Dataset Information

Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network.

ABSTRACT: Neuropsychiatric disorders have a complex genetic architecture. Human genetic population-based studies have identified numerous heritable sequence and structural genomic variants associated with susceptibility to neuropsychiatric disease. However, these germline variants do not fully account for disease risk. During brain development, progenitor cells undergo billions of cell divisions to generate the ~80 billion neurons in the brain. The failure to accurately repair DNA damage arising during replication, transcription, and cellular metabolism amid this dramatic cellular expansion can lead to somatic mutations. Somatic mutations that alter subsets of neuronal transcriptomes and proteomes can, in turn, affect cell proliferation and survival and lead to neurodevelopmental disorders. The long life span of individual neurons and the direct relationship between neural circuits and behavior suggest that somatic mutations in small populations of neurons can significantly affect individual neurodevelopment. The Brain Somatic Mosaicism Network has been founded to study somatic mosaicism both in neurotypical human brains and in the context of complex neuropsychiatric disorders.

SUBMITTER: McConnell MJ

PROVIDER: S-EPMC5558435 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network.

McConnell Michael J MJ Moran John V JV Abyzov Alexej A Akbarian Schahram S Bae Taejeong T Cortes-Ciriano Isidro I Erwin Jennifer A JA Fasching Liana L Flasch Diane A DA Freed Donald D Ganz Javier J Jaffe Andrew E AE Kwan Kenneth Y KY Kwon Minseok M Lodato Michael A MA Mills Ryan E RE Paquola Apua C M ACM Rodin Rachel E RE Rosenbluh Chaggai C Sestan Nenad N Sherman Maxwell A MA Shin Joo Heon JH Song Saera S Straub Richard E RE Thorpe Jeremy J Weinberger Daniel R DR Urban Alexander E AE Zhou Bo B Zhou Bo B Gage Fred H FH Lehner Thomas T Senthil Geetha G Walsh Christopher A CA Chess Andrew A Courchesne Eric E Gleeson Joseph G JG Kidd Jeffrey M JM Park Peter J PJ Pevsner Jonathan J Vaccarino Flora M FM

Science (New York, N.Y.) 20170427 6336

Neuropsychiatric disorders have a complex genetic architecture. Human genetic population-based studies have identified numerous heritable sequence and structural genomic variants associated with susceptibility to neuropsychiatric disease. However, these germline variants do not fully account for disease risk. During brain development, progenitor cells undergo billions of cell divisions to generate the ~80 billion neurons in the brain. The failure to accurately repair DNA damage arising during re ...[more]

PMID: 28450582

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Project description:The prevalence of somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM), is higher in Alzheimer's disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie this observed multimorbidity. We investigated the genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise global genetic correlations using the summary statistics of the largest available genome-wide association studies for these phenotypes. Having tested these hypotheses, other potential brain "insulinopathies" were also explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Stratified covariance analyses were then performed to investigate the contribution of insulin-related gene sets. Significant negative genetic correlations were found between OCD and MetS (rg = -0.315, p = 3.9 × 10-8), OCD and obesity (rg = -0.379, p = 3.4 × 10-5), and OCD and T2DM (rg = -0.172, p = 3 × 10-4). Significant genetic correlations with insulin-related phenotypes were also found for anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and schizophrenia (p < 6.17 × 10-4). Stratified analyses showed negative genetic covariances between AD, ASD, OCD, ADHD, AN, bipolar disorder, schizophrenia and somatic insulinopathies through gene sets related to insulin signalling and insulin receptor recycling, and positive genetic covariances between AN and T2DM, as well as ADHD and MetS through gene sets related to insulin processing/secretion (p < 2.06 × 10-4). Overall, our findings suggest the existence of two clusters of neuropsychiatric disorders, in which the genetics of insulin-related diseases/traits may exert divergent pleiotropic effects. These results represent a starting point for a new research line on "insulinopathies" of the brain.

Dataset Information

Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network.

Publications

Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network.

Similar Datasets

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