TY - JOUR
T1 - Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism
AU - Conciatori, Monica
AU - Stodgell, Christopher J.
AU - Hyman, Susan L.
AU - O'Bara, Melanie
AU - Militerni, Roberto
AU - Bravaccio, Carmela
AU - Trillo, Simona
AU - Montecchi, Francesco
AU - Schneider, Cindy
AU - Melmed, Raun
AU - Elia, Maurizio
AU - Crawford, Lori
AU - Spence, Sarah J.
AU - Muscarella, Lucianna
AU - Guarnieri, Vito
AU - D'Agruma, Leonardo
AU - Quattrone, Alessandro
AU - Zelante, Leopoldo
AU - Rabinowitz, Daniel
AU - Pascucci, Tiziana
AU - Puglisi-Allegra, Stefano
AU - Reichelt, Karl Ludvig
AU - Rodier, Patricia M.
AU - Persico, Antonio M.
PY - 2004/2/15
Y1 - 2004/2/15
N2 - Background: The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. Methods: We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. Results: A, and not G, alleles were associated with autism using both case-control (χ2 = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test χ2 = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. Conclusions: The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.
AB - Background: The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. Methods: We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. Results: A, and not G, alleles were associated with autism using both case-control (χ2 = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test χ2 = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. Conclusions: The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.
KW - Autistic disorder
KW - Cranial circumference
KW - Homeobox
KW - Macrocephaly
KW - Megalencephaly
KW - Pervasive developmental disorders
UR - http://www.scopus.com/inward/record.url?scp=10744221938&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=10744221938&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2003.10.005
DO - 10.1016/j.biopsych.2003.10.005
M3 - Article
C2 - 14960295
AN - SCOPUS:10744221938
SN - 0006-3223
VL - 55
SP - 413
EP - 419
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 4
ER -