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William G. Johnson, MD; Steven Buyske, PhD; Audrey E. Mars, MD; Madhura Sreenath, BA; Edward S. Stenroos, BS; Tanishia A. Williams, MD, PhD; Rosanne Stein, BA; George H. Lambert, MD

Arch Pediatr Adolesc Med. 2009;163(6):542-546.

Objectives  To test whether HLA-DR4 acts in the mother, possibly during pregnancy, to contribute to the phenotype of autistic disorder in her fetus.

Design  Transmission disequilibrium testing in case mothers and maternal grandparents.

Setting  Previous studies have consistently shown increased frequency of HLA-DR4 in probands with autism and their mothers, but not their fathers. However, this has been documented only in case-control studies and not by a more direct study design to determine whether HLA-DR4 acts in mothers during pregnancy to contribute to autism in their affected offspring.

Participants  We genotyped for HLA-DR alleles in members of 31 families with parents and maternal grandparents. Probands with autism were tested using the Autism Diagnostic Observation Schedule–Western Psychological Services and Autism Diagnostic Interview, Revised. There was 80% power to detect an odds ratio of 3.6. Participants were all families from New Jersey and were similar in number to earlier studies of autism and HLA-DR4.

Outcome Measures  Analysis was by standard transmission disequilibrium testing. As a secondary test we examined the possibility of maternal imprinting.

Results  Significant transmission disequilibrium for HLA-DR4 was seen (odds ratio, 4.67; 95% confidence interval, 1.34-16.24; P = .008) for transmissions from maternal grandparents to mothers of probands, supporting a role for HLA-DR4 as an autism risk factor acting in mothers during pregnancy. Transmission disequilibrium was not seen for HLA-DR4 transmissions from parents to probands or from mothers to probands.

Conclusions  The HLA-DR4 gene may act in mothers of children with autism during pregnancy to contribute to autism in their offspring. Further studies are required to confirm these findings.

Author Affiliations: Departments of Neurology (Drs Johnson and Williams, Ms Sreenath, and Mr Stenroos) and Pediatrics (Drs Mars, Williams, and Lambert) and the Center for Childhood Neurotoxicology and Exposure Assessment (Drs Johnson, Mars, and Lambert and Mr Stenroos), University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, New Jersey; Departments of Statistics and Genetics (Dr Buyske), Rutgers University, New Brunswick, New Jersey; BioSciences Research Associates, Cambridge, Massachusetts (Ms Stein); and Center for Blood Research, Harvard University, Boston, Massachusetts (Ms Stein).

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