Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes

EMBO Molecular Medicine

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 Bagni^2,7  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 】

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.

Synopsis

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.

• An accumulation model of 8 SNPs from the broader fragile X gene family (FMR1, FXR1, FXR2, and FMR2) is associated with autistic traits in a discovery sample of male schizophrenia patients as well as three independent replication samples of neuropsychiatric patients or general population.
• The underlying novel approach, named phenotype-based genetic association study (PGAS), may serve as universal guide in the exploration of genotype contributions to quantifiable phenotypes.
• Comparing peripheral blood mononuclear cells of extreme group subjects with high versus low genetic risk by small RNA sequencing revealed quantitative differences in the brain-expressed miR-181 family, which has several seed matches across the broader fragile X gene family.
• Future studies based on extensive in vivo work in animal models are needed to delineate how and when the miR-181 family may act as an overarching modulator of the fragile X genes.

【 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.