HLA-DR4 as a Risk Allele for Autism, Acting in Mothers of Probands During Pregnancy

Background: Previous studies of HLA-DR alleles in autism have consistently shown increased frequency of HLA-DR4 in autism probands and mothers but not fathers. However, this has been documented only in case-control studies and not by a more robust study design to determine whether HLA-DR4 might act in mothers to contribute to autism in their offspring.
Objectives: To determine whether HLA-DR4, acting a mother during pregnancy, contributes to the autism phenotype in her affected offspring.
Methods: We genotyped HLA-DR alleles in members of 34 families with parents and maternal grandparents whose autism proband was tested by ADOS-WPS and ADI-R. Analysis was by standard transmission/disequilibrium testing (TDT). The present study had 80% power to detect an odds ratio of 3.6. The present families were all from New Jersey, and their number was similar to those from geographically defined areas in the earlier studies of autism and HLA-DR4.
Results: Significant transmission disequilibrium for HLA-DR4 was seen (p=.0076; Odds Ratio 4.67 [OR], 95% confidence interval of OR 1.34, 16.24) for transmissions to mothers of autism probands from maternal grandparents, supporting a role for HLA-DR4 as an autism risk factor acting in the mothers. To examine an additional explanation, that HLA-DR4 is a risk allele in probands due to maternal imprinting and mothers are necessarily enriched for DR4, we did a secondary TDT test with probands and parents. Transmission disequilibrium was not seen for HLA-DR4 transmissions from parents to probands or from mothers to probands.
Conclusions: Thus, HLA-DR4 (or a closely linked gene) may act in mothers of probands during pregnancy to contribute to autism in their offspring. Further studies are required to confirm these findings.