LD Score Regression Distinguishes Confounding from Polygenicity in Genome-Wide Association Studies

Corvin, A.; Zai, C. C.; Zheng, X.; Zimprich, F.; Walters, J. T. R.; Farh, K.-H.; Holmans, P. A.; Lee, P.; Collier, D. A.; Huang, H.; Pers, T. H.; Agartz, I.; Agerbo, E.; Albus, M.; Alexander, M.; Amin, F.; Bacanu, S. A.; Begemann, M.; Belliveau, R. A.; Bulik-Sullivan, Brendan K.; Bk, Bulik Sullivan; Bene, J.; Bergen, S. E.; Bevilacqua, E.; Bigdeli, T. B.; Black, D. W.; Bruggeman, R.; Buccola, N. G.; Buckner, R. L.; Byerley, W.; Cahn, W.; Cai, G.; Cairns, M. J.; Campion, D.; Cantor, R. M.; Carr, V. J.; Carrera, N.; Catts, S.; Chambert, K. D.; Chan, R. C. K.; Chen, R. Y. L.; Loh, Po-Ru; Chen, E. Y. H.; Cheng, W.; Cheung, E. F. C.; Chong, S. A.; Cloninger, C. R.; Cohen, D.; Cohen, N.; Cormican, P.; Craddock, N.; Crespo-Facorro, B.; Crowley, J. J.; Curtis, D.; Davidson, M.; Davis, K. L.; Degenhardt, F.; Del Favero, J.; DeLisi, L. E.; Demontis, D.; Dikeos, D.; Dinan, T.; Finucane, Hilary K.; Djurovic, S.; Pr, Loh; Donohoe, G.; Drapeau, E.; Duan, J.; Dudbridge, F.; Durmishi, N.; Eichhammer, P.; Eriksson, J.; Escott-Price,; Essioux, L.; Fanous, A. H.; Farrell,; Frank, J.; Franke, L.; Freedman, R.; Freimer, N. B.; Friedl, M.; Friedman, J. I.; Fromer, M.; Ripke, Stephan; Genovese, G.; Georgieva, L.; Gershon, E. S.; Giegling, I.; Giusti-Rodríguez, P.; Godard, S.; Goldstein, J. I.; Golimbet,; Gopal, S.; Gratten, J.; De Haan, L.; Hammer, C.; Hamshere, M. L.; Hansen, M.; Hansen, T.; Haroutunian,; Hartmann, A. M.; Henskens, F. A.; Herms, S.; Hk, Finucane; Hirschhorn, J. N.; Hoffmann, P.; Hofman, A.; Hollegaard, M.; Yang, Jian; Hougaard, D. M.; Ikeda, M.; Joa, I.; Juliá, A.; Kahn, R. S.; Kalaydjieva, L.; Karachanak-Yankova, S.; Karjalainen, J.; Kavanagh, D.; Keller, M. C.; Kelly, B. J.; Kennedy, J. L.; Khrunin, A.; Kim, Y.; Klovins, J.; Knowles, J. A.; Konte, B.; Kucinskas,; Kucinskiene, Z. A.; Kuzelova-Ptackova, H.; Kähler, A. K.; Laurent, C.; Patterson, Nick; Keong, J. L. C.; Lee, S. H.; Legge, S. E.; Lerer, B.; Li, M.; Li, T.; Liang, K.-Y.; Lieberman, J.; Limborska, S.; Loughland, C. M.; Lubinski, J.; Lönnqvist, J.; Macek, M.; Magnusson, P. K. E.; Maher, B. S.; Maier, W.; Mallet, J.; Marsal, S.; Mattheisen, M.; Mattingsdal, M.; McCarley, R. W.; Daly, Mark J.; McDonald, C.; McIntosh, A. M.; Meier, S.; Meijer, C. J.; Melegh, B.; Melle, I.; Consorti, Schizophrenia Working Group of the Psychiatric Genomics; Mesholam-Gately, R. I.; Metspalu, A.; Michie, P. T.; Milani, L.; Milanova,; Mokrab, Y.; Morris, D. W.; Mors, O.; Murphy, K. C.; Murray, R. M.; Myin-Germeys, I.; Müller-Myhsok, B.; Nelis, M.; Nenadic, I.; Nertney, D. A.; Nestadt, G.; Nicodemus, K. K.; Price, Alkes L.; Nikitina-Zake, L.; Nisenbaum, L.; Consortium, Schizophrenia Working Group of the Psychiatric Genomics; Nordin, A.; O'Callaghan, E.; O'Dushlaine, C.; O'Neill, F. A.; Oh, S.-Y.; Olincy, A.; Olsen, L.; Van Os, J.; Pantelis, C.; Papadimitriou, G. N.; Papiol, S.; Parkhomenko, E.; Pato, M. T.; Paunio, T.; Pejovic-Milovancevic, M.; Perkins, D. O.; Pietiläinen, O.; Pimm, J.; Pocklington, A. J.; Neale, Benjamin M.; Psychiatric Genomics Consortium, S. W. G.; Powell, J.; Pulver, A. E.; Purcell, S. M.; Quested, D.; Rasmussen, H. B.; Reichenberg, A.; Reimers,; Richards, A. L.; Roffman, J. L.; Roussos, P.; Ruderfer, D. M.; Salomaa,; Sanders, A. R.; Schall, U.; Schubert, C. R.; Schulze, T. G.; Schwab, S. G.; Scolnick, E. M.; Scott, R. J.; Seidman, L. J.; Shi, J.; Sigurdsson, E.; Silagadze, T.; Silverman, J. M.; Sim, K.; Slominsky, P.; Smoller, J. W.; So, H.-C.; Spencer, C. C. A.; Stahl, E. A.; Stefansson, H.; Steinberg, S.; Stogmann, E.; Straub, R. E.; Mj, Daly; Strengman, E.; Strohmaier, J.; Stroup, T. S.; Subramaniam, M.; Suvisaari, J.; Svrakic, D. M.; Szatkiewicz, J. P.; Söderman, E.; Thirumalai, S.; Toncheva, D.; Tooney, P. A.; Tosato, S.; Veijola, J.; Waddington, J.; Walsh, D.; Wang, D.; Wang, Q.; Webb, B. T.; Weiser, M.; Wildenauer, D. B.; Williams, N. M.; Williams, S.; Witt, S. H.; Wolen, A. R.; Wong, E. H. M.; Wormley, B. K.; Wu, J. Q.; Xi, H. S.; Al, Price; Wray, N. R.; Stefansson, K.; Visscher, P. M.; Adolfsson, R.; Andreassen, O. A.; Blackwood, D. H. R.; Bramon, E.; Buxbaum,; Børglum, A. D.; Cichon, S.; Darvasi, A.; Domenici, E.; Ehrenreich, H.; Esko, T.; Gejman, P.; Gill, M.; Gurling, H.; Hultman, C. M.; Iwata, N.; Jablensky, A.; Jönsson, E. G.; Kendler, K. S.; Kirov, G.; Knight, J.; Lencz, T.; Levinson, D. F.; Li, Q. S.; Liu, J.; Malhotra, A. K.; McCarroll, S. A.; McQuillin, A.; Moran, J. L.; Mortensen, P. B.; Mowry, B. J.; Bm, Neale; Nöthen, M. M.; Ophoff, R. A.; Owen, M. J.; Palotie, A.; Pato, C. N.; Petryshen, T. L.; Posthuma, D.; Rietschel, M.; Riley, B. P.; Rujescu, D.; Sham, P. C.; Sklar, P.; St Clair, D.; Weinberger, D. R.; Wendland,; Werge, T.; Sullivan, P. F.; Grp, Schizophrenia Working; O'Donovan, M. C.

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Nature Research, Nature Genetics, 3(47), p. 291-295, 2015

DOI: 10.1038/ng.3211

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LD Score Regression Distinguishes Confounding from Polygenicity in Genome-Wide Association Studies

Journal article published in 2015 by A. Corvin, C. C. Zai

, X. Zheng, F. Zimprich, J. T. R. Walters, K.-H. Farh, P. A. Holmans, P. Lee, D. A. Collier, H. Huang, T. H. Pers, I. Agartz, E. Agerbo, M. Albus, M. Alexander and other authors.

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Abstract

Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

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LD Score Regression Distinguishes Confounding from Polygenicity in Genome-Wide Association Studies

Abstract