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Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes
- Source :
- PLoS genetics, vol 5, iss 6, PLoS Genetics, PLoS Genetics, Vol 5, Iss 6, p e1000536 (2009)
- Publication Year :
- 2009
- Publisher :
- eScholarship, University of California, 2009.
-
Abstract
- The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.<br />Author Summary Autism spectrum disorders (ASDs) are common neurodevelopmental syndromes with a strong genetic component. ASDs are characterized by disturbances in social behavior, impaired verbal and nonverbal communication, as well as repetitive behaviors and/or a restricted range of interests. To identify genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. To enrich for variants most likely to interfere with gene function, we restricted our analyses to deletions and gains encompassing exons. Of the many genomic regions highlighted, 27 were seen to harbor rare variants in cases and not controls, both in the first phase of our analysis, and also in an independent replication cohort comprised of 859 cases and 1,051 controls. More work in a larger number of individuals will be required to determine which of the rare alleles highlighted here are indeed related to the ASDs and how they act to shape risk.
- Subjects :
- Male
Cancer Research
Neuronal
Autism
Gene Dosage
Genome-wide association study
QH426-470
Genome
Cohort Studies
0302 clinical medicine
Gene Duplication
Gene duplication
2.1 Biological and endogenous factors
Copy-number variation
Aetiology
Child
Neural Cell Adhesion Molecules
Genetics (clinical)
Genetics and Genomics/Genetics of Disease
Sequence Deletion
Genetics
0303 health sciences
Exons
Pedigree
Mental Health
Child, Preschool
Medical genetics
Female
Research Article
medicine.medical_specialty
Adolescent
Cell Adhesion Molecules, Neuronal
Ubiquitin-Protein Ligases
Intellectual and Developmental Disabilities (IDD)
Nerve Tissue Proteins
Biology
Gene dosage
Structural variation
03 medical and health sciences
Young Adult
medicine
Humans
Genetic Predisposition to Disease
Autistic Disorder
Preschool
Molecular Biology
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Comparative genomics
Calcium-Binding Proteins
Human Genome
Brain Disorders
Case-Control Studies
Cell Adhesion Molecules
030217 neurology & neurosurgery
Genome-Wide Association Study
Developmental Biology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- PLoS genetics, vol 5, iss 6, PLoS Genetics, PLoS Genetics, Vol 5, Iss 6, p e1000536 (2009)
- Accession number :
- edsair.doi.dedup.....35a79de7cf676eff240e2465e64c7345