., Uda, M., Uitterlinden, AG., Usala, G., Uusitupa, M., Valle, TT., Vandenput, L., Vatin, V., Vedantam, S., de Vegt, F., Vermeulen, SH., Viikari, J., Virtamo, J., Visscher, PM., Vitart, V., Van Vliet-Ostaptchouk JV., Voight, BF., Vollenweider, P., Volpato, CB., Völzke, H., Waeber, G., Waite, LL., Wallaschofski, H., Walters, GB., Wang, Z., Wareham, NJ., Watanabe, RM., Watkins, H., Weedon, MN., Welch, R., Weyant, RJ., Wheeler, E., White, CC., Wichmann, HE., 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Subjects
Quality Control, Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, media_common.quotation_subject, quality control, GWAMAS, Control (management), Medizin, Genome-wide association study, Biology, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Software, SDG 17 - Partnerships for the Goals, Meta-Analysis as Topic, Comparable size, Quality (business), 030304 developmental biology, media_common, Protocol (science), 0303 health sciences, business.industry, Software package, Data science, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Genome-Wide Association Study/methods, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], quality control, genome-wide association meta-analyses, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Item does not contain fulltext Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.

Published
2014

38. Defining the role of common variation in the genomic and biological architecture of adult human height

Author

Wood, Ar, Esko, T, Yang, J, Vedantam, S, Pers, Th, Gustafsson, S, Chu, Ay, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, Ml, Croteau Chonka DC, Day, Fr, Duan, Y, Fall, T, Fehrmann, R, Ferreira, T, Jackson, Au, Karjalainen, J, Lo, Ks, Locke, Ae, Mägi, R, Mihailov, E, Porcu, E, Randall, Jc, Scherag, A, Vinkhuyzen, Aa, Westra, Hj, Winkler, Tw, Workalemahu, T, Zhao, Jh, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, Gb, Feenstra, B, Feitosa, Mf, Fischer, K, Fraser, Rm, Goel, A, Gong, J, Justice, Ae, Kanoni, S, Kleber, Me, Kristiansson, K, Lim, U, Lotay, V, Lui, Jc, Mangino, M, Mateo Leach, I, Medina Gomez, C, Nalls, Ma, Nyholt, Dr, Palmer, Cd, Pasko, D, Pechlivanis, S, Prokopenko, I, Ried, Js, Ripke, S, Shungin, D, Stancáková, A, Strawbridge, Rj, Sung, Yj, Tanaka, T, Teumer, A, Trompet, S, van der Laan SW, van Setten, J, Van Vliet Ostaptchouk JV, Wang, Z, Yengo, L, Zhang, W, Afzal, U, Arnlöv, J, Arscott, Gm, Bandinelli, S, Barrett, A, Bellis, C, Bennett, Aj, Berne, C, Blüher, M, Bolton, Jl, Böttcher, Y, Boyd, Ha, Bruinenberg, M, Buckley, Bm, Buyske, S, Caspersen, Ih, Chines, Ps, Clarke, R, Claudi Boehm, S, Cooper, M, Daw, Ew, De Jong PA, Deelen, J, Delgado, G, Denny, Jc, Dhonukshe Rutten, R, Dimitriou, M, Doney, As, Dörr, M, Eklund, N, Eury, E, Folkersen, L, Garcia, Me, Geller, F, Giedraitis, V, Go, As, Grallert, H, Grammer, Tb, Gräßler, J, Grönberg, H, de Groot LC, Groves, Cj, Haessler, J, Hall, P, Haller, T, Hallmans, G, Hannemann, A, Hartman, Ca, Hassinen, M, Hayward, C, Heard Costa NL, Helmer, Q, Hemani, G, Henders, Ak, Hillege, Hl, Hlatky, Ma, Hoffmann, W, Hoffmann, P, Holmen, O, Houwing Duistermaat JJ, Illig, T, Isaacs, A, James, Al, Jeff, J, Johansen, B, Johansson, Å, Jolley, J, Juliusdottir, T, Junttila, J, Kho, An, Kinnunen, L, Klopp, N, Kocher, T, Kratzer, W, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Lu, Y, Lyssenko, V, Magnusson, Pk, Mahajan, A, Maillard, M, Mcardle, Wl, Mckenzie, Ca, Mclachlan, S, Mclaren, Pj, Menni, C, Merger, S, Milani, L, Moayyeri, A, Monda, Kl, Morken, Ma, Müller, G, Müller Nurasyid, M, Musk, Aw, Narisu, N, Nauck, M, Nolte, Im, Nöthen, Mm, Oozageer, L, Pilz, S, Rayner, Nw, Renstrom, F, Robertson, Nr, Rose, Lm, Roussel, R, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, Fr, Schunkert, H, Scott, Ra, Sehmi, J, Seufferlein, T, Shi, J, Silventoinen, K, Smit, Jh, Smith, Av, Smolonska, J, Stanton, Av, Stirrups, K, Stott, Dj, Stringham, Hm, Sundström, J, Swertz, Ma, Syvänen, Ac, Tayo, Bo, Thorleifsson, G, Tyrer, Jp, van Dijk, S, van Schoor NM, van der Velde, N, van Heemst, D, van Oort FV, Vermeulen, Sh, Verweij, N, Vonk, Jm, Waite, Ll, Waldenberger, M, Wennauer, R, Wilkens, Lr, Willenborg, C, Wilsgaard, T, Wojczynski, Mk, Wong, A, Wright, Af, Zhang, Q, Arveiler, D, Bakker, Sj, Beilby, J, Bergman, Rn, Bergmann, S, Biffar, R, Blangero, J, Boomsma, Di, Bornstein, Sr, Bovet, P, Brambilla, P, Brown, Mj, Campbell, H, Caulfield, Mj, Chakravarti, A, Collins, R, 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M., Isotope Research, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Ehret, Georg Benedikt, Wood, A, Esko, T, Yang, J, Vedantam, S, Pers, T, Gustafsson, S, Chu, A, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, M, Croteau Chonka, D, Day, F, Duan, Y, Fall, T, Fehrmann, R, Ferreira, T, Jackson, A, Karjalainen, J, Lo, K, Locke, A, Mägi, R, Mihailov, E, Porcu, E, Randall, J, Scherag, A, Vinkhuyzen, A, Westra, H, Winkler, T, Workalemahu, T, Zhao, J, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, G, Feenstra, B, Feitosa, M, Fischer, K, Fraser, R, Goel, A, Gong, J, Justice, A, Kanoni, S, Kleber, M, Kristiansson, K, Lim, U, Lotay, V, Lui, J, Mangino, M, Leach, I, Medina Gomez, C, Nalls, M, Nyholt, D, Palmer, C, Pasko, D, Pechlivanis, S, Prokopenko, I, Ried, J, Ripke, S, Shungin, D, Stancáková, A, Strawbridge, R, Sung, Y, Tanaka, T, Teumer, A, Trompet, S, Van Der Laan, S, Van Setten, J, Van Vliet Ostaptchouk, J, Wang, Z, Yengo, L, Zhang, W, Afzal, U, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Bolton, J, Böttcher, Y, Boyd, H, Bruinenberg, M, Buckley, B, Buyske, S, Caspersen, I, Chines, P, Clarke, R, Claudi Boehm, S, Cooper, M, Daw, E, De Jong, P, Deelen, J, Delgado, G, Denny, J, Dhonukshe Rutten, R, Dimitriou, M, Doney, A, Dörr, M, Eklund, N, Eury, E, Folkersen, L, Garcia, M, Geller, F, Giedraitis, V, Go, A, Grallert, H, Grammer, T, Gräßler, J, Grönberg, H, De Groot, L, Groves, C, Haessler, J, Hall, P, Haller, T, Hallmans, G, Hannemann, A, Hartman, C, Hassinen, M, Hayward, C, Heard Costa, N, Helmer, Q, Hemani, G, Henders, A, Hillege, H, Hlatky, M, Hoffmann, W, Hoffmann, P, Holmen, O, Houwing Duistermaat, J, Illig, T, Isaacs, A, James, A, Jeff, J, Johansen, B, Johansson, Å, Jolley, J, Juliusdottir, T, Junttila, J, Kho, A, Kinnunen, L, Klopp, N, Kocher, T, Kratzer, W, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Lu, Y, Lyssenko, V, Magnusson, P, Mahajan, A, Maillard, M, Mcardle, W, Mckenzie, C, Mclachlan, S, Mclaren, P, Menni, C, Merger, S, Milani, L, Moayyeri, A, Monda, K, Morken, M, Müller, G, Müller Nurasyid, M, Musk, A, Narisu, N, Nauck, M, Nolte, I, Nöthen, M, Oozageer, L, Pilz, S, Rayner, N, Renstrom, F, Robertson, N, Rose, L, Roussel, R, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, F, Schunkert, H, Scott, R, Sehmi, J, Seufferlein, T, Shi, J, Silventoinen, K, Smit, J, Smith, A, 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Visscher, P, Hirschhorn, J, Frayling, T, Medical Research Council (MRC), APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Genomics (eMEMERGEGE) Consortium, MIGen Consortium, PAGEGE Consortium, LifeLines Cohort Study, Electronic Medical, Records, McCarty, CA., Starren, J., Peissig, P., Berg, R., Rasmussen, L., Linneman, J., Miller, A., Choudary, V., Chen, L., Waudby, C., Kitchner, T., Reeser, J., Fost, N., Ritchie, M., Wilke, RA., Chisholm, RL., Avila, PC., Greenland, P., Hayes, M., Kho, A., Kibbe, WA., Lemke, AA., Lowe, WL., Smith, ME., Wolf, WA., Pacheco, JA., Thompson, WK., Humowiecki, J., Law, M., Chute, C., Kullo, I., Koenig, B., de Andrade, M., Bielinski, S., Pathak, J., Savova, G., Wu, J., Henriksen, J., Ding, K., Hart, L., Palbicki, J., Larson, EB., Newton, K., Ludman, E., Spangler, L., Hart, G., Carrell, D., Jarvik, G., Crane, P., Burke, W., Fullerton, SM., Trinidad, SB., 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Hirschhorn, Jn, Frayling, Tm, Epidemiology, Surgery, Public Health, Internal Medicine, Erasmus MC other, Genetic Identification, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Biological Psychology, AIMMS, Functional Genomics, EMGO+ - Lifestyle, Overweight and Diabetes, Wood, AR, Vadantam, S, Hypponen, Elina, Frayling, TM, Wood A.R., Esko T., Yang J., Vedantam S., Pers T.H., Gustafsson S., Chu A.Y., Estrada K., Luan J., Kutalik Z., Amin N., Buchkovich M.L., Croteau-Chonka D.C., Day F.R., Duan Y., Fall T., Fehrmann R., Ferreira T., Jackson A.U., Karjalainen J., Lo K.S., Locke A.E., Magi R., Mihailov E., Porcu E., Randall J.C., Scherag A., Vinkhuyzen A.A.E., Westra H.-J., Winkler T.W., Workalemahu T., Zhao J.H., Absher D., Albrecht E., Anderson D., Baron J., Beekman M., Demirkan A., Ehret G.B., Feenstra B., Feitosa M.F., Fischer K., Fraser R.M., Goel A., Gong J., Justice A.E., Kanoni S., Kleber M.E., Kristiansson K., Lim U., Lotay V., Lui J.C., Mangino M., Leach I.M., 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Kastelein J.J.P., Kayser M., Kee F., Keinanen-Kiukaanniemi S.M., Kiemeney L.A., Kooner J.S., Kooperberg C., Koskinen S., Kovacs P., Kraja A.T., Kumari M., Kuusisto J., Lakka T.A., Langenberg C., Le Marchand L., Lehtimaki T., Lupoli S., Madden P.A.F., Mannisto S., Manunta P., Marette A., Matise T.C., McKnight B., Meitinger T., Moll F.L., Montgomery G.W., Morris A.D., Morris A.P., Murray J.C., Nelis M., Ohlsson C., Oldehinkel A.J., Ong K.K., Ouwehand W.H., Pasterkamp G., Peters A., Pramstaller P.P., Price J.F., Qi L., Raitakari O.T., Rankinen T., Rao D.C., Rice T.K., Ritchie M., Rudan I., Salomaa V., Samani N.J., Saramies J., Sarzynski M.A., Schwarz P.E.H., Sebert S., Sever P., Shuldiner A.R., Sinisalo J., Steinthorsdottir V., Stolk R.P., Tardif J.-C., Tonjes A., Tremblay A., Tremoli E., Virtamo J., Vohl M.-C., Amouyel P., Asselbergs F.W., Assimes T.L., Bochud M., Boehm B.O., Boerwinkle E., Bottinger E.P., Bouchard C., Cauchi S., Chambers J.C., Chanock S.J., Cooper R.S., De Bakker P.I.W., Dedoussis G., Ferrucci L., Franks P.W., Froguel P., Groop L.C., Haiman C.A., Hamsten A., Hayes M.G., Hui J., Hunter D.J., Hveem K., Jukema J.W., Kaplan R.C., Kivimaki M., Kuh D., Laakso M., Liu Y., Martin N.G., Marz W., Melbye M., Moebus S., Munroe P.B., Njolstad I., Oostra B.A., Palmer C.N.A., Pedersen N.L., Perola M., Perusse L., Peters U., Powell J.E., Power C., Quertermous T., Rauramaa R., Reinmaa E., Ridker P.M., Rivadeneira F., Rotter J.I., Saaristo T.E., Saleheen D., Schlessinger D., Slagboom P.E., Snieder H., Spector T.D., Strauch K., Stumvoll M., Tuomilehto J., Uusitupa M., Van Der Harst P., Volzke H., Walker M., Wareham N.J., Watkins H., Wichmann H.-E., Wilson J.F., Zanen P., Deloukas P., Heid I.M., Lindgren C.M., Mohlke K.L., Speliotes E.K., Thorsteinsdottir U., Barroso I., Fox C.S., North K.E., Strachan D.P., Beckmann J.S., Berndt S.I., Boehnke M., Borecki I.B., McCarthy M.I., Metspalu A., Stefansson K., Uitterlinden A.G., Van Duijn C.M., Franke L., Willer C.J., Price A.L., Lettre G., Loos R.J.F., Weedon M.N., Ingelsson E., O'Connell J.R., Abecasis G.R., Chasman D.I., Goddard M.E., Visscher P.M., Hirschhorn J.N., and Frayling T.M.

Subjects
Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Electronic Medical Records and Genomics (eMEMERGEGE) Consortium, Medizin, Genome-wide association study, Adult, Analysis of Variance, Body Height/genetics, European Continental Ancestry Group/genetics, Genetic Variation/genetics, Genetics, Population, Genome-Wide Association Study/methods, Humans, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide/genetics, heritability, 0302 clinical medicine, Genome-wide, SNPS, snps, Genetics & Heredity, ddc:616, Genetics, Medical And Health Sciences, 0303 health sciences, education.field_of_study, variants, GENETIC-VARIATION, Biological Sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], body height, genetic-variation, Life Sciences & Biomedicine, Single Nucleotide/genetics, Human, European Continental Ancestry Group, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, NO, complex traits, 03 medical and health sciences, Genetic variation, heritability, adult, height, Polymorphism, Human height, PAGEGE Consortium, education, Gene, VLAG, 030304 developmental biology, Global Nutrition, Wereldvoeding, genome-wide association study, Science & Technology, Whites, Oligonucleotide Array Sequence Analysi, MUTATIONS, COMPLEX TRAITS, ta1184, Klinisk medicin, population genetics, Genetic Variation, Heritability, ta3121, mutations, Genetic architecture, Body Height, genetic variation, MIGen Consortium, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Clinical Medicine, 030217 neurology & neurosurgery, height, LifeLines Cohort Study, Developmental Biology, Genome-Wide Association Study
Abstract

Item does not contain fulltext Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated approximately 2,000, approximately 3,700 and approximately 9,500 SNPs explained approximately 21%, approximately 24% and approximately 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Published
2014

41. Erratum to: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits (Nature Genetics, (2018), 50, 10, (1412-1425), 10.1038/s41588-018-0205-x)

Author

Evangelou E., Warren H. R., Mosen-Ansorena D., Mifsud B., Pazoki R., Gao H., Ntritsos G., Dimou N., Cabrera C. P., Karaman I., Ng F. L., Evangelou M., Witkowska K., Tzanis E., Hellwege J. N., Giri A., Velez Edwards D. R., Sun Y. V., Cho K., Gaziano J. M., Wilson P. W. F., Tsao P. S., Kovesdy C. P., Esko T., Magi R., Milani L., Almgren P., Boutin T., Debette S., Ding J., Giulianini F., Holliday E. G., Jackson A. U., Li-Gao R., Lin W. -Y., Luan J., Mangino M., Oldmeadow C., Prins B. P., Qian Y., Sargurupremraj M., Shah N., Surendran P., Theriault S., Verweij N., Willems S. M., Zhao J. -H., Amouyel P., Connell J., de Mutsert R., Doney A. S. F., Farrall M., Menni C., Morris A. D., Noordam R., Pare G., Poulter N. R., Shields D. C., Stanton A., Thom S., Abecasis G., Amin N., Arking D. E., Ayers K. L., Barbieri C. M., Batini C., Bis J. C., Blake T., Bochud M., Boehnke M., Boerwinkle E., Boomsma D. I., Bottinger E. P., Braund P. S., Brumat M., Campbell A., Campbell H., Chakravarti A., Chambers J. C., Chauhan G., Ciullo M., Cocca M., Collins F., Cordell H. J., Davies G., de Borst M. H., de Geus E. J., Deary I. J., Deelen J., Del Greco M F., Demirkale C. Y., Dorr M., Ehret G. B., Elosua R., Enroth S., Erzurumluoglu A. M., Ferreira T., Franberg M., Franco O. H., Gandin I., Gasparini P., Giedraitis V., Gieger C., Girotto G., Goel A., Gow A. J., Gudnason V., Guo X., Gyllensten U., Hamsten A., Harris T. B., Harris S. E., Hartman C. A., Havulinna A. S., Hicks A. A., Hofer E., Hofman A., Hottenga J. -J., Huffman J. E., Hwang S. -J., Ingelsson E., James A., Jansen R., Jarvelin M. -R., Joehanes R., Johansson A., Johnson A. D., Joshi P. K., Jousilahti P., Jukema J. W., Jula A., Kahonen M., Kathiresan S., Keavney B. D., Khaw K. -T., Knekt P., Knight J., Kolcic I., Kooner J. S., Koskinen S., Kristiansson K., Kutalik Z., Laan M., Larson M., Launer L. J., Lehne B., Lehtimaki T., Liewald D. C. M., Lin L., Lind L., Lindgren C. M., Liu Y. M., Loos R. J. F., Lopez L. M., Lu Y., Lyytikainen L. -P., Mahajan A., Mamasoula C., Marrugat J., Marten J., Milaneschi Y., Morgan A., Morris A. P., Morrison A. C., Munson P. J., Nalls M. A., Nandakumar P., Nelson C. P., Niiranen T., Nolte I. M., Nutile T., Oldehinkel A. J., Oostra B. A., O'Reilly P. F., Org E., Padmanabhan S., Palmas W., Palotie A., Pattie A., Penninx B. W. J. H., Perola M., Peters A., Polasek O., Pramstaller P. P., Nguyen Q. T., Raitakari O. T., Ren M., Rettig R., Rice K., Ridker P. M., Ried J. S., Riese H., Ripatti S., Robino A., Rose L. M., Rotter J. I., Rudan I., Ruggiero D., Saba Y., Sala C. F., Salomaa V., Samani N. J., Sarin A. -P., Schmidt R., Schmidt H., Shrine N., Siscovick D., Smith A. V., Snieder H., Sober S., Sorice R., Starr J. M., Stott D. J., Strachan D. P., Strawbridge R. J., Sundstrom J., Swertz M. A., Taylor K. D., Teumer A., Tobin M. D., Tomaszewski M., Toniolo D., Traglia M., Trompet S., Tuomilehto J., Tzourio C., Uitterlinden A. G., Vaez A., van der Most P. J., van Duijn C. M., Vergnaud A. -C., Verwoert G. C., Vitart V., Volker U., Vollenweider P., Vuckovic D., Watkins H., Wild S. H., Willemsen G., Wilson J. F., Wright A. F., Yao J., Zemunik T., Zhang W., Attia J. R., Butterworth A. S., Chasman D. I., Conen D., Cucca F., Danesh J., Hayward C., Howson J. M. M., Laakso M., Lakatta E. G., Langenberg C., Melander O., Mook-Kanamori D. O., Palmer C. N. A., Risch L., Scott R. A., Scott R. J., Sever P., Spector T. D., van der Harst P., Wareham N. J., Zeggini E., Levy D., Munroe P. B., Newton-Cheh C., Brown M. J., Metspalu A., Hung A. M., O'Donnell C. J., Edwards T. L., Psaty B. M., Tzoulaki I., Barnes M. R., Wain L. V., Elliott P., Caulfield M. J., Evangelou, E., Warren, H. R., Mosen-Ansorena, D., Mifsud, B., Pazoki, R., Gao, H., Ntritsos, G., Dimou, N., Cabrera, C. P., Karaman, I., Ng, F. L., Evangelou, M., Witkowska, K., Tzanis, E., Hellwege, J. N., Giri, A., Velez Edwards, D. R., Sun, Y. V., Cho, K., Gaziano, J. M., Wilson, P. W. F., Tsao, P. S., Kovesdy, C. P., Esko, T., Magi, R., Milani, L., Almgren, P., Boutin, T., Debette, S., Ding, J., Giulianini, F., Holliday, E. G., Jackson, A. U., Li-Gao, R., Lin, W. -Y., Luan, J., Mangino, M., Oldmeadow, C., Prins, B. P., Qian, Y., Sargurupremraj, M., Shah, N., Surendran, P., Theriault, S., Verweij, N., Willems, S. M., Zhao, J. -H., Amouyel, P., Connell, J., de Mutsert, R., Doney, A. S. F., Farrall, M., Menni, C., Morris, A. D., Noordam, R., Pare, G., Poulter, N. R., Shields, D. C., Stanton, A., Thom, S., Abecasis, G., Amin, N., Arking, D. E., Ayers, K. L., Barbieri, C. M., Batini, C., Bis, J. C., Blake, T., Bochud, M., Boehnke, M., Boerwinkle, E., Boomsma, D. I., Bottinger, E. P., Braund, P. S., Brumat, M., Campbell, A., Campbell, H., Chakravarti, A., Chambers, J. C., Chauhan, G., Ciullo, M., Cocca, M., Collins, F., Cordell, H. J., Davies, G., de Borst, M. H., de Geus, E. J., Deary, I. J., Deelen, J., Del Greco M, F., Demirkale, C. Y., Dorr, M., Ehret, G. B., Elosua, R., Enroth, S., Erzurumluoglu, A. M., Ferreira, T., Franberg, M., Franco, O. H., Gandin, I., Gasparini, P., Giedraitis, V., Gieger, C., Girotto, G., Goel, A., Gow, A. J., Gudnason, V., Guo, X., Gyllensten, U., Hamsten, A., Harris, T. B., Harris, S. E., Hartman, C. A., Havulinna, A. S., Hicks, A. A., Hofer, E., Hofman, A., Hottenga, J. -J., Huffman, J. E., Hwang, S. -J., Ingelsson, E., James, A., Jansen, R., Jarvelin, M. -R., Joehanes, R., Johansson, A., Johnson, A. D., Joshi, P. K., Jousilahti, P., Jukema, J. W., Jula, A., Kahonen, M., Kathiresan, S., Keavney, B. D., Khaw, K. -T., Knekt, P., Knight, J., Kolcic, I., Kooner, J. S., Koskinen, S., Kristiansson, K., Kutalik, Z., Laan, M., Larson, M., Launer, L. J., Lehne, B., Lehtimaki, T., Liewald, D. C. M., Lin, L., Lind, L., Lindgren, C. M., Liu, Y. M., Loos, R. J. F., Lopez, L. M., Lu, Y., Lyytikainen, L. -P., Mahajan, A., Mamasoula, C., Marrugat, J., Marten, J., Milaneschi, Y., Morgan, A., Morris, A. P., Morrison, A. C., Munson, P. J., Nalls, M. A., Nandakumar, P., Nelson, C. P., Niiranen, T., Nolte, I. M., Nutile, T., Oldehinkel, A. J., Oostra, B. A., O'Reilly, P. F., Org, E., Padmanabhan, S., Palmas, W., Palotie, A., Pattie, A., Penninx, B. W. J. H., Perola, M., Peters, A., Polasek, O., Pramstaller, P. P., Nguyen, Q. T., Raitakari, O. T., Ren, M., Rettig, R., Rice, K., Ridker, P. M., Ried, J. S., Riese, H., Ripatti, S., Robino, A., Rose, L. M., Rotter, J. I., Rudan, I., Ruggiero, D., Saba, Y., Sala, C. F., Salomaa, V., Samani, N. J., Sarin, A. -P., Schmidt, R., Schmidt, H., Shrine, N., Siscovick, D., Smith, A. V., Snieder, H., Sober, S., Sorice, R., Starr, J. M., Stott, D. J., Strachan, D. P., Strawbridge, R. J., Sundstrom, J., Swertz, M. A., Taylor, K. D., Teumer, A., Tobin, M. D., Tomaszewski, M., Toniolo, D., Traglia, M., Trompet, S., Tuomilehto, J., Tzourio, C., Uitterlinden, A. G., Vaez, A., van der Most, P. J., van Duijn, C. M., Vergnaud, A. -C., Verwoert, G. C., Vitart, V., Volker, U., Vollenweider, P., Vuckovic, D., Watkins, H., Wild, S. H., Willemsen, G., Wilson, J. F., Wright, A. F., Yao, J., Zemunik, T., Zhang, W., Attia, J. R., Butterworth, A. S., Chasman, D. I., Conen, D., Cucca, F., Danesh, J., Hayward, C., Howson, J. M. M., Laakso, M., Lakatta, E. G., Langenberg, C., Melander, O., Mook-Kanamori, D. O., Palmer, C. N. A., Risch, L., Scott, R. A., Scott, R. J., Sever, P., Spector, T. D., van der Harst, P., Wareham, N. J., Zeggini, E., Levy, D., Munroe, P. B., Newton-Cheh, C., Brown, M. J., Metspalu, A., Hung, A. M., O'Donnell, C. J., Edwards, T. L., Psaty, B. M., Tzoulaki, I., Barnes, M. R., Wain, L. V., Elliott, P., and Caulfield, M. J.

Subjects
Blood pressure, genetic analysis
Abstract

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Published
2018

43. Identification of common genetic risk variants for autism spectrum disorder

Author

Grove, J., Ripke, S., Als, T.D., Mattheisen, M., Walters, R.K., Won, H., Pallesen, J., Agerbo, E., Andreassen, O.A., Anney, R., Awashti, S., Belliveau, R., Bettella, F., Buxbaum, J.D., Bybjerg-Grauholm, J., Baekvad-Hansen, M., Cerrato, F., Chambert, K., Christensen, J.H., Churchhouse, C., Dellenvall, K., Demontis, D., Rubeis, S. de, Devlin, B., Djurovic, S., Dumont, A.L., Goldstein, J.I., Hansen, C.S., Hauberg, M.E., Hollegaard, M.V., Hope, S., Howrigan, D.P., Huang, H., Hultman, C.M., Klei, L., Maller, J., Martin, J., Martin, A.R., Moran, J.L., Nyegaard, M., Naeland, T., Palmer, D.S., Palotie, A., Pedersen, C.B., Pedersen, M.G., dPoterba, T., Poulsen, J.B., St Pourcain, B., Qvist, P., Rehnstrom, K., Reichenberg, A., Reichert, J., Robinson, E.B., Roeder, K., Roussos, P., Saemundsen, E., Sandin, S., Satterstrom, F.K., Smith, G.D., Stefansson, H., Steinberg, S., Stevens, C.R., Sullivan, P.F., Turley, P., Walters, G.B., Xu, X.Y., Stefansson, K., Geschwind, D.H., Nordentoft, M., Hougaard, D.M., Werge, T., Mors, O., Mortensen, P.B., Neale, B.M., Daly, M.J., Borglum, A.D., Wray, N.R., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Air, T.M., Andlauer, T.F.M., Bacanu, S.A., Beekman, A.T.F., Bigdeli, T.B., Binder, E.B., Blackwood, D.H.R., Bryois, J., Buttenschon, H.N., Cai, N., Castelao, E., Clarke, T.K., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, F.F.H., Finucane, H.K., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Hall, L.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Ising, M., Jansen, R., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., O'Reilly, P.F., Oskarsson, H., Owen, M.J., Painter, J.N., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shi, J.X., Shyn, S.I., Sigurdsson, E., Sinnamon, G.C.B., Smit, J.H., Smith, D.J., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Auwera, S. van der, Hemert, A.M. van, Viktorin, A., Visscher, P.M., Wang, Y.P., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.S., Yang, J., Zhang, F.T., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., Geus, E.J.C. de, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.S., Lucae, S., Madden, P.A.F., Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Muller-Myhsok, B., Nothen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, B.W.J.H., Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Tiemeier, H., Uher, R., Volzke, H., Weissman, M.M., Lewis, C.M., Levinson, D.F., Breen, G., Agee, M., Alipanahi, B., Auton, A., Bell, R.K., Bryc, K., Elson, S.L., Fontanillas, P., Furlotte, N.A., Hromatka, B.S., Huber, K.E., Kleinman, A., Litterman, N.K., McIntyre, M.H., Mountain, J.L., Noblin, E.S., Northover, C.A.M., Pitts, S.J., Sathirapongsasuti, J.F., Sazonova, O.V., Shelton, J.F., Shringarpure, S., Tung, J.Y., Vacic, V., Wilson, C.H., Psychiat Genomics Consortium, BUPGEN, 23andMe Re, Biological Psychology, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Adult Psychiatry, Psychiatry, Human genetics, Amsterdam Reproduction & Development (AR&D), VU University medical center, APH - Digital Health, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Me Research Team, Epidemiology, and Child and Adolescent Psychiatry / Psychology

Subjects
Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, Autism Spectrum Disorder, Denmark, LD SCORE REGRESSION, LOCI, Genome-wide association study, DE-NOVO, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, SYNAPTIC PLASTICITY, CELL-SURFACE, Child, Genetics, 0303 health sciences, HERITABILITY, Genetic Predisposition to Disease/genetics, 1184 Genetics, developmental biology, physiology, Polymorphism, Single Nucleotide/genetics, Phenotype, 3. Good health, Schizophrenia, Autism spectrum disorder, Child, Preschool, Genome-Wide Association Study/methods, Female, SIMONS SIMPLEX COLLECTION, Adolescent, Biology, NEURITE OUTGROWTH, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, 03 medical and health sciences, mental disorders, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, SDG 2 - Zero Hunger, Multifactorial Inheritance/genetics, METAANALYSIS, 030304 developmental biology, Case-control study, Heritability, medicine.disease, Autism Spectrum Disorder/genetics, Case-Control Studies, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Published in final edited form as: Nat Genet. 2019 March ; 51(3): 431–444. doi:10.1038/s41588-019-0344-8., Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture, we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD., The iPSYCH project is funded by the Lundbeck Foundation (grant numbers R102-A9118 and R155-2014-1724) and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH and PGC samples was supported by grants from the Lundbeck Foundation, the Stanley Foundation, the Simons Foundation (SFARI 311789 to MJD), and NIMH (5U01MH094432–02 to MJD). The Danish National Biobank resource was supported by the Novo Nordisk Foundation. Data handling and analysis on the GenomeDK HPC facility was supported by NIMH (1U01MH109514–01 to M O’Donovan and ADB). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to ADB). Drs. S De Rubeis and JD Buxbaum were supported by NIH grants MH097849 (to JDB) and MH111661 (to JDB), and by the Seaver Foundation (to SDR and JDB). Dr J Martin was supported by the Wellcome Trust (grant no: 106047). O. Andreassen received funding from Research Council of Norway (#213694, #223273, #248980, #248778), Stiftelsen KG Jebsen and South-East Norway Health Authority. We thank the research participants and employees of 23andMe for making this work possible.

Published
2019

44. Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

Author

Arnau-Soler, A., Macdonald-Dunlop, E., Adams, M.J., Clarke, T.K., MacIntyre, D.J., Milburn, K., Navrady, L., Hayward, C., McIntosh, A.M., Thomson, P.A., Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Agerbo, E., Air, T.M., Andlauer, T.F.M., Bacanu, S.A., Baekvad-Hansen, M., Beekman, A.T.F., Bigdeli, T.B., Binder, E.B., Blackwood, D.H.R., Bryois, J., Buttenscon, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J.H., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Rawford, G.E.C., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, F.F.H., Finucane, H.K., Foo, J.C., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hall, L.S., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Ising, M., Jansen, R., Jones, I., Jones, L.A., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y.H., Lind, P.A., Macintyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., O'Reilly, P.F., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shi, J.X., Shyn, S.I., Sigurdsson, E., Sinnamon, G.C.B., Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Auwera, S. van der, Hemert, A.M. van, Viktorin, A., Visscher, P.M., Wang, Y.P., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.L.S., Yang, J., Zhang, F.T., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., Geus, E.J.C. de, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.Q.S., Lucae, S., Madden, P.A.F., Magnusson, P.K., Martin, N.G., Metspalu, A., Mors, O., Mortensen, P.B., Muller-Myhsok, B., Nordentoft, M., Nothen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, B.W.J.H., Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Stefansson, K., Tiemeier, H., Uher, R., Volzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Breen, G., Borglum, A.S.D., Sullivan, P.F., Generation Scotland, and Psychiat Genomics Consortium

Abstract

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 x 10(-6)). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 x 10(-9); total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 x 10(-8); dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 x 10(-8); dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 x 10(-6)). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 x 10(-3)). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.

Published
2019

45. Evidence for increased genetic risk load for major depression in patients assigned to electroconvulsive therapy

Author

Foo, J.C., Streit, F., Frank, J., Witt, S.H., Treutlein, J., Baune, B.T., Moebus, S., Jockel, K.H., Forstner, A.J., Nothen, M.M., Rietschel, M., Sartorius, A., Kranaster, L., Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Agerbo, E., Air, T.M., Andlauer, T.F.M., Bacanu, S.A., Baekvad-Hansen, M., Beekman, A.T.F., Bigdeli, T.B., Binder, E.B., Blackwood, D.H.R., Bryois, J., Buttenschon, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J.H., Clarke, T.K., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, F.F.H., Finucane, H.K., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hall, L.S., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Ising, M., Jansen, R., Jones, I., Jones, L.A., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y.H., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., O'Reilly, P.F., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shi, J.X., Shyn, S.I., Sigurdsson, E., Sinnamon, G.C.B., Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Auwera, S. van der, Hemert, A.M. van, Viktorin, A., Visscher, P.M., Wang, Y., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Wu, Y., Xi, H.L.S., Yang, J., Zhang, F.T., Arolt, V., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., Geus, E.J.C. de, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.Q.S., Lucae, S., Madden, P.A.F., Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Mors, O., Mortensen, P.B., Muller-Myhsok, B., Nordentoft, M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, B.W.J.H., Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Stefansson, K., Tiemeier, H., Uher, R., Voelzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Breen, G., Borglum, A.D., Sullivan, P.F., and Major Depressive Disorder Worki

Subjects
treatment-resistance, polygenic risk scores, depression, major depression, electroconvulsive therapy
Abstract

Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistantdepression; disorder severity and unfavorable treatment outcomes are shown to be influencedby an increased genetic burden for major depression (MD). Here, we tested whether ECT assign-ment and response/nonresponse are associated with an increased genetic burden for majordepression (MD) using polygenic risk score (PRS), which summarize the contribution of disease-related common risk variants. Fifty-one psychiatric inpatients suffering from a major depressiveepisode underwent ECT. MD-PRS were calculated for these inpatients and a separatepopulation-based sample (n = 3,547 healthy; n = 426 self-reported depression) based on sum-mary statistics from the Psychiatric Genomics Consortium MDD-working group (Cases:n = 59,851; Controls: n = 113,154). MD-PRS explained a significant proportion of disease statusbetween ECT patients and healthy controls (p = .022, R2 = 1.173%); patients showed higherMD-PRS. MD-PRS in population-based depression self-reporters were intermediate betweenECT patients and controls (n.s.). Significant associations between MD-PRS and ECT response(50% reduction in Hamilton depression rating scale scores) were not observed. Our findings indi-cate that ECT cohorts show an increased genetic burden for MD and are consistent with thehypothesis that treatment-resistant MD patients represent a subgroup with an increased geneticrisk for MD. Larger samples are needed to better substantiate these findings.

Published
2019

46. Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances

Author

Timmers, P.R., Mounier, N., Lall, K., Fischer, K., Ning, Z., Feng, X., Bretherick, A.D., Clark, D.W., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Awadalla, P., Battle, A., Bonder, M.J., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., van Dongen, J., Esko, T., Favé, M., Franke, L., Frayling, T., Gharib, S.A., Gibson, G., Hemani, G., Jansen, R., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg-Guzman, J., Kukushkina, V., Kutalik, Z., Kähönen, M., Lee, B., Lehtimäki, T., Loeffler, M., Marigorta, U., Metspalu, A., van Meurs, J., Milani, L., Müller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B., Powell, J., Prokisch, H., Psaty, B.M., Raitakari, O., Ring, S., Ripatti, S., Rotzschke, O., Ruëger, S., Saha, A., Scholz, M., Schramm, K., Seppälä, I., Stumvoll, M., Sullivan, P., Teumer, A., Thiery, J., Tong, L., Tönjes, A., Verlouw, J., Visscher, P.M., Võsa, U., Völker, U., Yaghootkar, H., Yang, J., Zeng, B., Zhang, F., Shen, X., Wilson, J.F., Joshi, P.K., eQTLGen Consortium, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, and APH - Digital Health

Subjects
Male, Parents, Multifactorial Inheritance, QH301-705.5, Science, Longevity, Complex Trait, Genetics, Genomics, Human, Lifespan, Age Factors, Aged, Bayes Theorem, DNA Methylation/genetics, Disease/genetics, Female, Genetic Loci, Genome-Wide Association Study, Humans, Longevity/genetics, Middle Aged, Multifactorial Inheritance/genetics, Polymorphism, Single Nucleotide/genetics, Risk Factors, Sex Characteristics, Signal Transduction/genetics, Survival Analysis, complex trait, genetics, genomics, human, lifespan, longevity, Polymorphism, Single Nucleotide, Research Communication, Disease, Biology (General), Genetics and Genomics, DNA Methylation, Medicine, Signal Transduction
Abstract

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer – but not other cancers – explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter)., eLife digest Ageing happens to us all, and as the cabaret singer Maurice Chevalier pointed out, "old age is not that bad when you consider the alternative". Yet, the growing ageing population of most developed countries presents challenges to healthcare systems and government finances. For many older people, long periods of ill health are part of the end of life, and so a better understanding of ageing could offer the opportunity to prolong healthy living into old age. Ageing is complex and takes a long time to study – a lifetime in fact. This makes it difficult to discern its causes, among the countless possibilities based on an individual’s genes, behaviour or environment. While thousands of regions in an individual’s genetic makeup are known to influence their risk of different diseases, those that affect how long they will live have proved harder to disentangle. Timmers et al. sought to pinpoint such regions, and then use this information to predict, based on their DNA, whether someone had a better or worse chance of living longer than average. The DNA of over 500,000 people was read to reveal the specific ‘genetic fingerprints’ of each participant. Then, after asking each of the participants how long both of their parents had lived, Timmers et al. pinpointed 12 DNA regions that affect lifespan. Five of these regions were new and had not been linked to lifespan before. Across the twelve as a whole several were known to be involved in Alzheimer’s disease, smoking-related cancer or heart disease. Looking at the entire genome, Timmers et al. could then predict a lifespan score for each individual, and when they sorted participants into ten groups based on these scores they found that top group lived five years longer than the bottom, on average. Many factors beside genetics influence how long a person will live and our lifespan cannot be read from our DNA alone. Nevertheless, Timmers et al. had hoped to narrow down their search and discover specific genes that directly influence how quickly people age, beyond diseases. If such genes exist, their effects were too small to be detected in this study. The next step will be to expand the study to include more participants, which will hopefully pinpoint further genomic regions and help disentangle the biology of ageing and disease.

Published
2019

47. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Author

Porcu, E. (Eleonora), Rueger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawusse), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A. (Anand), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M. J. (Marc Jan), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tonu), Fave, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T. (Timothy), Gharib, S. A. (Sina A.), Gibson, G. (Gregory), Heijmans, B. T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kahonen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Lee, B. (Bernett), Lehtimaki, T. (Terho), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G. W. (Grant W.), Mueler-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, B. L. (Brandon L.), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. M. (Bruce M.), Raitakari, O. T. (Olli T.), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppala, I. (Ilkka), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), van Meurs, J. (Joyce), Veldink, J. H. (Jan H.), Verlouw, J. (Joost), Visscher, P. M. (Peter M.), Volker, U. (Uwe), Vosa, U. (Urmo), Westra, H.-J. (Harm-Jan), Wijmenga, C. (Cisca), Yaghootkar, H. (Hanieh), Yang, J. (Jian), Zeng, B. (Biao), Zhang, F. (Futao), Beekman, M. (Marian), Boomsma, D. I. (Dorret I.), Bot, J. (Jan), Deelen, J. (Joris), Hofman, B. A. (Bert A.), Hottenga, J. J. (Jouke J.), Isaacs, A. (Aaron), Jhamai, P. M. (P. Mila), Kielbasa, S. M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (Rene), Mei, H. (Hailiang), Moed, M. (Matthijs), Nooren, I. (Irene), Pool, R. (Rene), Schalkwijk, C. G. (Casper G.), Slagboom, P. E. (P. Eline), Suchiman, H. E. (H. Eka D.), Swertz, M. A. (Morris A.), Tigchelaar, E. F. (Ettje F.), Uitterlinden, A. G. (Andre G.), van den Berg, L. H. (Leonard H.), van der Breggen, R. (Ruud), van der Kallen, C. J. (Carla J. H.), van Dijk, F. (Freerk), van Duijn, C. M. (Cornelia M.), van Galen, M. (Michiel), van Greevenbroek, M. M. (Marleen M. J.), van Heemst, D. (Diana), van Rooij, J. (Jeroen), Van't Hof, P. (Peter), van Zwet, E. W. (Erik. W.), Vermaat, M. (Martijn), Verbiest, M. (Michael), Verkerk, M. (Marijn), Zhernakova, D. V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F. A. (Federico A.), Reymond, A. (Alexandre), and Kutalik, Z. (Zoltan)

Abstract

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.

Published
2019

48. Erratum: Meta-analysis of genome-wide association studies of anxiety disorders

Author

Otowa, T, Hek, K, Lee, M, Byrne, E M, Mirza, S S, Nivard, M G, Bigdeli, T, Aggen, S H, Adkins, D, Wolen, A, Fanous, A, Keller, M C, Castelao, E, Kutalik, Z, der Auwera, S V, Homuth, G, Nauck, M, Teumer, A, Milaneschi, Y, Hottenga, J-J, Direk, N, Hofman, A, Uitterlinden, A, Mulder, C L, Henders, A K, Medland, S E, Gordon, S, Heath, A C, Madden, P A F, Pergadia, M L, van der Most, P J, Nolte, I M, van Oort, F V A, Hartman, C A, Oldehinkel, A J, Preisig, M, Grabe, H J, Middeldorp, C M, Penninx, B W J H, Boomsma, D, Martin, N G, Montgomery, G, Maher, B S, van den Oord, E J, Wray, N R, Tiemeier, H, and Hettema, J M

Published
2016
Full Text
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50. Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits (vol 50, pg 1412, 2018)

Author

Evangelou, E, Warren, HR, Mosen-Ansorena, D, Mifsud, B, Pazoki, R, Gao, H, Ntritsos, G, Dimou, N, Cabrera, CP, Karaman, I, Fu, LN, Evangelou, M, Witkowska, K, Tzanis, E, Hellwege, JN, Giri, A, Edwards, DRV, Sun, YV, Cho, K, Gaziano, JM, Wilson, PWF, Tsao, PS, Kovesdy, CP, Esko, T, Magi, R, Milani, L, Almgren, P, Boutin, T, Debette, S, Ding, J, Giulianini, F, Holliday, EG, Jackson, AU, Li-Gao, R, Lin, W-Y, Luan, J, Mangino, M, Oldmeadow, C, Prins, BP, Qian, Y, Sargurupremraj, M, Shah, N, Surendran, P, Theriault, S, Verweij, N, Willems, SM, Zhao, J-H, Amouyel, P, Connell, J, De Mutsert, R, Doney, ASF, Farrall, M, Menni, C, Morris, AD, Noordam, R, Pare, G, Poulter, NR, Shields, DC, Stanton, A, Thom, S, Abecasis, G, Amin, N, Arking, DE, Ayers, KL, Barbieri, CM, Batini, C, Bis, JC, Blake, T, Bochud, M, Boehnke, M, Boerwinkle, E, Boomsma, DI, Bottinger, EP, Braund, PS, Brumat, M, Campbell, A, Campbell, H, Chakravarti, A, Chambers, JC, Chauhan, G, Ciullo, M, Cocca, M, Collins, F, Cordell, HJ, Davies, G, De Borst, MH, De Geus, EJ, Deary, IJ, Deelen, J, Del Greco, FM, Demirkale, CY, Dorr, M, Ehret, GB, Elosua, R, Enroth, S, Erzurumluoglu, AM, Ferreira, T, Franberg, M, Franco, OH, Gandin, I, Gasparini, P, Giedraitis, V, Gieger, C, Girotto, G, Goel, A, Gow, AJ, Gudnason, V, Guo, X, Gyllensten, U, Hamsten, A, Harris, TB, Harris, SE, Hartman, CA, Havulinna, AS, Hicks, AA, Hofer, E, Hofman, A, Hottenga, J-J, Huffman, JE, Hwang, S-J, Ingelsson, E, James, A, Jansen, R, Jarvelin, M-R, Joehanes, R, Johansson, A, Johnson, AD, Joshi, PK, Jousilahti, P, Jukema, JW, Jula, A, Kahonen, M, Kathiresan, S, Keavney, BD, Khaw, K-T, Knekt, P, Knight, J, Kolcic, I, Kooner, JS, Koskinen, S, Kristiansson, K, Kutalik, Z, Laan, M, Larson, M, Launer, LJ, Lehne, B, Lehtimaki, T, Liewald, DCM, Lin, L, Lind, L, Lindgren, CM, Liu, Y, Loos, RJF, Lopez, LM, Lu, Y, Lyytikainen, L-P, Mahajan, A, Mamasoula, C, Marrugat, J, Marten, J, Milaneschi, Y, Morgan, A, Morris, AP, Morrison, AC, Munson, PJ, Nalls, MA, Nandakumar, P, Nelson, CP, Niiranen, T, Nolte, IM, Nutile, T, Oldehinkel, AJ, Oostra, BA, O'Reilly, PF, Org, E, Padmanabhan, S, Palmas, W, Palotie, A, Pattie, A, Penninx, BWJH, Perola, M, Peters, A, Polasek, O, Pramstaller, PP, Quang, TN, Raitakari, OT, Ren, M, Rettig, R, Rice, K, Ridker, PM, Ried, JS, Riese, H, Ripatti, S, Robino, A, Rose, LM, Rotter, JI, Rudan, I, Ruggiero, D, Saba, Y, Sala, CF, Salomaa, V, Samani, NJ, Sarin, A-P, Schmidt, R, Schmidt, H, Shrine, N, Siscovick, D, Smith, AV, Snieder, H, Sober, S, Sorice, R, Starr, JM, Stott, DJ, Strachan, DP, Strawbridge, RJ, Sundstrom, J, Swertz, MA, Taylor, KD, Teumer, A, Tobin, MD, Tomaszewski, M, Toniolo, D, Traglia, M, Trompet, S, Tuomilehto, J, Tzourio, C, Uitterlinden, AG, Vaez, A, Van der Most, PJ, Van Duijn, CM, Vergnaud, A-C, Verwoert, GC, Vitart, V, Volker, U, Vollenweider, P, Vuckovic, D, Watkins, H, Wild, SH, Willemsen, G, Wilson, JF, Wright, AF, Yao, J, Zemunik, T, Zhang, W, Attia, JR, Butterworth, AS, Chasman, DI, Conen, D, Cucca, F, Danesh, J, Hayward, C, Howson, JMM, Laakso, M, Lakatta, EG, Langenberg, C, Melander, O, Mook-Kanamori, DO, Palmer, CNA, Risch, L, Scott, RA, Scott, RJ, Sever, P, Spector, TD, Van der Harst, P, Wareham, NJ, Zeggini, E, Levy, D, Munroe, PB, Newton-Cheh, C, Brown, MJ, Metspalu, A, Hung, AM, O'Donnell, CJ, Edwards, TL, Psaty, BM, Tzoulaki, I, Barnes, MR, Wain, LV, Elliott, P, and Caulfield, MJ

Subjects
Genetics & Heredity, Science & Technology, Million Veteran Program, 06 Biological Sciences, Life Sciences & Biomedicine, 11 Medical and Health Sciences, Developmental Biology
Abstract

Correction to: Nature Genetics https://doi.org/10.1038/s41588-018-0205-x, published online 17 September 2018.

Published
2018

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