EMBO Molecular Medicine | |
Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes | |
Beata Stepniak7  Anne Kästner7  Giulia Poggi7  Marina Mitjans7  Martin Begemann7  Annette Hartmann5  Sandra Van der Auwera9  Farahnaz Sananbenesi4  Dilja Krueger-Burg8  Gabriela Matuszko6  Cornelia Brosi10  Georg Homuth3  Henry Völzke1  Fritz Benseler8  Claudia Bagni2,7  Utz Fischer10  Alexander Dityatev6  Hans-Jörgen Grabe9  Dan Rujescu5  Andre Fischer4  | |
[1] Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany;KU Leuven, Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, Leuven, Belgium;Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany;Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany;Department of Psychiatry and Psychotherapy, University of Halle, Halle, Germany;Molecular Neuroplasticity, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany;Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany;Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany;Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany;Department of Biochemistry, University of Würzburg, Würzburg, Germany | |
关键词: FMR1; FMR2; FXR1; FXR2; miR‐181; PGAS; | |
DOI : 10.15252/emmm.201505696 | |
来源: Wiley | |
【 摘 要 】
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.Abstract
Synopsis
【 授权许可】
CC BY
© 2015 The Authors. Published under the terms of the CC BY 4.0 license
Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
RO202107150009638ZK.pdf | 689KB | download |