Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases

Alexander Gusev; S Hong Lee; Gosia Trynka; Hilary Finucane; Bjarni J Vilhjálmsson; Han Xu; Chongzhi Zang; Stephan Ripke; Brendan Bulik-Sullivan; Eli Stahl; Schizophrenia Working Group of the Psychiatric Genomics Consortium; SWE-SCZ Consortium; Anna K Kähler; Christina M Hultman; Shaun M Purcell; Steven A McCarroll; Mark Daly; Bogdan Pasaniuc; Patrick F Sullivan; Benjamin M Neale; Naomi R Wray; Soumya Raychaudhuri; Alkes L Price; Schizophrenia Working Group of the Psychiatric Genomics Consortium; SWE-SCZ Consortium

doi:10.1016/j.ajhg.2014.10.004

Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases

Am J Hum Genet. 2014 Nov 6;95(5):535-52. doi: 10.1016/j.ajhg.2014.10.004. Epub 2014 Nov 6.

Authors

Alexander Gusev¹, S Hong Lee², Gosia Trynka³, Hilary Finucane⁴, Bjarni J Vilhjálmsson⁵, Han Xu⁶, Chongzhi Zang⁶, Stephan Ripke⁷, Brendan Bulik-Sullivan⁷, Eli Stahl⁸; Schizophrenia Working Group of the Psychiatric Genomics Consortium; SWE-SCZ Consortium; Anna K Kähler⁹, Christina M Hultman⁹, Shaun M Purcell¹⁰, Steven A McCarroll¹¹, Mark Daly¹², Bogdan Pasaniuc¹³, Patrick F Sullivan¹⁴, Benjamin M Neale¹², Naomi R Wray², Soumya Raychaudhuri¹⁵, Alkes L Price¹⁶; Schizophrenia Working Group of the Psychiatric Genomics Consortium; SWE-SCZ Consortium

Collaborators

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, Anders D Børglum, Richard Bruggeman, Nancy G Buccola, Randy L Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, 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, 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-Rodrguez, Stephanie Godard, Jacqueline I Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Jakob Grove, 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 Lnnqvist, 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, Preben B Mortensen, Kieran C Murphy, Robin M Murray, Inez Myin-Germeys, Bertram Mller-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 Pietilinen, 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 Sderman, 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 B 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 Brglum, 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 Nthen, 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, Stephan Ripke, Colm O'Dushlaine, Kimberly Chambert, Jennifer L Moran, Anna K Kähler, Susanne Akterin, Sarah Bergen, Patrik K E Magnusson, Benjamin M Neale, Douglas Ruderfer, Edward Scolnick, Shaun Purcell, Steve McCarroll, Pamela Sklar, Christina M Hultman, Patrick F Sullivan

Affiliations

¹ Harvard School of Public Health, Boston, MA 02115, USA. Electronic address: agusev@hsph.harvard.edu.
² The University of Queensland, Queensland Brain Institute, Brisbane, QLD 4072, Australia.
³ Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Rheumatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Partners Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁵ Harvard School of Public Health, Boston, MA 02115, USA.
⁶ Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA.
⁷ Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
¹⁰ Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
¹¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹³ Department of Pathology and Laboratory Medicine, Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁵ Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Rheumatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Partners Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PL, UK.
¹⁶ Harvard School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: aprice@hsph.harvard.edu.

Abstract

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg(2)) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg(2) from imputed SNPs (5.1× enrichment; p = 3.7 × 10(-17)) and 38% (SE = 4%) of hg(2) from genotyped SNPs (1.6× enrichment, p = 1.0 × 10(-4)). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of hg(2) despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.

Publication types

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

MeSH terms

Computer Simulation
Genetic Diseases, Inborn / genetics*
Genetic Variation / genetics*
Genome-Wide Association Study / methods*
Humans
Inheritance Patterns / genetics*
Models, Genetic
Open Reading Frames / genetics*
Regulatory Elements, Transcriptional / genetics*

Abstract

Publication types

MeSH terms

Grants and funding