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Genomic SEM Provides Insights into the Multivariate Genetic Architecture of Complex Traits

Andrew D. Grotzinger, Mijke Rhemtulla, Ronald de Vlaming, Stuart J. Ritchie, Travis T. Mallard, W. David Hill, Hill F. Ip, Andrew M. McIntosh, Ian J. Deary, Philipp D. Koellinger, K. Paige Harden, Michel G. Nivard, Elliot M. Tucker-Drob
doi: https://doi.org/10.1101/305029
Andrew D. Grotzinger
1Department of Psychology, University of Texas at Austin, Austin, TX USA
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Mijke Rhemtulla
2Department of Psychology, University of California, Davis, Davis, CA USA
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Ronald de Vlaming
3Department of Economics, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
4Erasmus University Rotterdam Institute for Behavior and Biology, Rotterdam, the Netherlands
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Stuart J. Ritchie
5Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
6Department of Psychology, University of Edinburgh, Edinburgh, UK
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Travis T. Mallard
1Department of Psychology, University of Texas at Austin, Austin, TX USA
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W. David Hill
5Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
6Department of Psychology, University of Edinburgh, Edinburgh, UK
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Hill F. Ip
7Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands
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Andrew M. McIntosh
5Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
8Division of Psychiatry, University of Edinburgh, Edinburgh, UK
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Ian J. Deary
5Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
6Department of Psychology, University of Edinburgh, Edinburgh, UK
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Philipp D. Koellinger
3Department of Economics, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
4Erasmus University Rotterdam Institute for Behavior and Biology, Rotterdam, the Netherlands
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K. Paige Harden
1Department of Psychology, University of Texas at Austin, Austin, TX USA
9Population Research Center, University of Texas at Austin, Austin, TX USA
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Michel G. Nivard
7Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands
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Elliot M. Tucker-Drob
1Department of Psychology, University of Texas at Austin, Austin, TX USA
9Population Research Center, University of Texas at Austin, Austin, TX USA
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Abstract

Methods for using GWAS to estimate genetic correlations between pairwise combinations of traits have produced “atlases” of genetic architecture. Genetic atlases reveal pervasive pleiotropy, and genome-wide significant loci are often shared across different phenotypes. We introduce genomic structural equation modeling (Genomic SEM), a multivariate method for analyzing the joint genetic architectures of complex traits. Using formal methods for modeling covariance structure, Genomic SEM synthesizes genetic correlations and SNP-heritabilities inferred from GWAS summary statistics of individual traits from samples with varying and unknown degrees of overlap. Genomic SEM can be used to identify variants with effects on general dimensions of cross-trait liability, boost power for discovery, and calculate more predictive polygenic scores. Finally, Genomic SEM can be used to identify loci that cause divergence between traits, aiding the search for what uniquely differentiates highly correlated phenotypes. We demonstrate several applications of Genomic SEM, including a joint analysis of GWAS summary statistics from five genetically correlated psychiatric traits. We identify 27 independent SNPs not previously identified in the univariate GWASs, 5 of which have been reported in other published GWASs of the included traits. Polygenic scores derived from Genomic SEM consistently outperform polygenic scores derived from GWASs of the individual traits. Genomic SEM is flexible, open ended, and allows for continuous innovations in how multivariate genetic architecture is modeled.

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Posted April 21, 2018.
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Genomic SEM Provides Insights into the Multivariate Genetic Architecture of Complex Traits
Andrew D. Grotzinger, Mijke Rhemtulla, Ronald de Vlaming, Stuart J. Ritchie, Travis T. Mallard, W. David Hill, Hill F. Ip, Andrew M. McIntosh, Ian J. Deary, Philipp D. Koellinger, K. Paige Harden, Michel G. Nivard, Elliot M. Tucker-Drob
bioRxiv 305029; doi: https://doi.org/10.1101/305029
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Genomic SEM Provides Insights into the Multivariate Genetic Architecture of Complex Traits
Andrew D. Grotzinger, Mijke Rhemtulla, Ronald de Vlaming, Stuart J. Ritchie, Travis T. Mallard, W. David Hill, Hill F. Ip, Andrew M. McIntosh, Ian J. Deary, Philipp D. Koellinger, K. Paige Harden, Michel G. Nivard, Elliot M. Tucker-Drob
bioRxiv 305029; doi: https://doi.org/10.1101/305029

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