A comparison of ten polygenic score methods for psychiatric disorders applied across multiple cohorts

作者：G. Ni, Jian Zeng, J. Revez, Ying Wang, Zhili Zheng, T. Ge, Restuadi Restuadi, Jacqueline Kiewa, D. Nyholt, J. Coleman, J. Smoller, Jian Yang, P. Visscher, N. Wray, S. Ripke, B. Neale, A. Corvin, J. Walters, Kai-How Farh, P. Holmans, Phil H. Lee, B. Bulik-Sullivan, D. Collier, Hailiang Huang, T. Pers, I. Agartz, E. Agerbo, M. Albus, Madeline Alexander, F. Amin, S. Bacanu, M. Begemann, R. Belliveau, J. Bene, Sarah L Bergen, Elizabeth Bevilacqua, T. Bigdeli, D. Black, R. Bruggeman, N. Buccola, R. Buckner, W. Byerley, W. Cahn, Guiqing Cai, D. Campion, R. Cantor, V. Carr, N. Carrera, S. Catts, Kimberley D. Chambert, R. Chan, Ronald Y. L. Chen, Eric Y. H. Chen, Wei Cheng, E. Cheung, S. Chong, C. Cloninger, David Cohen, Nadine Cohen, P. Cormican, N. Craddock, J. Crowley, Michal Davidson, K. Davis, F. Degenhardt, J. D. Favero, D. Demontis, D. Dikeos, T. Dinan, S. Djurovic, G. Donohoe, Elodie Drapeau, J. Duan, F. Dudbridge, N. Durmishi, P. Eichhammer, Johan Eriksson, V. Escott-Price, L. Essioux, A. Fanous, M. Farrell, J. Frank, L. Franke, R. Freedman, N. Freimer, M. Friedl, J. Friedman, M. Fromer, G. Genovese, L. Georgieva, I. Giegling, P. Giusti-Rodríguez, S. Godard, J. Goldstein, V. Golimbet, S. Gopal, J. Gratten, L. Haan, C. Hammer, M. Hamshere, M. Hansen, T. Hansen, V. Haroutunian, A. Hartmann, F. Henskens, S. Herms, J. Hirschhorn, P. Hoffmann, A. Hofman, M. Hollegaard, D. Hougaard, M. Ikeda, I. Joa, A. Julià, R. Kahn, L. Kalaydjieva, Sena Karachanak-Yankova, J. Karjalainen, David Kavanagh, M. Keller, James L. Kennedy, A. Khrunin, Yunjung Kim, J. Kloviņš, J. Knowles, B. Konte, V. Kučinskas, Z. Kučinskienė, Hana Kuzelova-Ptackova, A. Kähler, C. Laurent, Jimmy Lee, S. H. Lee, S. Legge, B. Lerer, Miaoxin Li, Tao Li, K. Liang, J. Lieberman, S. Limborska, C. Loughland, J. Lubiński, J. Lönnqvist, M. Macek, P. Magnusson, B. Maher, W. Maier, J. Mallet, S. Marsal, M. Mattheisen, M. Mattingsdal, R. McCarley, C. Mcdonald, A. McIntosh, S. Meier, C. Meijer, B. Melegh, I. Melle, R. Mesholam-Gately, A. Metspalu, P. Michie, L. Milani, V. Milanova, Younes Mokrab, D. Morris, O. Mors, K. Murphy, R. Murray, I. Myin-Germeys, B. Müller-Myhsok, M. Nelis, I. Nenadić, D. Nertney, G. Nestadt, K. Nicodemus, L. Nikitina-Zake, L. Nisenbaum, Annelie Nordin, E. O'callaghan, C. O’Dushlaine, F. O'Neill, Sang-Yun Oh, A. Olincy, L. Olsen, J. Os, Psychosis Endophenotypes International Consortium, C. Pantelis, G. Papadimitriou, S. Papiol, E. Parkhomenko, M. Pato, T. Paunio, M. Pejović-Milovančević, D. Perkins, O. Pietiläinen, J. Pimm, A. Pocklington, J. Powell, A. Price, A. Pulver, Shaun M. Purcell, D. Quested, H. Rasmussen, A. Reichenberg, M. Reimers, A. Richards, J. Roffman, P. Roussos, D. Ruderfer, V. Salomaa, A. Sanders, U. Schall, C. Schubert, T. Schulze, S. Schwab, E. Scolnick, Rodney J. Scott, L. Seidman, Jianxin Shi, E. Sigurdsson, T. Silagadze, J. Silverman, K. Sim, P. Slominsky, H. So, C. Spencer, E. Stahl, H. Stefánsson, S. Steinberg, E. Stogmann, R. Straub, E. Strengman, J. Strohmaier, T. Stroup, M. Subramaniam, J. Suvisaari, D. Svrakic, J. Szatkiewicz, E. Söderman, S. Thirumalai, D. Toncheva, S. Tosato, J. Veijola, J. Waddington, Dermot Walsh, Dai Wang, Qiang Wang, B. Webb, M. Weiser, D. Wildenauer, N. Williams, S. Williams, S. Witt, Aaron R Wolen, Emily H. M. Wong, B. Wormley, H. Xi, C. Zai, Xue-bin Zheng, F. Zimprich, K. Stefansson, Wellcome Trust Case-Control Consortium, R. Adolfsson, O. Andreassen, D. Blackwood, E. Bramon, J. Buxbaum, A. Børglum, S. Cichon, A. Darvasi, E. Domenici, H. Ehrenreich, T. Esko, P. Gejman, M. Gill, H. Gurling, C. Hultman, N. Iwata, A. Jablensky, E. Jönsson, K. Kendler, G. Kirov, J. Knight, T. Lencz, D. Levinson, Qingqin S. Li, Jianjun Liu, A. Malhotra, S. Mccarroll, A. McQuillin, J. Moran, P. Mortensen, B. Mowry, M. Nöthen, R. Ophoff, M. Owen, A. Palotie, C. Pato, T. Petryshen, D. Posthuma, M. Rietschel, B. Riley, D. Rujescu, P. Sham, P. Sklar, D. S. Clair, D. Weinberger, J. Wendland, T. Werge, M. Daly, Patrick F. Sullivan, M. O’Donovan, M. Trzaskowski, E. Byrne, A. Abdellaoui, M. Adams, Tracy M. Air, Till F. M. Andlauer, S. Bacanu, Marie Bækvad-Hansen, A. Beekman, E. Binder, J. Bryois, H. Buttenschøn, J. Bybjerg-Grauholm, N. Cai, E. Castelao, J. Christensen, Toni‐Kim Clarke, L. Colodro-Conde, B. Couvy-Duchesne, G. Crawford, G. Davies, I. Deary, E. Derks, N. Direk, C. Dolan, E. Dunn, T. Eley, Farnush Farhadi Hassan Kiadeh, H. Finucane, J. Foo, A. Forstner, Héléna A. Gaspar, F. Goes, S. Gordon, J. Grove, L. Hall, C. Hansen, T. Hansen, I. Hickie, G. Homuth, Carsten Horn, J. Hottenga, David Mark Howard, M. Ising, R. Jansen, I. Jones, L. Jones, E. Jorgenson, I. Kohane, J. Kraft, Warren W. Kretzschmar, Z. Kutalik, Yihan Li, P. Lind, D. Macintyre, D. MacKinnon, Robert M. Maier, J. Marchini, H. Mbarek, Patrick J. McGrath, P. McGuffin, S. Medland, D. Mehta, C. Middeldorp, E. Mihailov, Y. Milaneschi, Francis M. Mondimore, G. Montgomery, S. Mostafavi, N. Mullins, M. Nauck, B. Ng, M. Nivard, Paul F O'Reilly, H. Oskarsson, J. Painter, C. Pedersen, M. Pedersen, Roseann E. Peterson, W. Peyrot, G. Pistis, J. Quiroz, P. Qvist, John P. Rice, M. Rivera, S. Mirza, R. Schoevers, E. Schulte, Ling Shen, S. Shyn, Grant C. B. Sinnamon, J. Smit, Danny J. Smith, F. Streit, K. Tansey, H. Teismann, A. Teumer, Wesley Thompson, P. Thomson, T. Thorgeirsson, M. Traylor, J. Treutlein, V. Trubetskoy, A. Uitterlinden, D. Umbricht, S. Auwera, A. M. Hemert, A. Viktorin, Yunpeng Wang, S.M. Weinsheimer, J. Wellmann, G. Willemsen, Yang Wu, H. Xi, Futao Zhang, V. Arolt, B. Baune, K. Berger, D. Boomsma, U. Dannlowski, E. D. Geus, J. R. DePaulo, K. Domschke, H. Grabe, S. Hamilton, C. Hayward, A. Heath, S. Kloiber, G. Lewis, S. Lucae, P. Madden, P. Magnusson, N. Martin, P. Mortensen, M. Nordentoft, S. Paciga, N. Pedersen · 发表于：Biological Psychiatry · 年份：2021 · DOI：10.1016/j.biopsych.2021.04.018 · 被引用次数：167 · 研究领域：Medicine

Background: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies (GWASs). PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors. Methods: The Psychiatric Genomics Consortium working groups for schizophrenia (SCZ) and major depressive disorder (MDD) bring together many independently collected case-control cohorts. We used these resources (31K SCZ cases, 41K controls; 248K MDD cases, 563K controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and nine methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) are compared. Results: Compared to PC+T, the other nine methods give higher prediction statistics, MegaPRS, LDPred2 and SBayesR significantly so, up to 9.2% variance in liability for SCZ across 30 target cohorts, an increase of 44%. For MDD across 26 target cohorts these statistics w...