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

Hum Genet. 2014 Jun;133(6):781-92. doi: 10.1007/s00439-013-1416-y. Epub 2014 Jan 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adolescent
  • Alleles
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / genetics*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism
  • Child
  • Child Development Disorders, Pervasive / ethnology
  • Child Development Disorders, Pervasive / genetics*
  • Child Development Disorders, Pervasive / metabolism
  • Child Development Disorders, Pervasive / pathology
  • Child, Preschool
  • European Continental Ancestry Group
  • Female
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Mental Retardation Protein / metabolism
  • Gene Expression Regulation
  • Genetic Predisposition to Disease*
  • Genotyping Techniques
  • Humans
  • Male
  • Neuronal Plasticity / genetics
  • Polymorphism, Single Nucleotide*
  • Protein Binding
  • Risk Factors
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • CYFIP1 protein, human
  • FMR1 protein, human
  • Fragile X Mental Retardation Protein
  • CAMK4 protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4