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

作者：Stepniak Beata; Kaestner Anne; Poggi Giulia; Mitjans Marina; Begemann Martin; Hartmann Annette; Van der Auwera Sandra; Sananbenesi Farahnaz; Krueger Burg Dilja; Matuszko Gabriela; Brosi Cornelia; Homuth Georg; Voelzke Henry; Benseler Fritz; Bagni Claudia; Fischer Utz; Dityatev Alexander; Grabe Hans Joergen; Rujescu Dan; Fischer Andre; Ehrenreich Hannelore^*

来源：EMBO Molecular Medicine, 2015, 7(12): 1565-1579.

DOI：10.15252/emmm.201505696

• FMR1
• FMR2
• FXR1
• FXR2
• miR-181
• PGAS

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.

• 出版日期2015-12