Abstract
Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with high heritability, although the underlying genetic determinants of ASDs remain largely unknown. Large-scale whole-genome studies of copy number variation in Han Chinese samples are still lacking. We performed a genome-wide copy number variation analysis of 343 ASD trios, 203 patients with sporadic cases and 988 controls in a Chinese population using Illumina genotyping platforms to identify CNVs and related genes that may contribute to ASD risk. We identified 32 rare CNVs larger than 1 Mb in 31 patients. ASD patients were found to carry a higher global burden of rare, large CNVs than controls. Recurrent de novo or case-private CNVs were found at 15q11-13, Xp22.3, 15q13.1–13.2, 3p26.3 and 2p12. The de novo 15q11–13 duplication was more prevalent in this Chinese population than in those with European ancestry. Several genes, including GRAMD2 and STAM, were implicated as novel ASD risk genes when integrating whole-genome CNVs and whole-exome sequencing data. We also identified several CNVs that include known ASD genes (SHANK3, CDH10, CSMD1) or genes involved in nervous system development (NYAP2, ST6GAL2, GRM6). Besides, our study also implicated Contactins-NYAPs-WAVE1 pathway in ASD pathogenesis. Our findings identify ASD-related CNVs in a Chinese population and implicate novel ASD risk genes and related pathway for further study.
Highlights
Studies and candidate resequencing studies of large cohorts have identified multiple genes with recurrent de novo, likely gene-disruptive (LGD) mutations in Autism spectrum disorders (ASDs) patients, such as CHD8, SYNGAP1, DYRK1A, ARID1B, SCN2A, DSCAM, ANK2, ADNP, POGZ, GRIN2B and CHD214–20
18 CNV calls per individual were made for samples genotyped using the HumanCNV370 BeadChip, 24.7 CNV calls for samples genotyped using the HumanCNV610 BeadChip and 357.3 CNV calls for samples genotyped using the HumanCNV660 BeadChip (Figure S1)
A total of 33 rare CNVs (
Summary
Studies and candidate resequencing studies of large cohorts have identified multiple genes with recurrent de novo, likely gene-disruptive (LGD) mutations in ASD patients, such as CHD8, SYNGAP1, DYRK1A, ARID1B, SCN2A, DSCAM, ANK2, ADNP, POGZ, GRIN2B and CHD214–20. Common genetic variants have been reported at 5p14.1 (CDH10-CDH9)21, 5p15.2 (SEMA5A)[22], MACROD223, CNTNAP224 and 1p13.2 (CSDE1, TRIM33) loci[25] through genome-wide association studies (GWAS). Together, these results suggest that ASD has a complex inheritance pattern; its genetic architecture and underlying mechanism are still largely unknown. Several large-cohort genome-wide CNV studies have been performed, few studies have investigated CNVs related to ASD in Chinese populations[26,27]. We performed a GWAS of autism in a Han Chinese population for common genetic variants associated with ASD25. We found 32 rare, large CNVs longer than 1 Mb accounting for 5.68% of the total patients, of which five CNVs were recurrently identified in ASD patients
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