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Conditional GWAS analysis to identify disorder-specific SNPs for psychiatric disorders

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  • Enda M Byrne, Institute for Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia. enda.byrne@uq.edu.au.
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  • Zhihong Zhu, Institute for Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia.
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  • Ting Qi, Institute for Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia.
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  • Nathan G Skene, Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
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  • Julien Bryois, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden2Hematology Center, Karolinska University Hospital, Stockholm, Sweden.
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  • Antonio F Pardinas, Cardiff University
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  • Eli Stahl, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of
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  • Jordan W Smoller, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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  • Marcella Rietschel, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • Michael J Owen, Cardiff University
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  • James T R Walters, Cardiff University
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  • Michael C O'Donovan, Cardiff University
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  • John G McGrath, National Centre for Register-based Research, Aarhus University, Aarhus, Denmark; Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
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  • Jens Hjerling-Leffler, Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
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  • Patrick F Sullivan, Department of Psychiatry, University of North Carolina, Chapel Hill, NC, 27599-7264, USA.
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  • Michael E Goddard, Agriculture Victoria, AgriBio, Centre for AgriBiosciences, Bundoora, Vic, 3083, Australia.
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  • Peter M Visscher, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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  • Jian Yang, Institute for Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia., Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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  • Naomi R Wray, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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  • Bipolar Working Group of the Psychiatric Genomics Consortium

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 genome-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. 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.

OriginalsprogEngelsk
TidsskriftMolecular Psychiatry
Vol/bind26
Nummer6
Sider (fra-til)2070-2081
Antal sider12
ISSN1359-4184
DOI
StatusUdgivet - jun. 2021

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