Association of the ENGRAILED 2 (EN2) gene with autism in Chinese Han population

Abstract

Human ENGRAILED 2 (EN2) gene is localized to 7q36, an autism susceptibility locus. En2 knockout mice display hypoplasia of cerebellum and a decrease in the number of Purkinje cell, which are similar to those reported for individuals with autism. Furthermore, deficits in social behavior were detected in En2(-/-) mice. Two recent studies have demonstrated that two intronic SNPs (rs1861972, rs1861973) in the EN2 gene are significantly associated with autism. To investigate whether this finding could be replicated in Chinese Han population, we performed the association study between eight single nucleotide polymorphisms (SNPs) of the EN2 gene and autism in 210 Chinese Han trios, using the family-based association test (FBAT). The present study demonstrated that a preferential transmission of the rs3824068 A-allele to affected offspring (A > G: Z = 2.399, P = 0.0165). After the Bonferroni correction, this statistical significance of preferential transmission did not remain. However, when haplotypes were constructed with multiple markers, a number of haplotypes including three two-marker haplotypes, nine three-marker haplotypes, one four-marker haplotype, and one six-marker haplotype, all of which contain the major allele A of rs3824068, displayed significantly associated with autism. These results were still significant after using the permutation method to obtain empirical P values. Thus, our data provide evidence that the EN2 gene may be implicated in the predisposition to autism in the Chinese Han population.

Intronic Single Nucleotide Polymorphisms of <i>Engrailed Homeobox 2</i> Modulate the Disease Vulnerability of Autism in a Han Chinese Population

“…In addition, rs3824068 might play a role in modulating the genetic effect of the haplotype A-C. These findings partly agree with some previous results obtained by analyzing the allelic frequency of EN2 in Han Chinese and Caucasian populations [8,9,18] . Preferably, the haplotype A-C of rs1861972 and rs1861973 is suggested to be transmitted more frequently from parents to the affected children.…”

“…More recently, a study [17] also reported that EN2 rs1861972 is associated with broad ASD in a recessive model in the NIH Collaborative Programs of Excellence in Autism cohort, even though the result was not totally consistent with previous findings of Benayed et al [8] . Following this, Wang et al [18] conducted a study to determine whether EN2 SNPs are associated with ASD in a Han Chinese population, using a family-based association test. Another polymorphism, rs3824068, was suggested as a Han Chinese ethnic-specific SNP site that is associated with autism, excepting rs1861972 and rs1861973.…”

Association of the Homeobox Transcription Factor Gene ENGRAILED 2 with Autistic Disorder in Chinese Children

“…This suggests it likely to be nonfunctional polymorphisms in LD with other variant(s) that contribute to autism. In addition, rs1861972-A and rs1861973-C were reported for their association with autism only when integrated into 3-marker haplotypes with another 2 SNPs (rs3824068, rs4717034) in the Chinese Han population [20] . Definitely, the discordant findings of these family-based gene association studies might be explained by ethnic difference, genetic heterogeneity and different statistical methodologies used.…”

Autism Spectrum Disorders: Insights from Genomics

“…In three separate datasets, Benayed et al (2005Benayed et al ( , 2009 [36,37] have reported and replicated a significant association between EN2 and both broad and narrow ASD phenotypes. Wang et al (2008) [38] also found an association between EN2 and ASD in a Chinese Han sample, although Zhong et al (2003) [39] failed to find evidence of an underlying association. …”