Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes
Year: 2015
Type: article
Study design: Observational Study
Abstract: Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high‐ versus low‐risk constellation regarding the accumulation model. Thereby, the brain‐expressed miR‐181 species emerged as potential “umbrella regulator”, with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes. Based on a novel approach, phenotype‐based genetic association study, first evidence is provided that a particular constellation of completely normal genotypes in the “broader fragile X gene family” contributes to autistic phenotypes. Based on a novel approach, phenotype‐based genetic association study, first evidence is provided that a particular constellation of completely normal genotypes in the “broader fragile X gene family” contributes to autistic phenotypes.
Source: EMBO Molecular Medicine
Authors: Beata Stepniak, Anne Kästner, Giulia Poggi, Marina Mitjans, Martin Begemann, Annette Hartmann, Sandra Van der Auwera, Farahnaz Sananbenesi, Dilja Krueger‐Burg, Gabriela Matuszko, Cornelia Brosi, Georg Homuth, Henry Völzke, Fritz Benseler, Claudia Bagni, Utz Fischer, Alexander Dityatev, Hans‐Jörgen Grabe, Dan Rujescu, Andre Fischer, Hannelore Ehrenreich
Institutions: Max Planck Institute of Experimental Medicine, Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103, Martin Luther University Halle-Wittenberg, Universitätsmedizin Greifswald, Universität Greifswald, German Center for Neurodegenerative Diseases, University of Würzburg, University of Rome Tor Vergata, KU Leuven, University of Göttingen
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,143
Funders: Autism Speaks, European Federation of Pharmaceutical Industries and Associations, Max-Planck-Förderstiftung, European Commission, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Max-Planck-Gesellschaft, Innovative Medicines Initiative, Universität Greifswald, Ministry of Cultural Affairs
Awards: G1073258374, G1518085888, G1732308444, G2325242462, G2996863859, G3207356259, G3283323707, G3868930229, G393177772, European Autism Interventions - A Multicentre Study for Developing New Medications, G4760961572, G4764896896, Verbesserung der Leistungsfähigkeit der klinischen Forschung besonders in den Schwerpunkten Community Medicine und Molekulare Medizin, Phase II, G5233356934, G5702163051, G6029994567, G7453583093, G8399513454, Verbesserung der Struktur- und Leistungsfähigkeit der klinischen Forschung besonders in den Schwerpunkten Community Medicine und Molekulare Medizin, G915808470
OpenAlex ID: W2177046580