title: Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder.
abstract: Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk.
authors: The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Robert
authors: R
authors: Maier
authors: The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Gerhard
authors: G
authors: Moser
authors: The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Guo-Bo
authors: GB
authors: Chen
authors: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Stephan
authors: S
authors: Ripke
authors: Department of Psychiatry, University of Iowa, Iowa City, IA 52242, USA.
authors: William
authors: W
authors: Coryell
authors: Department of Psychiatry, University of Iowa, Iowa City, IA 52242, USA.
authors: James B
authors: JB
authors: Potash
authors: Department of Psychiatry, Rush University Medical Center, Chicago, IL 60612, USA.
authors: William A
authors: WA
authors: Scheftner
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors: Jianxin
authors: J
authors: Shi
authors: Department of Psychiatry, Columbia University, and New York State Psychiatric Institute, New York, NY 10032, USA.
authors: Myrna M
authors: MM
authors: Weissman
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden.
authors: Christina M
authors: CM
authors: Hultman
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden; Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, 413 45 Gothenburg, Sweden.
authors: Mikael
authors: M
authors: Landén
authors: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
authors: Douglas F
authors: DF
authors: Levinson
authors: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Kenneth S
authors: KS
authors: Kendler
authors: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Jordan W
authors: JW
authors: Smoller
authors: The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Naomi R
authors: NR
authors: Wray
authors: The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: hong.lee@uq.edu.au.
authors: S Hong
authors: SH
authors: Lee
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics; D003865:Major Depressive Disorder / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D005826:Genetics, Medical / Q000379:methods*; D006801:Humans; D016014:Linear Models; D001523:Mental Disorders / Q000235:genetics*; D020412:Multifactorial Inheritance / Q000235:genetics*; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018570:Risk Assessment / Q000379:methods*; D012559:Schizophrenia / Q000235:genetics
references: Nat Genet. 2012 Mar;44(3):247-50
references: 22344220
references: J Dairy Sci. 2012 Jul;95(7):4114-29
references: 22720968
references: Mol Psychiatry. 2012 Sep;17(9):880-6
references: 22688191
references: Nat Genet. 2012 Sep;44(9):1066-71
references: 22902788
references: Bioinformatics. 2012 Oct 1;28(19):2540-2
references: 22843982
references: Nature. 2012 Nov 1;491(7422):56-65
references: 23128226
references: Mol Psychiatry. 2012 Dec;17(12):1174-9
references: 22869033
references: Am J Hum Genet. 2012 Dec 7;91(6):1011-21
references: 23217325
references: PLoS Genet. 2013;9(2):e1003264
references: 23408905
references: PLoS Genet. 2013 Mar;9(3):e1003348
references: 23555274
references: Lancet. 2013 Apr 20;381(9875):1371-9
references: 23453885
references: Bioinformatics. 2013 Jun 1;29(11):1399-406
references: 23539302
references: PLoS One. 2013;8(8):e71494
references: 23977056
references: Nat Genet. 2013 Sep;45(9):984-94
references: 23933821
references: Nat Genet. 2013 Oct;45(10):1150-9
references: 23974872
references: Nature. 2014 Feb 13;506(7487):185-90
references: 24463508
references: BMC Genet. 2014;15:30
references: 24593261
references: Nat Methods. 2014 Apr;11(4):407-9
references: 24531419
references: Hum Genet. 2014 May;133(5):639-50
references: 24337655
references: Nature. 2014 Jul 24;511(7510):421-7
references: 25056061
references: Genome Res. 2014 Sep;24(9):1550-7
references: 24963154
references: J Med Chem. 2002 Jan 3;45(1):137-42
references: 11754585
references: Biometrics. 1975 Jun;31(2):423-47
references: 1174616
references: Genetics. 1990 Apr;124(4):979-93
references: 2323560
references: Am J Hum Genet. 2008 Sep;83(3):347-58
references: 18760391
references: Genet Sel Evol. 2006 Jan-Feb;38(1):25-43
references: 16451790
references: PLoS One. 2008;3(10):e3395
references: 18852893
references: J Dairy Sci. 2008 Nov;91(11):4414-23
references: 18946147
references: PLoS Genet. 2008 Oct;4(10):e1000231
references: 18949033
references: Genet Res (Camb). 2009 Feb;91(1):47-60
references: 19220931
references: Nat Rev Drug Discov. 2007 Apr;6(4):287-93
references: 17380152
references: J Dairy Sci. 2009 Jun;92(6):2971-5
references: 19448030
references: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references: 19474294
references: PLoS Genet. 2009 Oct;5(10):e1000678
references: 19816555
references: Am J Psychiatry. 2010 Jul;167(7):748-51
references: 20595427
references: Nature. 2010 Sep 2;467(7311):52-8
references: 20811451
references: PLoS Genet. 2010 Sep;6(9):e1001097
references: 20838587
references: Am J Hum Genet. 2011 Jan 7;88(1):76-82
references: 21167468
references: Mol Psychiatry. 2011 Feb;16(2):193-201
references: 20125088
references: Am J Hum Genet. 2012 Jan 13;90(1):7-24
references: 22243964