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Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.

ABSTRACT: Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

SUBMITTER: Glessner JT

PROVIDER: S-EPMC2925224 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.

Glessner Joseph T JT Wang Kai K Cai Guiqing G Korvatska Olena O Kim Cecilia E CE Wood Shawn S Zhang Haitao H Estes Annette A Brune Camille W CW Bradfield Jonathan P JP Imielinski Marcin M Frackelton Edward C EC Reichert Jennifer J Crawford Emily L EL Munson Jeffrey J Sleiman Patrick M A PM Chiavacci Rosetta R Annaiah Kiran K Thomas Kelly K Hou Cuiping C Glaberson Wendy W Flory James J Otieno Frederick F Garris Maria M Soorya Latha L Klei Lambertus L Piven Joseph J Meyer Kacie J KJ Anagnostou Evdokia E Sakurai Takeshi T Game Rachel M RM Rudd Danielle S DS Zurawiecki Danielle D McDougle Christopher J CJ Davis Lea K LK Miller Judith J Posey David J DJ Michaels Shana S Kolevzon Alexander A Silverman Jeremy M JM Bernier Raphael R Levy Susan E SE Schultz Robert T RT Dawson Geraldine G Owley Thomas T McMahon William M WM Wassink Thomas H TH Sweeney John A JA Nurnberger John I JI Coon Hilary H Sutcliffe James S JS Minshew Nancy J NJ Grant Struan F A SF Bucan Maja M Cook Edwin H EH Buxbaum Joseph D JD Devlin Bernie B Schellenberg Gerard D GD Hakonarson Hakon H

Nature 20090428 7246

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in ...[more]

PMID: 19404257

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Project description:Copy number variations (CNVs) are important structural variations that can cause significant phenotypic diversity. Reliable CNVs mapping can be achieved by identification of CNVs from different genetic backgrounds. Investigations on the characteristics of overlapping between CNV regions (CNVRs) and protein-coding genes (CNV genes) or miRNAs (CNV-miRNAs) can reveal the potential mechanisms of their regulation. In this study, we used 50 K SNP arrays to detect CNVs in Duroc purebred pig. A total number of 211 CNVRs were detected with a total length of 118.48 Mb, accounting for 5.23% of the autosomal genome sequence. Of these CNVRs, 32 were gains, 175 losses, and four contained both types (loss and gain within the same region). The CNVRs we detected were non-randomly distributed in the swine genome and were significantly enriched in the segmental duplication and gene density region. Additionally, these CNVRs were overlapping with 1,096 protein-coding genes (CNV-genes), and 39 miRNAs (CNV-miRNAs), respectively. The CNV-genes were enriched in terms of dosage-sensitive gene list. The expression of the CNV genes was significantly higher than that of the non-CNV genes in the adult Duroc prostate. Of all detected CNV genes, 22.99% genes were tissue-specific (TSI > 0.9). Strong negative selection had been underway in the CNV-genes as the ones that were located entirely within the loss CNVRs appeared to be evolving rapidly as determined by the median dN plus dS values. Non-CNV genes tended to be miRNA target than CNV-genes. Furthermore, CNV-miRNAs tended to target more genes compared to non-CNV-miRNAs, and a combination of two CNV-miRNAs preferentially synergistically regulated the same target genes. We also focused our efforts on examining CNV genes and CNV-miRNAs functions, which were also involved in the lipid metabolism, including DGAT1, DGAT2, MOGAT2, miR143, miR335, and miRLET7. Further molecular experiments and independent large studies are needed to confirm our findings.

Dataset Information

Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.

Publications

Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.

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