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Common genetic variants on 1p13.2 associate with risk of autism


Autism is a highly heritable neurodevelopmental disorder, and known genetic variants, mostly rare, account only for a small proportion of cases. Here we report a genome-wide association study on autism using two Chinese cohorts as gene discovery (n=2150) and three data sets of European ancestry populations for replication analysis of top association signals. Meta-analysis identified three single-nucleotide polymorphisms, rs936938 (P=4.49 × 10−8), non-synonymous rs6537835 (P=3.26 × 10−8) and rs1877455 (P=8.70 × 10−8), and related haplotypes, AMPD1-NRAS-CSDE1, TRIM33 and TRIM33-BCAS2, associated with autism; all were mapped to a previously reported linkage region (1p13.2) with autism. These genetic associations were further supported by a cis-acting regulatory effect on the gene expressions of CSDE1, NRAS and TRIM33 and by differential expression of CSDE1 and TRIM33 in the human prefrontal cortex of post-mortem brains between subjects with and those without autism. Our study suggests TRIM33 and NRAS-CSDE1 as candidate genes for autism, and may provide a novel insight into the etiology of autism.

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We are grateful to all the children with autism, their families and to the normal controls who participated in this study. We thank Autism Speaks for sharing resources from the Autism Genetic Resources Exchange (AGRE), the Simons Foundation for Autism Research Initiative (SFARI) for providing data from the Simons Simplex Collection (SCC), the NIH GWAS Data Repository (AGP data set: phs000267.v1.p1) and the Contributing Investigator(s) who contributed the phenotype and genotype data from his/her original studies. We also thank Mr Tianzhang Ye, Dr Carlo Colantuoni and Dr Joel E Kleinman for assisting in accessing the brain expression data and Dr Elizabeth Sherman for comments. The research was supported by the National Basic Research Program of China (2012CB517900, 2011CB510002), the National Natural Science Foundation of China (81330027, 81161120544), the National Alliance for Research on Schizophrenia and Depression (NARSAD) Award (17616 to LZ) and Intramural Research Program funding from the National Institute of Mental Health, The National Institutes of Health in the United States.

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Correspondence to K Xia, J Zhao or F Zhang.

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Xia, K., Guo, H., Hu, Z. et al. Common genetic variants on 1p13.2 associate with risk of autism. Mol Psychiatry 19, 1212–1219 (2014).

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  • association fine mapping
  • autism
  • common genetic variants
  • genome-wide association study
  • human genetics

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