title: Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders.
abstract: Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders-attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). We curated a well-vetted list of genes based on large-scale human genetic studies based on the NHGRI catalog of published genome-wide association studies (GWAS). A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (<10(-5)). 22% of genes overlapped two or more disorders. The most widely shared subset of genes-common to five of six disorders-included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20-30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Our systematic comparative analysis of shared and unique genetic factors highlights key gene sets and molecular processes that may ultimately translate into improved diagnosis and treatment of these debilitating disorders.
authors.affiliation: Department of Adult Psychiatry and the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center Jerusalem, Israel.
authors.forename: Amit
authors.initials: A
authors.lastname: Lotan
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center Nijmegen, Netherlands.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fenckova
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center Nijmegen, Netherlands ; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center Nijmegen, Netherlands.
authors.forename: Janita
authors.initials: J
authors.lastname: Bralten
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Neurobiology Program, University of Würzburg Würzburg, Germany.
authors.forename: Aet
authors.initials: A
authors.lastname: Alttoa
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg Mannheim, Germany.
authors.forename: Luanna
authors.initials: L
authors.lastname: Dixson
authors.affiliation: Department of Genetics, Genomics and Informatics, Center for Integrative and Translational Genomics, University of Tennessee Health Science Center Memphis, TN, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center Nijmegen, Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: van der Voet
keywords: cross-species; enrichment; genetic components; genome wide association studies; major neuropsychiatric disorders; neuroinformatics; translational