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Common EIF4E variants modulate risk for autism spectrum disorders in the high-functioning range

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

The genetic architecture of Autism Spectrum Disorders (ASD) is complex. Common genetic variation has especially been related to high-functioning ASD. In addition, some studies favoured analysis of strictly diagnosed autism individuals, which resulted in more robust findings than the combined analysis of all spectrum individuals. Functional variants modulating EIF4E expression have previously been indicated as risk factors for ASD. Pharmacological modulation of glutamate receptors which regulate EIF4E activity resulted in reduced repetitive behaviours in human and animal studies. Based on these findings, we tested common EIF4E variants for association with overall ASD, with strict autism and with the strict high-functioning autism (strict HFA) subgroup, and their effect on repetitive and/or stereotypic behaviour. We observed over-transmission of rs13109000G in the strict HFA and the strict autism cohort but not in the larger ASD cohort. We report protective effects for the minor allele of rs4699369T on stereotyped and ritualized behaviour in the overall ASD cohort, the strict autism but not in the strict HFA group. In addition, a protective role for rs4699369T and a risk effect of rs12498533G on hand and finger mannerisms was observed. These results need to be replicated in larger ASD and strict autism samples. The predicted impact on transcription through the ASD associated EIF4E variants rs4699369T and rs12498533G as well as the association of the EIF4E interaction partners FMRP and CYFIP1 with ASD point to an mRNA mediated pathomechanism for ASD.

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References

  • Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9(5):341–355

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (5th edn; DSM-5). VA: American Psychiatric Publishing 2013, Arlington

  • Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu X, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Melhem NM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Piven J, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Wing K, Wittemeyer K, Wood S, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gallagher L, Geschwind DH, Gill M, Haines JL, Miller J, Monaco AP, Nurnberger JI, Paterson AD, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Devlin B, Ennis S, Hallmayer J, Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu X, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Melhem NM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Piven J, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Wing K, Wittemeyer K, Wood S, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gallagher L, Geschwind DH, Gill M, Haines JL, Miller J, Monaco AP, Nurnberger JI, Paterson AD, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Devlin B, Ennis S, Hallmayer J (2010) A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet 19(20):4072–4082

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265

    Article  CAS  PubMed  Google Scholar 

  • Ben-David E, Shifman S, Gibson G (2012) Networks of neuronal genes affected by common and rare variants in autism spectrum disorders. PLoS Genet 8(3):e1002556

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Betancur C (2011) Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res 1380:42–77

    Article  CAS  PubMed  Google Scholar 

  • Bölte S, Poustka F (2004) Diagnostic observation scale for autistic disorders (ADOS): initial results of reliability and validity. Z Kinder Jugendpsychiatr Psychother 32:45–50

    Article  PubMed  Google Scholar 

  • Bruno JL, Shelly EW, Quintin E, Rostami M, Patnaik S, Spielman D, Mayer D, Gu M, Lightbody AA, Reiss AL (2013) Aberrant basal ganglia metabolism in fragile X syndrome: a magnetic resonance spectroscopy study. J Neurodev Disord 5(1):20

    Article  PubMed Central  PubMed  Google Scholar 

  • Chiocchetti AG, Bour HS, Freitag CM (2014) Glutamatergic candidate genes in autism spectrum disorder: an overview. J Neural Transm. (Epub ahead of print)

  • Devlin B, Scherer SW (2012) Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev 22(3):229–237

    Article  CAS  PubMed  Google Scholar 

  • Dölen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF, Rao BSS (2007) Correction of fragile X syndrome in mice. Neuron 56(6):955–962

    Article  PubMed Central  PubMed  Google Scholar 

  • Dudbridge F (2008) Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 66(2):87–98. doi:10.1159/000119108

  • Durand CM, Perroy J, Loll F, Perrais D, Fagni L, Bourgeron T, Montcouquiol M, Sans N (2012) SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism. Mol Psychiatry 17(1):71–84

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ehninger D (2013) From genes to cognition in tuberous sclerosis: implications for mTOR inhibitor-based treatment approaches. Neuropharmacology 68:97–105

    Article  CAS  PubMed  Google Scholar 

  • Erickson CA, Posey DJ, Stigler KA, Mullett J, Katschke AR, McDougle CJ (2007) A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology 191(1):141–147

    Article  CAS  PubMed  Google Scholar 

  • Estes A, Shaw DWW, Sparks BF, Friedman S, Giedd JN, Dawson G, Bryan M, Dager SR (2011) Basal ganglia morphometry and repetitive behaviour in young children with autism spectrum disorder. Autism Res 4(3):212–220

    Article  PubMed Central  PubMed  Google Scholar 

  • Freitag CM, Staal W, Klauck SM, Duketis E, Waltes R (2010) Genetics of autistic disorders: review and clinical implications. Eur Child Adolesc Psychiatry 19(3):169–178

    Article  PubMed Central  PubMed  Google Scholar 

  • Gauderman WJ, Morrison JM (2006) QUANTO 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies. http://hydra.usc.edu/gxe

  • Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, Weatherill DB, Vasuta C, Yee S, Truitt M, Dallaire P, Major F, Lasko P, Ruggero D, Nader K, Lacaille J, Sonenberg N (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493(7432):371–377

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Goodfellow IG, Roberts LO (2008) Eukaryotic initiation factor 4E. Int J Biochem Cell Biol 40(12):2675–2680

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gutierrez R, Hung J, Zhang Y, Kertesz A, Espina F, Colicos M, Gutierrez RC, Kertesz AC, Espina FJ, Colicos MA (2009) Altered synchrony and connectivity in neuronal networks expressing an autism-related mutation of neuroligin 3. Neuroscience 162(1):208–221

    Article  CAS  PubMed  Google Scholar 

  • Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Risch N (2011) Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 68(11):1095–1102

    Article  PubMed  Google Scholar 

  • Hollander E, Anagnostou E, Chaplin W, Esposito K, Haznedar MM, Licalzi E, Wasserman S, Soorya L, Buchsbaum M (2005) Striatal volume on magnetic resonance imaging and repetitive behaviours in autism. Biol Psychiatry 58(3):226–232

    Article  PubMed  Google Scholar 

  • Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 34(1):27–29

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jiao Y, Chen R, Ke X, Cheng L, Chu K, Lu Z, Herskovits E, Herskovits EH (2011) Predictive models for subtypes of autism spectrum disorder based on single-nucleotide polymorphisms and magnetic resonance imaging. Adv Med Sci 56(2):334–342

    Article  CAS  PubMed  Google Scholar 

  • Kelleher RJ, Bear MF (2008) The autistic neuron: troubled translation? Cell 135(3):401–406

    Article  CAS  PubMed  Google Scholar 

  • Klauck SM, Poustka F, Benner A, Lesch KP, Poustka A (1997) Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet 6(13):2233–2238

    Article  CAS  PubMed  Google Scholar 

  • Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ, Moreno-De-Luca D, Yu TW, Fombonne E, Geschwind D, Grice DE, Ledbetter DH, Lord C, Mane SM, Martin CL, Martin DM, Morrow EM, Walsh CA, Melhem NM, Chaste P, Sutcliffe JS, State MW, Cook EH Jr, Roeder K, Devlin B (2012) Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism 3(1):9

    Article  PubMed Central  PubMed  Google Scholar 

  • Lichtenstein P, Carlström E, Råstam M, Gillberg C, Anckarsäter H (2010) The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry 167(11):1357–1363

    Article  PubMed  Google Scholar 

  • Lord C, Lord C, Rutter M, Le Couteur A (1994) Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 24(5):659–685

    Article  CAS  PubMed  Google Scholar 

  • Lord C, Risi S, Lambrecht L, Cook EH, Leventhal BL, DiLavore PC, Pickles A, Rutter M (2000) The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 30(3):205–223

    Article  CAS  PubMed  Google Scholar 

  • McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP, Hirschhorn JN (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 9(5):356–69. doi:10.1038/nrg2344

  • Mehta MV, Gandal MJ, Siegel SJ, Coleman M (2011) mGluR5-antagonist mediated reversal of elevated stereotyped, repetitive behaviours in the VPA model of autism. PLoS One 6(10):e26077

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Michaelson JJ, Shi Y, Gujral M, Zheng H, Malhotra D, Jin X, Jian M, Liu G, Greer D, Bhandari A, Wu W, Corominas R, Peoples A, Koren A, Gore A, Kang S, Lin GN, Estabillo J, Gadomski T, Singh B, Zhang K, Akshoomoff N, Corsello C, McCarroll S, Iakoucheva LM, Li Y, Wang J, Sebat J (2012) Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151(7):1431–1442

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Munesue T, Yokoyama S, Nakamura K, Anitha A, Yamada K, Hayashi K, Asaka T, Liu H, Jin D, Koizumi K, Islam MS, Huang J, Ma W, Kim U, Kim S, Park K, Kim D, Kikuchi M, Ono Y, Nakatani H, Suda S, Miyachi T, Hirai H, Salmina A, Pichugina YA, Soumarokov AA, Takei N, Mori N, Tsujii M, Sugiyama T, Yagi K, Yamagishi M, Sasaki T, Yamasue H, Kato N, Hashimoto R, Taniike M, Hayashi Y, Hamada J, Suzuki S, Ooi A, Noda M, Kamiyama Y, Kido MA, Lopatina O, Hashii M, Amina S, Malavasi F, Huang EJ, Zhang J, Shimizu N, Yoshikawa T, Matsushima A, Minabe Y, Higashida H (2010) Two genetic variants of CD38 in subjects with autism spectrum disorder and controls. Neurosci Res 67(2):181–191

    Article  CAS  PubMed  Google Scholar 

  • Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, de Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M, Witke W, Costa-Mattioli M, Sonenberg N, Achsel T, Bagni C (2008) The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134(6):1042–1054

    Article  CAS  PubMed  Google Scholar 

  • Neves-Pereira M, Muller B, Massie D, Williams JHG, O’Brien PCM, Hughes A, Shen S, Clair DS, Miedzybrodzka Z, Müller B, Clair DS (2009) Deregulation of EIF4E: a novel mechanism for autism. J Med Genet 46(11):759–765

    Article  CAS  PubMed  Google Scholar 

  • Owley T, Salt J, Guter S, Grieve A, Walton L, Ayuyao N, Leventhal BL, Cook EH (2006) A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders. J Child Adolesc Psychopharmacol 16(5):517–524

    Article  PubMed  Google Scholar 

  • Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BHY, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu X, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, Piven J, Ponting CP, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger JI, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, Betancur C (2010) Functional impact of global rare copy number variation in autism spectrum disorder. Nature 466(7304):368–372

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Poustka F, Lisch S, Rühl D, Sacher A, Schmötzer G, Werner K (1996) The standardized diagnosis of autism, autism diagnostic interview-revised: interrater reliability of the German form of the interview. Psychopathology 29(3):145–153

    Article  CAS  PubMed  Google Scholar 

  • Salyakina D, Ma DQ, Jaworski JM, Konidari I, Whitehead PL, Henson R, Martinez D, Robinson JL, Sacharow S, Wright HH, Abramson RK, Gilbert JR, Cuccaro ML, Pericak-Vance MA (2010) Variants in several genomic regions associated with asperger disorder. Autism Res 3(6):303–310

    Article  CAS  PubMed  Google Scholar 

  • Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Šestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485(7397):237–241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Santini E, Huynh TN, MacAskill AF, Carter AG, Pierre P, Ruggero D, Kaphzan H, Klann E (2013) Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 493(7432):411–415

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sharma A, Hoeffer CA, Takayasu Y, Miyawaki T, McBride SM, Klann E, Zukin RS, Sharma A, Hoeffer CA, Takayasu Y, Miyawaki T, McBride SM, Klann E, Zukin RS (2010) Dysregulation of mTOR signalling in fragile X syndrome. J Neurosci 30(2):694–702

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Thomas AM, Bui N, Perkins JR, Yuva-Paylor LA, Paylor R (2012) Group I metabotropic glutamate receptor antagonists alter select behaviours in a mouse model for fragile X syndrome. Psychopharmacology 219(1):47–58

    Article  CAS  PubMed  Google Scholar 

  • Toro R, Konyukh M, Delorme R, Leblond C, Chaste P, Fauchereau F, Coleman M, Leboyer M, Gillberg C, Bourgeron T (2010) Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends Genet 26(8):363–372

    Article  CAS  PubMed  Google Scholar 

  • Vieland VJ, Hallmayer J, Huang Y, Pagnamenta AT, Pinto D, Khan H, Monaco AP, Paterson AD, Scherer SW, Sutcliffe JS, Szatmari P (2011) Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autism. J Neurodevelop Disord 3(2):113–123

    Article  Google Scholar 

  • Werling DM, Geschwind DH (2013) Sex differences in autism spectrum disorders. Curr Opin Neurol 26(2):146–153

    Article  CAS  PubMed  Google Scholar 

  • Wermter A, Kamp-Becker I, Hesse P, Schulte-Körne G, Strauch K, Remschmidt H (2010) Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the aetiology of autistic disorders on high-functioning level. Am J Med Genet B Neuropsychiatr Genet 153(2):629–639

    Google Scholar 

  • World Health Organization (1993) The ICD-10 classification of mental and behavioural disorders. Diagnostic criteria for research, 10th edn. WHO, Geneva

  • Ylisaukko-oja T, Alarcón M, Cantor RM, Auranen M, Vanhala R, Kempas E, von Wendt L, Järvelä I, Geschwind DH, Peltonen L (2006) Search for autism loci by combined analysis of autism genetic resource exchange and Finnish families. Ann Neurol 59(1):145–155

    Article  PubMed  Google Scholar 

  • Zoghbi HY, Bear MF, Zoghbi HY, Bear MF (2012) Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb Perspect Biol 4(3):a009886

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We thank all patients and their families for taking part in this study. In addition, we thoroughly thank Silvia Lindlar and Hiacynta Jelen 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 European Union and the Bundesministerium für Bildung und Forschung (ERA-NET NEURON project: EUHF-AUTISM-01EW1105 to C.M.F.); and the Landes-Offensive zur Entwicklung wissenschaftlich ökonomischer Exzellenz (LOEWE): Neuronal Coordination Research Focus Frankfurt (NeFF to C.M.F.).

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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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  1. Department of Child and Adolescent Psychiatry, Johann Wolfgang Goethe-University, 60528, Frankfurt am Main, Germany

    Regina Waltes, Johannes Gfesser, Denise Haslinger, Christine M. Freitag & Andreas G. Chiocchetti

  2. Department of Child and Adolescent Psychiatry, University Hospital Freiburg, 79104, Freiburg, Germany

    Katja Schneider-Momm & Monica Biscaldi

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

    Anette Voran

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  1. Regina Waltes
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Waltes, R., Gfesser, J., Haslinger, D. et al. Common EIF4E variants modulate risk for autism spectrum disorders in the high-functioning range. J Neural Transm 121, 1107–1116 (2014). https://doi.org/10.1007/s00702-014-1230-2

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