title: Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability.
abstract: Recent findings revealed rare copy number variants and missense changes in the X-linked gene PTCHD1 in autism spectrum disorder (ASD) and intellectual disability (ID). Here, we aim to explore the contribution of common PTCHD1 variants in ASD and gain additional evidence for the role of rare variants of this gene in ASD and ID. A two-stage case-control association study investigated 28 tag single nucleotide polymorphisms (SNPs) in 994 ASD cases and 1035 controls from four European populations. Mutation screening was performed in 673 individuals who included 240 ASD cases, 183 ID patients and 250 controls. The case-control association study showed a significant association with rs7052177 (P=6.13E-4) in the ASD discovery sample that was replicated in an independent sample (P=0.03). A Mantel-Haenszel meta-analysis for rs7052177T considering the four European populations showed an odds ratio of 0.58 (P=7E-05). This SNP is predicted to be located in a transcription factor binding site. No rare missense PTCHD1 variants were found in our ASD cohort and only one was identified in the ID sample. A duplication (27 bp) in the promoter region, absent from 590 controls, was found in three ASD patients (Fisher exact test, P=0.024). A gene reporter assay showed a significant decrease in the transcriptional activity (26%) driven by this variant. Moreover, we found that the longest allele of a trinucleotide repeat located upstream from PTCHD1 was associated with ASD (P=0.003, permP=0.0186). Our results further support the involvement of PTCHD1 in ASD, suggesting that both common and rare variants contribute to the disorder.
authors.affiliation: Departament de Genètica, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain.
authors.forename: Bàrbara
authors.initials: B
authors.lastname: Torrico
authors.affiliation: Departament de Genètica, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain.
authors.forename: Noèlia
authors.initials: N
authors.lastname: Fernàndez-Castillo
authors.affiliation: Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Terrassa, Spain.|Developmental Disorders Unit (UETD), Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Hervás
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Biochemistry and Molecular Genetics Department, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Milà
authors.affiliation: Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Terrassa, Spain.|Developmental Disorders Unit (UETD), Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Salgado
authors.affiliation: Developmental Disorders Unit (UETD), Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rueda
authors.affiliation: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen, The Netherlands.|Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands.|Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Psychiatry, Nijmegen, The Netherlands.
authors.forename: Nanda
authors.initials: N
authors.lastname: Rommelse
authors.affiliation: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen, The Netherlands.|Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands.
authors.forename: Anoek M
authors.initials: AM
authors.lastname: Oerlemans
authors.affiliation: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen, The Netherlands.|Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Human Genetics, Nijmegen, The Netherlands.
authors.forename: Janita
authors.initials: J
authors.lastname: Bralten
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe-University Frankfurt am Main, Frankfurt, Germany.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Freitag
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, JW Goethe-University Frankfurt am Main, Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.affiliation: Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, Calambrone, Pisa, Italy.
authors.forename: Agatino
authors.initials: A
authors.lastname: Battaglia
authors.affiliation: Child Neuropsychiatry Unit, Department of Neuroscience, I.R.C.C.S. Children's Hospital Bambino Gesù, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Mazzone
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Maestrini
authors.affiliation: Departament de Genètica, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain.
authors.forename: Bru
authors.initials: B
authors.lastname: Cormand
authors.affiliation: Departament de Genètica, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain.
authors.forename: Claudio
authors.initials: C
authors.lastname: Toma
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018911:Trinucleotide Repeats
chemical_list: D008565:Membrane Proteins; C000607409:PTCHD1 protein, human