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.
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Abbreviations
- ASD:
-
Autism spectrum disorders
- AGP:
-
Autism genome project
- SNP:
-
Single nucleotide polymorphism
- MAF:
-
Minor allele frequency
- LD:
-
Linkage disequilibrium
- TDT:
-
Transmission disequilibrium test
- OR:
-
Odds ratio
- CI:
-
Confidence interval
- SD:
-
Standard deviation
- CNV:
-
Copy number variation
- CYFIP1 :
-
Cytoplasmic FMR1 interacting protein 1
- FXS:
-
Fragile X syndrome
- TSC:
-
Tuberous sclerosis
- FMR1:
-
Fragile X mental retardation gene1
- FMRP:
-
FMR1 protein
- GRM1/5 :
-
Metabotropic glutamate receptor 1 and 5
- CAMK4 :
-
Calcium/calmodulin-dependent protein kinase 4
- GUSB :
-
Beta-d-glucuronidase
- LTD:
-
Long-term depression
- LTP:
-
Long-term potentiation
- ESE:
-
Exonic splicing enhancer
- AS:
-
Alternatively spliced isoforms
- WRC:
-
WAVE regulatory complex
- eQTL:
-
Expression quantitative trait locus
- TFBS:
-
Transcription factor binding site
- ASF/SF2:
-
Serine/arginine-rich splicing factor 1
- SC35:
-
Serine/arginine-rich splicing factor 2
- SRP55:
-
Serine/arginine-rich splicing factor 6
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Acknowledgments
We thank all patients and their families for taking part in this study. In addition, we thoroughly thank Veronika Delcheva, Silvia Lindlar, Marnie Kopp, Hiacynta Jelen and Cornelia Wirth for excellent technical assistance and Heiko Zerlaut and Rusico Weber for database management. This work was supported by the Saarland University (T6 03 10 00-45 to C.M.F.); the Deutsche Forschungsgemeinschaft DFG (Po 255/17-4 to F.P.); the European Commission and the German Bundesministerium für Bildung und Forschung BMBF (ERA-NET NEURON project: EUHFAUTISM) (EUHFAUTISM-01EW1105 to C.M.F.); and the Landes-Offensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz (LOEWE): Neuronal Coordination Research Focus Frankfurt (NeFF).Furthermore, we gratefully acknowledge the families participating in the Autism Genome Project (AGP) and the main funders: Autism Speaks (USA), the Health Research Board (HRB; Ireland), the Medical Research Council (MRC; UK), Genome Canada/Ontario Genomics Institute and the Hilibrand Foundation (USA).
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The authors are not aware of any conflict of interest interfering with publication of this work, data collection or experimental design.
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Waltes, R., Duketis, E., Knapp, M. et al. Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders. Hum Genet 133, 781–792 (2014). https://doi.org/10.1007/s00439-013-1416-y
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DOI: https://doi.org/10.1007/s00439-013-1416-y