Neuroinformatic Analyses of Common and Distinct Genetic Components Associated with Major Neuropsychiatric Disorders

Frontiers in Neuroscience

Amit eLotan²  Janita eBralten³  Michaela eFenckova³  Monique evan der Voet³  Luanna eDixson⁵  Robert W Williams⁶  Aet eAlttoa⁷ 

[1] Donders Institute for Brain, Cognition and Behaviour;Hadassah Medical Organization;Radboud Institute for Molecular Life Sciences;Radboud University Medical Centre;University of Heidelberg;University of Tennessee Health Science Center;University of Würzburg;

关键词: translational;    neuroinformatics;    Enrichment;    genome wide association studies;    cross-species;    major neuropsychiatric disorders;   

DOI  :  10.3389/fnins.2014.00331

来源: DOAJ

【 摘 要 】

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, anxiety disorders, autistic spectrum disorders, bipolar disorder, major depressive disorder and schizophrenia. We curated a well-vetted list of genes based on large-scale human genetic studies and verified their appearance on the NHGRI catalog of published genome-wide association studies. 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, 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. Nevertheless, the convergence of different analytical approaches on similar targets may bear important implications. Thus, although adding mostly confirmatory findings, higher resolution of shared and unique genetic factors provided in this manuscript could ultimately translate into improved diagnosis and treatment of these debilitating disorders.

【 授权许可】

Unknown