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

• Published in: American journal of human genetics Vol. 77; no. 5; pp. 851 - 868
• Main Authors: Benayed, Rym, Gharani, Neda, Rossman, Ian, Mancuso, Vincent, Lazar, Gloria, Kamdar, Silky, Bruse, Shannon E., Tischfield, Samuel, Smith, Brett J., Zimmerman, Raymond A., DiCicco-Bloom, Emanuel, Brzustowicz, Linda M., Millonig, James H.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.11.2005; University of Chicago Press; Cell Press; American Society of Human Genetics
• Subjects: Autism; Autistic Disorder - genetics; Autistic Disorder - physiopathology; Biological and medical sciences; Cell Culture Techniques; Child clinical studies; Developmental disorders; Gene expression; Gene Expression Regulation, Developmental; Gene loci; General aspects. Genetic counseling; Genes; Genetic Predisposition to Disease; Genetics; Haplotypes; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Homeodomain Proteins - physiology; Humans; Infantile autism; Introns - genetics; Linkage Disequilibrium; Medical genetics; Medical sciences; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Pedigree; Polymorphism, Single Nucleotide; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Human; Nervous system diseases; Pathogenesis; Developmental disorder; Genetic determinism; Spectrum; Autism; Sensitivity; Homeotic gene; Predisposition; Genetics; Transcription factor; Neurological disorder
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/497705

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.