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

Abstract

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1 -4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5 -9. 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 ~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 × 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 × 10 −3 ). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 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.ASDs, including autism, are neurodevelopmental disorders characterized by impairments in social and communication skills, as well as stereotyped and repetitive behaviours and/or a restricted range of interests. Current prevalence estimates in the United States are 0.1-0.2% for autism and 0.6% for ASDs 1,2 .Linkage and candidate gene association studies have implicated several chromosomal regions in autism 3,4 . However, positive findings in one study often fail to replicate in other studies, and a consistent picture of susceptibility loci in autism is still lacking. Some telling clues about ASD genetics arose from recent studies on CNVs 5 , including the association of de novo CNVs with ASDs 6 . Although de novo CNVs that disrupt specific genes may contribute to the pathogenesis of ASDs, heritable CNVs are much more common but have been less studied as risk factors of ASDs. A family-based genome-wide linkage and CNV analysis by the Autism Genome Project Consortium using Affymetrix 10K single nucleotide polymorphism (SNP) arrays implicated chromosome 11p12-13 and neurexin 1 (NRXN1) as candidate loci 7 . A study using the Affymetrix 500K SNP array in a Canadian population reported 277 rare CNVs that were only observed in ASD patients but not in 1,652 healthy controls or in the Database of Genomic Variants 8 . Furthermore, 16p11.2 deletions and Glessner et al.Page 2 Nature. Author manuscript; available in PMC 2010 August 23. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscri...

The Emerging Link Between Autoimmune Disorders and Neuropsychiatric Disease

“…In some instances, neuropsychiatric disorders such as autism and schizophrenia are postulated to result from genetic mutations in these neuronal cell-adhesion systems. 27,28 Recent discoveries now indicate that acquired autoimmune syndromes also target trans -synaptic signals. Leucine-rich glioma-inactivated 1 (LGI1) is a secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22 to create a trans -synaptic protein complex, which also includes potassium channels and AMPA-type glutamate receptors.…”

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

“…1,2 Recent studies have demonstrated that ASDs can be caused by rare, highly penetrant point mutations, deletions, duplications and larger chromosomal abnormalities that can either arise de novo or be inherited. [3][4][5][6][7][8][9] Known monogenic disorders account for 2-5% of syndromic cases; fragile X syndrome is usually the most common cause, followed by PTEN macrocephaly syndrome and tuberous sclerosis, each accounting for o1% of individuals with ASD. 1,10 Large copy number variants (CNVs) are found in 5-10% of autistic patients, especially in those with syndromic ASDs.…”

“…4,5,13 Private CNVs in individuals with autism often disrupt genes encoding synaptic proteins, such as neuroligins, neurexins and SHANK proteins, or neuronal cell-adhesion proteins, which have important roles in neurodevelopment and/or neurotransmission. 3,[14][15][16][17] However, most CNVs and variants in genes involved in autism so far are also found in other neurodevelopmental disorders such as ID without autistic features and/or schizophrenia. 12,18 Recent studies point to polygenic or oligogenic inheritance.…”

The discovery of human genetic variations and their use as disease markers: past, present and future

“…These studies have yielded some exciting results for several diseases, such as schizophrenia and autism. [56][57][58] Therefore, it further supports the use of CNVs as genetic markers to uncover new susceptibility loci for future disease association studies. Interestingly, genome-wide homozygosity mapping approaches have also been applied to dissect the genetic basis of complex diseases and have successfully identified a number of susceptibility loci for schizophrenia.…”