title: The landscape of copy number variations in Finnish families with autism spectrum disorders.
abstract: Rare de novo and inherited copy number variations (CNVs) have been implicated in autism spectrum disorder (ASD) risk. However, the genetic underpinnings of ASD remain unknown in more than 80% of cases. Therefore, identification of novel candidate genes and corroboration of known candidate genes may broaden the horizons of determining genetic risk alleles, and subsequent development of diagnostic testing. Here, using genotyping arrays, we characterized the genetic architecture of rare CNVs (<1% frequency) in a Finnish case-control dataset. Unsurprisingly, ASD cases harbored a significant excess of rare, large (>1 Mb) CNVs and rare, exonic CNVs. The exonic rare de novo CNV rate (∼22.5%) seemed higher compared to previous reports. We identified several CNVs in well-known ASD regions including GSTM1-5, DISC1, FHIT, RBFOX1, CHRNA7, 15q11.2, 15q13.2-q13.3, 17q12, and 22q11.21. Additionally, several novel candidate genes (BDKRB1, BDKRB2, AP2M1, SPTA1, PTH1R, CYP2E1, PLCD3, F2RL1, UQCRC2, LILRB3, RPS9, and COL11A2) were identified through gene prioritization. The majority of these genes belong to neuroactive ligand-receptor interaction pathways, and calcium signaling pathways, thus suggesting that a subset of these novel candidate genes may contribute to ASD risk. Furthermore, several metabolic pathways like caffeine metabolism, drug metabolism, retinol metabolism, and calcium-signaling pathway were found to be affected by the rare exonic ASD CNVs. Additionally, biological processes such as bradykinin receptor activity, endoderm formation and development, and oxidoreductase activity were enriched among the rare exonic ASD CNVs. Overall, our findings may add data about new genes and pathways that contribute to the genetic architecture of ASD.
authors.affiliation: Department of Medical Genetics, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland.
authors.forename: Chakravarthi
authors.initials: C
authors.lastname: Kanduri
authors.affiliation: Department of Medical Genetics, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Kantojärvi
authors.affiliation: Department of Medical Genetics, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Salo
authors.affiliation: Hospital of Children and Adolescents, University of Helsinki, P.O. Box 56, 00014, Helsinki.
authors.forename: Raija
authors.initials: R
authors.lastname: Vanhala
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosewelt Drive, Oxford, OX3 7BN.
authors.forename: Gemma
authors.initials: G
authors.lastname: Buck
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosewelt Drive, Oxford, OX3 7BN.
authors.forename: Christine
authors.initials: C
authors.lastname: Blancher
authors.affiliation: Department of Information and Computer Science, Aalto University School of Science, Espoo, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Lähdesmäki
authors.affiliation: Department of Medical Genetics, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland.
authors.forename: Irma
authors.initials: I
authors.lastname: Järvelä
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics*; D016022:Case-Control Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D005387:Finland; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
keywords: Finnish population; autism spectrum disorders; copy number variations; genome wide SNP arrays