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Conditional GWAS analysis identifies putative disorder-specific SNPs for psychiatric disorders

View ORCID ProfileEnda M Byrne, Zhihong Zhu, Ting Qi, Nathan G Skene, Julien Bryois, Antonio F Pardinas, Eli Stahl, Jordan W Smoller, Marcella Rietschel, Bipolar Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Michael J Owen, James T.R. Walters, Michael C O’Donovan, John G McGrath, Jens Hjerling-Leffler, Patrick F Sullivan, Michael E Goddard, Peter M Visscher, View ORCID ProfileJian Yang, View ORCID ProfileNaomi R Wray
doi: https://doi.org/10.1101/592899
Enda M Byrne
1Institute for Molecular Biosciences, University of Queensland, Brisbane, Australia
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Zhihong Zhu
1Institute for Molecular Biosciences, University of Queensland, Brisbane, Australia
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Ting Qi
1Institute for Molecular Biosciences, University of Queensland, Brisbane, Australia
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Nathan G Skene
2Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Julien Bryois
3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Antonio F Pardinas
4MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK
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Eli Stahl
5Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Jordan W Smoller
6Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
7Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
8Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
9Department of Psychiatry, Harvard Medical School, Boston, MA, USA
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Marcella Rietschel
10Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg
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Michael J Owen
4MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK
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James T.R. Walters
4MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK
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Michael C O’Donovan
4MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK
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John G McGrath
11Queensland Brain Institute, University of Queensland, Brisbane, Australia
12Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Australia
13National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
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Jens Hjerling-Leffler
2Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Patrick F Sullivan
3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
14Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264, USA
15Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599-7264, USA
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Michael E Goddard
16Faculty of Veterinary and Agricultural Science, University of Melbourne, Parkville, Victoria, Australia
17Biosciences Research Division, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, Australia
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Peter M Visscher
1Institute for Molecular Biosciences, University of Queensland, Brisbane, Australia
11Queensland Brain Institute, University of Queensland, Brisbane, Australia
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Jian Yang
1Institute for Molecular Biosciences, University of Queensland, Brisbane, Australia
11Queensland Brain Institute, University of Queensland, Brisbane, Australia
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Naomi R Wray
1Institute for Molecular Biosciences, University of Queensland, Brisbane, Australia
11Queensland Brain Institute, University of Queensland, Brisbane, Australia
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  • ORCID record for Naomi R Wray
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Abstract

Substantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium – schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT). Most genom-wide significant variants for these disorders had evidence of pleiotropy (i.e., impact on multiple psychiatric disorders) and hence have reduced mtCOJO conditional effect sizes. However, subsets of genome-wide significant variants had larger conditional effect sizes consistent with disorder-specific effects: 15 of 130 genome-wide significant variants for schizophrenia, 5 of 40 for major depression, 3 of 11 for ADHD and 1 of 2 for autism. In addition, we identified a number of variants that approached genome-wide significance in the original GWAS and have larger conditional effect sizes after conditioning on the other disorders. We show that decreased expression of VPS29 in the brain may increase risk to SCZ only and increased expression of CSE1L is associated with SCZ and MD, but not with BIP. Likewise, decreased expression of PCDHA7 in the brain is linked to increased risk of MD but decreased risk of SCZ and BIP.

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Posted March 31, 2019.
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Conditional GWAS analysis identifies putative disorder-specific SNPs for psychiatric disorders
Enda M Byrne, Zhihong Zhu, Ting Qi, Nathan G Skene, Julien Bryois, Antonio F Pardinas, Eli Stahl, Jordan W Smoller, Marcella Rietschel, Bipolar Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Michael J Owen, James T.R. Walters, Michael C O’Donovan, John G McGrath, Jens Hjerling-Leffler, Patrick F Sullivan, Michael E Goddard, Peter M Visscher, Jian Yang, Naomi R Wray
bioRxiv 592899; doi: https://doi.org/10.1101/592899
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Conditional GWAS analysis identifies putative disorder-specific SNPs for psychiatric disorders
Enda M Byrne, Zhihong Zhu, Ting Qi, Nathan G Skene, Julien Bryois, Antonio F Pardinas, Eli Stahl, Jordan W Smoller, Marcella Rietschel, Bipolar Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Michael J Owen, James T.R. Walters, Michael C O’Donovan, John G McGrath, Jens Hjerling-Leffler, Patrick F Sullivan, Michael E Goddard, Peter M Visscher, Jian Yang, Naomi R Wray
bioRxiv 592899; doi: https://doi.org/10.1101/592899

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