Adenosine deaminase alleles and autistic disorder: Case-control and family-based association studies

Adenosine deaminase (ADA) plays a relevant role in purine metabolism, immun e responses, and peptidase activity, which may be altered in some autistic patients. Codominant ADA1 and ADA2 alleles code for ADA1 and ADA2 allozymes , the most frequent protein isoforms in the general population. Individuals carrying one copy of the ADA2 allele display 15 to 20% lower catalytic act ivity compared to ADA1 homozygotes. Recent preliminary data suggest that AD A2 alleles may be more frequent among autistic patients than healthy contro ls. The present study was undertaken to replicate these findings in a new c ase-control study, to test for linkage/association using a family-based des ign, and to characterize ADA2-carrying patients by serotonin blood levels, peptiduria, and head circumference. ADA2 alleles were significantly more fr equent in 91 Caucasian autistic patients of Italian descent than in 152 una ffected controls (17.6% vs. 7.9%, P = 0.018), as well as among their father s. Family-based tests involving these 91 singleton families, as well as 44 additional Caucasian-American trios, did not support significant linkage/as sociation. However, the observed preferential maternal transmission of ADA2 alleles, if replicated, may point toward linkage disequilibrium between th e ADA2 polymorphism and an imprinted gene variant located in its vicinity. Racial and ethnic differences in ADA allelic distributions, together with t he low frequency of the ADA2 allele, may pose methodological problems to fu ture linkage/association studies. Direct assessments of ADA catalytic activ ity in autistic individuals and unaffected siblings carrying ADA1/ADA1 vs A DA1/ADA2 genotypes may provide stronger evidence of ADA2 contributions to a utistic disorder. 2000 Wiley-Liss, Inc.