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

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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).

Conflict of interest

The authors are not aware of any conflict of interest interfering with publication of this work, data collection or experimental design.

Author information

Authors and Affiliations

  1. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Johann Wolfgang Goethe-University, Deutschordenstraße 50, 60528, Frankfurt am Main, Germany

    Regina Waltes, Eftichia Duketis, Sabine Schlitt, Tomasz A. Jarczok, Michael Sachse, Laura M. Kämpfer, Tina Kleinböck, Fritz Poustka, Sven Bölte, Gabriele Schmötzer, Christine M. Freitag & Andreas G. Chiocchetti

  2. Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, 53105, Bonn, Germany

    Michael Knapp

  3. Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland

    Richard J. L. Anney

  4. Human Genetics and Cognitive Functions, Institut Pasteur, 75015, Paris, France

    Guillaume Huguet & Thomas Bourgeron

  5. CNRS URA 2182, Fondation FondaMental, University Paris Diderot-Paris 7, 75015, Paris, France

    Guillaume Huguet & Thomas Bourgeron

  6. Department of Women’s and Children’s Health, Center of Neurodevelopmental Disorders (KIND), Karolinska Institutet, 11330, Stockholm, Sweden

    Sven Bölte

  7. Division of Child and Adolescent Psychiatry, Stockholm County Council, 11895, Stockholm, Sweden

    Sven Bölte

  8. Department of Child and Adolescent Psychiatry, Saarland University Hospital, 66421, Homburg, Germany

    Anette Voran & Ellen Huy

  9. Department of Neurobehavioral Genetics, Institute of Psychobiology, University of Trier, 54290, Trier, Germany

    Jobst Meyer

  10. Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany

    Sabine M. Klauck

Authors
  1. Regina Waltes
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  2. Eftichia Duketis
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  3. Michael Knapp
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  4. Richard J. L. Anney
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  5. Guillaume Huguet
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  6. Sabine Schlitt
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  7. Tomasz A. Jarczok
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  8. Michael Sachse
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  9. Laura M. Kämpfer
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  11. Fritz Poustka
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  13. Gabriele Schmötzer
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  14. Anette Voran
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  15. Ellen Huy
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  16. Jobst Meyer
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  17. Thomas Bourgeron
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  18. Sabine M. Klauck
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  19. Christine M. Freitag
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  20. Andreas G. Chiocchetti
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Corresponding author

Correspondence to Andreas G. Chiocchetti.

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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

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