Association study between genes in Reelin signaling pathway and autism identifiesDAB1as a susceptibility gene in a Chinese Han population

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Abstract

Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. The genetic factors might play an important role in its pathogenesis. Previous studies revealed that Reelin (RELN) polymorphisms were associated with autism. However, the roles of genes in Reelin signaling pathway for autism are largely unknown. As several knockout mice models in which the Reelin pathway genes (i.e. DAB1, VLDLR/APOER2, FYN/SRC and CRK/CRKL) are deficient have the similar phenotype as the reeler mice (Reelin−/−), we hypothesized that the Reelin signaling pathway genes might play roles in the etiology of autism. Therefore, we conducted a family-based association study. Sixty-two tagged single nucleotide polymorphisms (SNPs) covering 15 genes in Reelin pathway were genotyped in 239 trios, and 14 significant SNPs were further investigated in the additional 188 trios. In the total 427 trios, we found significant genetic association between autism and four SNPs in DAB1 (rs12035887 G: p = 0.0006; rs3738556 G: p = 0.0044; rs1202773 A: p = 0.0048; rs12740765 T: p = 0.0196). After the Bonferroni correction, SNP rs12035887 remained significant. Furthermore, the haplotype constructed with rs1202773 and rs12023109 in DAB1 showed significant excess transmission in both individual and global haplotype analyses (p = 0.0052 and 0.0279, respectively). Our findings suggested that variations in DAB1 involved in the Reelin signaling pathway might contribute to genetic susceptibility to autism with Chinese Han decent, supporting the defect in the Reelin signaling pathway as a predisposition factor for autism.

Highlights

▪ We conducted a family-based association study in Chinese Han population. ▪ We tested association between autism and 62 SNPs covering 15 Reelin pathway genes. ▪ Four SNPs and one haplotype in DAB1 displayed significant association. ▪ Variations in DAB1 might contribute to genetic susceptibility to autism.

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