title: LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.
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.
authors: 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.
authors: Brendan K
authors: BK
authors: Bulik-Sullivan
authors: 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.
authors: Po-Ru
authors: PR
authors: Loh
authors: 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.
authors: Hilary K
authors: HK
authors: Finucane
authors: 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.
authors: Stephan
authors: S
authors: Ripke
authors: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
authors: Jian
authors: 0000000320012474
authors: J
authors: Yang
authors: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Nick
authors: N
authors: Patterson
authors: 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.
authors: Mark J
authors: MJ
authors: Daly
authors: 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.
authors: Alkes L
authors: AL
authors: Price
authors: 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.
authors: Benjamin M
authors: BM
authors: Neale
mesh_terms: D003198:Computer Simulation; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D018401:Sample Size
references: Am J Hum Genet. 2000 May;66(5):1616-30
references: 10762547
references: Nature. 2010 Sep 2;467(7311):52-8
references: 20811451
references: Nature. 2010 Oct 14;467(7317):832-8
references: 20881960
references: Nat Genet. 2010 Nov;42(11):949-60
references: 20935629
references: Nat Genet. 2010 Nov;42(11):937-48
references: 20935630
references: Am J Hum Genet. 2011 Jan 7;88(1):76-82
references: 21167468
references: Nat Genet. 2011 Apr;43(4):333-8
references: 21378990
references: Eur J Hum Genet. 2011 Jul;19(7):807-12
references: 21407268
references: Nature. 2011 Aug 11;476(7359):214-9
references: 21833088
references: Nat Genet. 2011 Oct;43(10):977-83
references: 21926972
references: Nat Methods. 2011;8(10):833-5
references: 21892150
references: Nature. 2011 Oct 6;478(7367):103-9
references: 21909115
references: Nat Genet. 2012 May;44(5):491-501
references: 22504420
references: Nat Genet. 2012 Jun;44(6):659-69
references: 22581228
references: Nat Genet. 2012 Sep;44(9):981-90
references: 22885922
references: Nat Genet. 2012 Sep;44(9):1066-71
references: 22902788
references: Nature. 2012 Nov 1;491(7422):56-65
references: 23128226
references: Nature. 2012 Nov 1;491(7422):119-24
references: 23128233
references: Mol Psychiatry. 2013 Apr;18(4):497-511
references: 22472876
references: Lancet. 2013 Apr 20;381(9875):1371-9
references: 23453885
references: PLoS Biol. 2013;11(5):e1001555
references: 23667324
references: Science. 2013 Jun 21;340(6139):1467-71
references: 23722424
references: Nature. 2014 Jul 24;511(7510):421-7
references: 25056061
references: Biometrics. 1999 Dec;55(4):997-1004
references: 11315092
references: Am J Hum Genet. 2001 Jul;69(1):1-14
references: 11410837
references: Am J Hum Genet. 2004 Jun;74(6):1111-20
references: 15114531
references: Nature. 2004 Aug 19;430(7002):857-64
references: 15318213
references: Genome Res. 2005 Nov;15(11):1519-34
references: 16251462
references: PLoS Genet. 2005 Sep;1(3):e32
references: 16151517
references: Nat Genet. 2006 Aug;38(8):904-9
references: 16862161
references: Am J Epidemiol. 2007 Jun 1;165(11):1328-35
references: 17372189
references: PLoS Genet. 2006 Dec;2(12):e190
references: 17194218
references: Am J Hum Genet. 2008 Jul;83(1):132-5; author reply 135-9
references: 18606306
references: Am J Hum Genet. 2008 Dec;83(6):787-94
references: 19061986
references: Mol Psychiatry. 2009 Apr;14(4):359-75
references: 19065144
references: PLoS Genet. 2009 May;5(5):e1000471
references: 19424416
references: PLoS Genet. 2009 Jun;5(6):e1000505
references: 19503599
references: Am J Hum Genet. 2009 Dec;85(6):862-72
references: 20004761
references: Nat Genet. 2010 Apr;42(4):348-54
references: 20208533
references: Nat Genet. 2010 May;42(5):441-7
references: 20418890
references: Nat Genet. 2010 Jun;42(6):508-14
references: 20453842
references: J Am Acad Child Adolesc Psychiatry. 2010 Sep;49(9):884-97
references: 20732625