title: Lack of replication of previous autism spectrum disorder GWAS hits in European populations.
abstract: Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes available for association studies. During the last decade several genome-wide association studies (GWAS) have enabled the detection of a few plausible risk variants. The three main studies are family-based and pointed at SEMA5A (rs10513025), MACROD2 (rs4141463) and MSNP1 (rs4307059). In our study we attempted to replicate these GWAS hits using a case-control association study in five European populations of ASD patients and gender-matched controls, all Caucasians. Results showed no association of individual variants with ASD in any of the population groups considered or in the combined European sample. We performed a meta-analysis study across five European populations for rs10513025 (1,904 ASD cases and 2,674 controls), seven European populations for rs4141463 (2,855 ASD cases and 36,177 controls) and five European populations for rs4307059 (2,347 ASD cases and 2,764 controls). The results showed an odds ratio (OR) of 1.05 (95% CI = 0.84-1.32) for rs10513025, 1.0002 (95% CI = 0.93-1.08) for rs4141463 and 1.01 (95% CI = 0.92-1.1) for rs4307059, with no significant P-values (rs10513025, P = 0.73; rs4141463, P = 0.95; rs4307059, P = 0.9). No association was found when we considered either only high functioning autism (HFA), genders separately or only multiplex families. Ongoing GWAS projects with larger ASD cohorts will contribute to clarify the role of common variation in the disorder and will likely identify risk variants of modest effect not detected previously. Autism Res 2017, 10: 202-211. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
authors.affiliation: Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, 28029, Madrid, Spain.|Institut de Biomedicina, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.|Institut de Recerca Pediàtrica Hospital Sant Joan de Dáu, Santa Rosa 39-57, 08950, Esplugues de Llobregat, Spain.
authors.forename: Bàrbara
authors.initials: B
authors.lastname: Torrico
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence Frankfurt, JW Goethe University, Deutschordenstraße 50 60528 Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Chiocchetti
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, via Selmi 3, 40126, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bacchelli
authors.affiliation: Department of Neurological, Biomedical and Movement Sciences, Section of Biology and Genetics, University of Verona, Strada le Grazie 8, 37134, Verona, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Trabetti
authors.affiliation: Child and Adolescent Mental Health Unit, University Hospital MutuaTerrassa, Plaza del Dr Robert s/n, 08221, Terrassa, Barcelona, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Hervás
authors.affiliation: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Human Genetics, Geert Grooteplein-Zuid 10, 6525, GA Nijmegen, The Netherlands.|Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Psychiatry, Geert Grooteplein-Zuid 10, 6525, GA Nijmegen, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Geert Grooteplein Noord 21, 6525, EZ Nijmegen, The Netherlands.|Karakter Child and Adolescent Psychiatry University Center, Reinier Postlaan 12, 6525, GC Nijmegen, The Netherlands.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Psychiatry, Geert Grooteplein-Zuid 10, 6525, GA Nijmegen, The Netherlands.|Karakter Child and Adolescent Psychiatry University Center, Reinier Postlaan 12, 6525, GC Nijmegen, The Netherlands.
authors.forename: Nanda
authors.initials: N
authors.lastname: Rommelse
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence Frankfurt, JW Goethe University, Deutschordenstraße 50 60528 Frankfurt am Main, Frankfurt am Main, Germany.|Institute for Molecular Bioinformatics, Johann Wolfgang Goethe-University, Robert-Mayer-Str. 11-15, 60325, Frankfurt am Main, Germany.
authors.forename: Afsheen
authors.initials: A
authors.lastname: Yousaf
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence Frankfurt, JW Goethe University, Deutschordenstraße 50 60528 Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Eftichia
authors.initials: E
authors.lastname: Duketis
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence Frankfurt, JW Goethe University, Deutschordenstraße 50 60528 Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Freitag
authors.affiliation: Autism unit, department of Psychiatry, University of Seville, C/ San Fernando 4, 41004, Sevilla, Spain.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Caballero-Andaluz
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Av. Manuel Siurot s/n, 41013, Seville, Spain.
authors.forename: Amalia
authors.initials: A
authors.lastname: Martinez-Mir
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Av. Manuel Siurot s/n, 41013, Seville, Spain.
authors.forename: Francisco G
authors.initials: FG
authors.lastname: Scholl
authors.affiliation: Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.|Biomedical Network Research Center on Mental Health (CIBERSAM), Av. Monforte de Lemos, 3-5, 28029, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ribasés
authors.affiliation: ITAN, the Italian Autism Network, Strada le Grazie 8, Verona, Italy.
authors.affiliation: Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, via dei Giacinti 2, 56128 Calambrone, Pisa, Italy.
authors.forename: Agatino
authors.initials: A
authors.lastname: Battaglia
authors.affiliation: Department of Neurological, Biomedical and Movement Sciences, Section of Biology and Genetics, University of Verona, Strada le Grazie 8, 37134, Verona, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Malerba
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, 25, rue du docteur Roux, 75015, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, 25, rue du docteur Roux, 75015, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, 5 Rue Thomas Mann, 75013, Paris, France.|Assistance Publique-Hôpitaux de Paris, Child and Adolescent Psychiatry Department, Robert Debré Hospital, 48Bd Sérurier, 75019, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Delorme
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, 25, rue du docteur Roux, 75015, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, 25, rue du docteur Roux, 75015, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, 5 Rue Thomas Mann, 75013, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Benabou
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, via Selmi 3, 40126, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Maestrini
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, 25, rue du docteur Roux, 75015, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, 25, rue du docteur Roux, 75015, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, 5 Rue Thomas Mann, 75013, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bourgeron
authors.affiliation: Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, 28029, Madrid, Spain.|Institut de Biomedicina, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.|Institut de Recerca Pediàtrica Hospital Sant Joan de Dáu, Santa Rosa 39-57, 08950, Esplugues de Llobregat, Spain.
authors.forename: Bru
authors.initials: B
authors.lastname: Cormand
authors.affiliation: Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, 28029, Madrid, Spain.|Institut de Biomedicina, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.|Neuroscience Research Australia, Barker St, Randwick, 2031, Sydney, New South Wales, Australia.|School of Medical Sciences, University of New South Wales, High St, Kensington, 2052, Sydney, New South Wales, Australia.
authors.forename: Claudio
authors.initials: C
authors.lastname: Toma
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics*; D016022:Case-Control Studies; D005060:Europe; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods / Q000706:statistics & numerical data*; D006801:Humans; D008297:Male; D015203:Reproducibility of Results
keywords: European populations; MACROD2; MSNP1; SEMA5A; autism spectrum disorder; genome-wide association study; replication