HLA-DR4 as a Risk Allele for Autism Acting in Mothers of Probands Possibly During Pregnancy
Abstract
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.
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HLA-DR4 appears at increased rates in children with autism and in their mothers.
“Multiple studies have suggested HLA-DR4 as another risk factor, appearing at increased rates in children with autism as well as their mothers (Johnson et al, 2009;Lee et al, 2006).”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Johnson et al, 2009
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Genetic Markers Association in Autism Spectrum Disorder
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Immunological and Immunogenetic Changes in Children with Autistic Disorder in Republic of Macedonia
Spiroski, M. Z. (2015) · South East European Journal of Immunology · doi:10.3889/seejim.2015.20003 · Cited by 2 · see citing works
Johnson, W. G., Buyske, S. G., Stenroos, E. S., & Lambert, G. H. (2010) · Springer eBooks · doi:10.1007/978-1-60327-921-5_9 · Cited by 2 · see citing works
Self-citationElhossiny, R. M., El-Baz, F. M., Abdelaziz, E. A., Abbass, A. A., Abdelmageed, R. I., & Raouf, B. M. A. (2023) · The Egyptian Journal of Pediatric Allergy and Immunology · doi:10.21608/ejpa.2023.294364 · Cited by 2 · see citing works
The Role of Beta−Adrenergic Receptor Blockers in Autism
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Association of MIF with Autism Spectrum Disorders
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Autism, Teratogenic Alleles, HLA-DR4, and Immune Function
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Self-citationA Subgroup Analysis of Genome-wide Association Study for Panic Disorder
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Fang, C., Sun, Y., Fan, C., & Lei, D. (2024) · Figshare · doi:10.6084/m9.figshare.26740142
Fang, C., Sun, Y., Fan, C., & Lei, D. (2024) · Figshare · doi:10.6084/m9.figshare.26740175
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Fang, C., Sun, Y., Fan, C., & Lei, D. (2024) · Figshare · doi:10.6084/m9.figshare.26740151
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Familial Co‐Aggregation of Neurodevelopmental Conditions and Childhood‐Onset Type 1 Diabetes
Liu, S., Machado, G. M., Hardiansyah, I., Gu, X., Ludvigsson, J. F., Lichtenstein, P., Guðbjörnsdóttir, S., Rietz, E. D., D'Onofrio, B. M., Larsson, H., et al. (2026) · Acta Paediatrica · doi:10.1111/apa.70732
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- Authors
- Johnson, W. G., Buyske, S., Mars, A. E., Sreenath, M., Stenroos, E. S., Williams, T. A., Stein, R., & Lambert, G. H.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- ORCID
- Buyske, Steven
- Venue
- Archives of Pediatrics & Adolescent Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2009-06-01
- Volume
- 163
- Issue
- 6
- Pages
- 542
- ISSN
- 1072-4710 (ISSN-L)
- OpenAlex
- W2169434031
- Cited by
- 77
- References
- 38
- Citations by year
- 2026: 2 · 2024: 6 · 2023: 2 · 2022: 8 · 2021: 6 · 2020: 3 · 2019: 1 · 2018: 5 · 2017: 6 · 2016: 4 · 2015: 5 · 2014: 6 · 2013: 3 · 2012: 6
- FWCI
- 3.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Pediatrics and Adolescent Medicine (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- U.S. Public Health Service (R21-44244)
- National Institute on Alcohol Abuse and Alcoholism (K25AA015346)
- National Institute of General Medical Sciences (2R25 GM55145, R25GM055145)
- National Institute of Environmental Health Sciences (P01 ES11256, P50-ES09598, P01ES011256)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- HLA-DR4, autism spectrum disorder, mother-to-child transmission, pregnancy, maternal imprinting, transmission disequilibrium, maternal grandparents, HLA class II
- MeSH terms
- Alleles, Autistic Disorder, Child, Child Development Disorders, Pervasive, Female, Gene Frequency, Genetic Testing, Genotype, HLA-DR Antigens, Humans, Male, Pregnancy, Prenatal Exposure Delayed Effects, HLA-DR4 Antigen, Linkage Disequilibrium, Odds Ratio, Case-Control Studies, Genomic Imprinting, Genetic Predisposition to Disease, HLA-DRB1 Chains
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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