title: Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus.
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.
authors.affiliation: Center for Advanced Biotechnology and Medicine, Piscataway, NJ, 08854-5638, USA.
authors.forename: Rym
authors.initials: R
authors.lastname: Benayed
authors.forename: Neda
authors.initials: N
authors.lastname: Gharani
authors.forename: Ian
authors.initials: I
authors.lastname: Rossman
authors.forename: Vincent
authors.initials: V
authors.lastname: Mancuso
authors.forename: Gloria
authors.initials: G
authors.lastname: Lazar
authors.forename: Silky
authors.initials: S
authors.lastname: Kamdar
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Bruse
authors.forename: Samuel
authors.initials: S
authors.lastname: Tischfield
authors.forename: Brett J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Zimmerman
authors.forename: Emanuel
authors.initials: E
authors.lastname: Dicicco-Bloom
authors.forename: Linda M
authors.initials: LM
authors.lastname: Brzustowicz
authors.forename: James H
authors.initials: JH
authors.lastname: Millonig
mesh_terms: D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology; D018929:Cell Culture Techniques; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D000099266:Engrailed 2 Protein
chemical_list: D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000099266:Engrailed 2 Protein