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Integrative analysis of rare variants and pathway information shows convergent results between immune pathways, drug targets and epilepsy genes

View ORCID ProfileHoang T. Nguyen, Amanda Dobbyn, Alexander W. Charney, Julien Bryois, April Kim, Whitney Mcfadden, Nathan G. Skene, Laura M. Huckins, Weiqing Wang, Douglas M Ruderfer, Xinyi Xu, Menachem Fromer, Shaun M Purcell, Kasper Lage, Matthijs Verhage, August B. Smit, Jens Hjerling-Leffler, Joseph D. Buxbaum, Dalila Pinto, Xin He, Patrick F Sullivan, View ORCID ProfileEli A. Stahl
doi: https://doi.org/10.1101/410100
Hoang T. Nguyen
1Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • ORCID record for Hoang T. Nguyen
Amanda Dobbyn
1Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Alexander W. Charney
1Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Julien Bryois
3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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April Kim
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Whitney Mcfadden
1Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Nathan G. Skene
5Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Laura M. Huckins
1Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Weiqing Wang
1Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Douglas M Ruderfer
6Division of Genetic Medicine, Departments of Medicine, Psychiatry and Biomedical Informatics, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
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Xinyi Xu
7Seaver Autism Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Menachem Fromer
8Verily Life Sciences, 269 E Grand Ave, South San Francisco, CA, USA
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Shaun M Purcell
9Sleep Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Kasper Lage
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Matthijs Verhage
10Department of Functional Genomics, The Center for Neurogenomics and Cognitive Research, VU University and VU Medical Center, Amsterdam, The Netherlands
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August B. Smit
11Department of Molecular and Cellular Neurobiology, The Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands
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Jens Hjerling-Leffler
5Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Joseph D. Buxbaum
7Seaver Autism Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Dalila Pinto
1Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
7Seaver Autism Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
12The Mindich Child Health & Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
13Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Xin He
14Department of Human Genetics, University of Chicago, Chicago, IL, USA
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Patrick F Sullivan
15Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA
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Eli A. Stahl
1Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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  • ORCID record for Eli A. Stahl
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Abstract

Trio family and case-control studies of next-generation sequencing data have proven integral to understanding the contribution of rare inherited and de novo single-nucleotide variants to the genetic architecture of complex disease. Ideally, such studies should identify individual risk genes of moderate to large effect size to generate novel treatment hypotheses for further follow-up. However, due to insufficient power, gene set enrichment analyses have come to be relied upon for detecting differences between cases and controls, implicating sets of hundreds of genes rather than specific targets for further investigation. Here, we present a Bayesian statistical framework, termed gTADA, that integrates gene-set membership information with gene-level de novo and rare inherited case-control counts, to prioritize risk genes with excess rare variant burden within enriched gene sets. Applying gTADA to available whole-exome sequencing datasets for several neuropsychiatric conditions, we replicated previously reported gene set enrichments and identified novel risk genes. For epilepsy, gTADA prioritized 40 risk genes (posterior probabilities > 0.95), 6 of which replicate in an independent whole-genome sequencing study. In addition, 30/40 genes are novel genes. We found that epilepsy genes had high protein-protein interaction (PPI) network connectivity, and show specific expression during human brain development. Some of the top prioritized EPI genes were connected to a PPI subnetwork of immune genes and show specific expression in prenatal microglia. We also identified multiple enriched drug-target gene sets for EPI which included immunostimulants as well as known antiepileptics. Immune biology was supported specifically by case-control variants from familial epilepsies rather than do novo mutations in generalized encephalitic epilepsy.

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Posted November 24, 2018.
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Integrative analysis of rare variants and pathway information shows convergent results between immune pathways, drug targets and epilepsy genes
Hoang T. Nguyen, Amanda Dobbyn, Alexander W. Charney, Julien Bryois, April Kim, Whitney Mcfadden, Nathan G. Skene, Laura M. Huckins, Weiqing Wang, Douglas M Ruderfer, Xinyi Xu, Menachem Fromer, Shaun M Purcell, Kasper Lage, Matthijs Verhage, August B. Smit, Jens Hjerling-Leffler, Joseph D. Buxbaum, Dalila Pinto, Xin He, Patrick F Sullivan, Eli A. Stahl
bioRxiv 410100; doi: https://doi.org/10.1101/410100
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Integrative analysis of rare variants and pathway information shows convergent results between immune pathways, drug targets and epilepsy genes
Hoang T. Nguyen, Amanda Dobbyn, Alexander W. Charney, Julien Bryois, April Kim, Whitney Mcfadden, Nathan G. Skene, Laura M. Huckins, Weiqing Wang, Douglas M Ruderfer, Xinyi Xu, Menachem Fromer, Shaun M Purcell, Kasper Lage, Matthijs Verhage, August B. Smit, Jens Hjerling-Leffler, Joseph D. Buxbaum, Dalila Pinto, Xin He, Patrick F Sullivan, Eli A. Stahl
bioRxiv 410100; doi: https://doi.org/10.1101/410100

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