Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders

Waltes, Regina, Duketis, Eftichia, Knapp, Michael, Anney, Richard ORCID: https://orcid.org/0000-0002-6083-407X, Huguet, Guillaume, Schlitt, Sabine, Jarczok, Tomasz A., Sachse, Michael, Kaempfer, Laura M., Kleinboeck, Tina, Poustka, Fritz, Boelte, Sven, Schmoetzer, Gabriele, Voran, Anette, Huy, Ellen, Meyer, Jobst, Bourgeron, Thomas, Klauck, Sabine M., Freitag, Christine M. and Chiocchetti, Andreas G. 2014. Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders. Human Genetics 133 (6) , pp. 781-792. 10.1007/s00439-013-1416-y

Full text not available from this repository.

Abstract

Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Springer Verlag
ISSN: 0340-6717
Date of Acceptance: 23 December 2013
Last Modified: 31 Oct 2022 10:31
URI: https://orca.cardiff.ac.uk/id/eprint/85216

Citation Data

Cited 45 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item