Support for the Homeobox Transcription Factor Gene ENGRAILED 2 as an Autism Spectrum Disorder Susceptibility Locus

Center for Advanced Biotechnology and Medicine, Piscataway, NJ, 08854-5638, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 12/2005; 77(5):851-68. DOI: 10.1086/497705
Source: PubMed

ABSTRACT Our previous research involving 167 nuclear families from the Autism Genetic Resource Exchange (AGRE) demonstrated that two intronic SNPs, rs1861972 and rs1861973, in the homeodomain transcription factor gene ENGRAILED 2 (EN2) are significantly associated with autism spectrum disorder (ASD). In this study, significant replication of association for rs1861972 and rs1861973 is reported for two additional data sets: an independent set of 222 AGRE families (rs1861972-rs1861973 haplotype, P=.0016) and a separate sample of 129 National Institutes of Mental Health families (rs1861972-rs1861973 haplotype, P=.0431). Association analysis of the haplotype in the combined sample of both AGRE data sets (389 families) produced a P value of .0000033, whereas combining all three data sets (518 families) produced a P value of .00000035. Population-attributable risk calculations for the associated haplotype, performed using the entire sample of 518 families, determined that the risk allele contributes to as many as 40% of ASD cases in the general population. Linkage disequilibrium (LD) mapping with the use of polymorphisms distributed throughout the gene has shown that only intronic SNPs are in strong LD with rs1861972 and rs1861973. Resequencing and association analysis of all intronic SNPs have identified alleles associated with ASD, which makes them candidates for future functional analysis. Finally, to begin defining the function of EN2 during development, mouse En2 was ectopically expressed in cortical precursors. Fewer En2-transfected cells than controls displayed a differentiated phenotype. Together, these data provide further genetic evidence that EN2 might act as an ASD susceptibility locus, and they suggest that a risk allele that perturbs the spatial/temporal expression of EN2 could significantly alter normal brain development.

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    ABSTRACT: Engrailed (En) is a member of the homeobox gene family, which encodes a homeodomain-containing transcription factor that is essential during early development. The only known site of normal adult Engrailed protein (EN) expression is in the nervous system, and it has been implicated in the development of both young-onset Parkinson's disease as well as autism. Over-expression of EN has been linked to tumour development in adults, particularly in breast, prostate, melanoma and ovarian cancers, and there is a growing interest in its role as a diagnostic and prognostic biomarker. It is hoped that further work may confirm associations between En expression and therapy-resistant, poor prognosis cancers, similar to that identified with other homeobox gene profiles.
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    ABSTRACT: Engrailed 2 (EN2) is a homeobox transcription factor involved in the patterning of cerebellum during brain development. Linkage analysis and studies on knockout mice support EN2, located on chromosome 7q36.3, as a potential risk locus for autism. Candidate gene approach also suggested association of EN2 with autism spectrum disorder (ASD) in various populations. Here, we have investigated the association of five markers [rs3735653 (C/T) in exon 1; rs34808376 (GC/-) and rs6150410 (CGCATCCCC/-) in promoter region; rs1861972 (A/G) and rs1861973 (C/T) in the intron] of the gene with autism and ASD in Indian population using family-based approach. Probands have been recruited using Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) diagnostic criteria. Genotypic distributions conform to Hardy-Weinberg equilibrium. Genotyping analysis showed that the intronic single nucleotide polymorphisms (SNPs) are in complete linkage disequilibrium showing A-C and corresponding G-T allelic association. We observed significant preferential transmission of C allele of rs1861973 from the parents to affected offspring [transmission disequilibrium test (TDT): narrow diagnosis likelihood ratio statistics (LRS) = 6.63, P = 0.006; broad diagnosis LRS = 4.47, P = 0.05]. Interestingly, gender-based investigations showed significant transmission of C allele to the affected females [TDT: LRS = 7.36, P = 0.0025; haplotype-based haplotype relative risk (HHRR): LRS = 7.16, P = 0.02]. A maternal overtransmission for these alleles was also noted (TDT: LRS = 3.65, P = 0.036; HHRR: LRS = 2.81, P = 0.036). Bioinformatic analysis using TFSearch showed generation of Sp1 binding site in the presence of C allele. While Del-T haplotype formed from rs34808376-rs1861973 markers showed increased non-transmission, the Ins-C showed significant transmission suggesting protective effect and risk, respectively, conferred by these haplotypes in autism etiology. These results suggest positive genetic correlation of EN2 with autism in the Indian population.
    Genes Brain and Behavior 03/2010; 9(2):248-55. DOI:10.1111/j.1601-183X.2009.00556.x


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