LD Score regression distinguishes confounding from polygenicity in genome-wide association studies

Brendan K Bulik-Sullivan; Po-Ru Loh; Hilary K Finucane; Stephan Ripke; Jian Yang; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Nick Patterson; Mark J Daly; Alkes L Price; Benjamin M Neale

doi:10.1038/ng.3211

LD Score regression distinguishes confounding from polygenicity in genome-wide association studies

Nat Genet. 2015 Mar;47(3):291-5. doi: 10.1038/ng.3211. Epub 2015 Feb 2.

Authors

Brendan K Bulik-Sullivan¹, Po-Ru Loh², Hilary K Finucane³, Stephan Ripke⁴, Jian Yang⁵; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Nick Patterson⁶, Mark J Daly¹, Alkes L Price⁷, Benjamin M Neale¹

Collaborators

Schizophrenia Working Group of the Psychiatric Genomics Consortium:
Stephan Ripke, Benjamin M Neale, Aiden Corvin, James T R Walters, Kai-How Farh, Peter A Holmans, Phil Lee, Brendan Bulik-Sullivan, David A Collier, Hailiang Huang, Tune H Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A Bacanu, Martin Begemann, Richard A Belliveau Jr, Judit Bene, Sarah E Bergen, Elizabeth Bevilacqua, Tim B Bigdeli, Donald W Black, Richard Bruggeman, Nancy G Buccola, Randy L Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Murray J Cairns, Dominique Campion, Rita M Cantor, Vaughan J Carr, Noa Carrera, Stanley V Catts, Kimberly D Chambert, Raymond C K Chan, Ronald Y L Chen, Eric Y H Chen, Wei Cheng, Eric F C Cheung, Siow Ann Chong, C Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, Benedicto Crespo-Facorro, James J Crowley, David Curtis, Michael Davidson, Kenneth L Davis, Franziska Degenhardt, Jurgen Del Favero, Lynn E DeLisi, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H Fanous, Martilias S Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B Freimer, Marion Friedl, Joseph I Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Elliot S Gershon, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M Hartmann, Frans A Henskens, Stefan Herms, Joel N Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V Hollegaard, David M Hougaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C Keller, Brian J Kelly, James L Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S Hong Lee, Sophie E Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek Jr, Patrik K E Magnusson, Brion S Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W McCarley, Colm McDonald, Andrew M McIntosh, Sandra Meier, Carin J Meijer, Bela Melegh, Ingrid Melle, Raquelle I Mesholam-Gately, Andres Metspalu, Patricia T Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W Morris, Ole Mors, Kieran C Murphy, Robin M Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A Nertney, Gerald Nestadt, Kristin K Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O'Callaghan, Colm O'Dushlaine, F Anthony O'Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J Pocklington, John Powell, Alkes Price, Ann E Pulver, Shaun M Purcell, Digby Quested, Henrik B Rasmussen, Abraham Reichenberg, Mark A Reimers, Alexander L Richards, Joshua L Roffman, Panos Roussos, Douglas M Ruderfer, Veikko Salomaa, Alan R Sanders, Ulrich Schall, Christian R Schubert, Thomas G Schulze, Sibylle G Schwab, Edward M Scolnick, Rodney J Scott, Larry J Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M Silverman, Kang Sim, Petr Slominsky, Jordan W Smoller, Hon-Cheong So, Chris C A Spencer, Eli A Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E Straub, Eric Strengman, Jana Strohmaier, T Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M Svrakic, Jin P Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Paul A Tooney, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T Webb, Mark Weiser, Dieter D Wildenauer, Nigel M Williams, Stephanie Williams, Stephanie H Witt, Aaron R Wolen, Emily H M Wong, Brandon K Wormley, Jing Qin Wu, Hualin Simon Xi, Clement C Zai, Xuebin Zheng, Fritz Zimprich, Naomi R Wray, Kari Stefansson, Peter M Visscher, Rolf Adolfsson, Ole A Andreassen, Douglas H R Blackwood, Elvira Bramon, Joseph D Buxbaum, Anders D Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V Gejman, Michael Gill, Hugh Gurling, Christina M Hultman, Nakao Iwata, Assen V Jablensky, Erik G Jönsson, Kenneth S Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F Levinson, Qingqin S Li, Jianjun Liu, Anil K Malhotra, Steven A McCarroll, Andrew McQuillin, Jennifer L Moran, Preben B Mortensen, Bryan J Mowry, Markus M Nöthen, Roel A Ophoff, Michael J Owen, Aarno Palotie, Carlos N Pato, Tracey L Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P Riley, Dan Rujescu, Pak C Sham, Pamela Sklar, David St Clair, Daniel R Weinberger, Jens R Wendland, Thomas Werge, Mark J Daly, Patrick F Sullivan, Michael C O'Donovan

Affiliations

¹ 1] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
² 1] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
³ 1] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. [2] Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
⁴ 1] Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁵ Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
⁶ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁷ 1] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. [3] Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

PMID: 25642630
PMCID: PMC4495769
DOI: 10.1038/ng.3211

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Computer Simulation
Genome, Human
Genome-Wide Association Study / methods*
Humans
Linkage Disequilibrium*
Polymorphism, Single Nucleotide
Regression Analysis
Sample Size

Abstract

Publication types

MeSH terms

Grants and funding