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Maternal mid-gestational and child cord blood immune signatures are strongly associated with offspring risk of ASD

Molecular Psychiatry volume 27, pages 1527–1541 (2022)Cite this article

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Abstract

Epidemiological studies and work in animal models indicate that immune activation may be a risk factor for autism spectrum disorders (ASDs). We measured levels of 60 cytokines and growth factors in 869 maternal mid-gestational (MMG) and 807 child cord blood (CB) plasma samples from 457 ASD (385 boys, 72 girls) and 497 control children (418 boys, 79 girls) from the Norwegian Autism Birth Cohort. We analyzed associations first using sex-stratified unadjusted and adjusted logistic regression models, and then employed machine learning strategies (LASSO + interactions, Random Forests, XGBoost classifiers) with cross-validation and randomly sampled test set evaluation to assess the utility of immune signatures as ASD biomarkers. We found prominent case–control differences in both boys and girls with alterations in a wide range of analytes in MMG and CB plasma including but not limited to IL1RA, TNFα, Serpin E1, VCAM1, VEGFD, EGF, CSF1, and CSF2. MMG findings were most striking, with particularly strong effect sizes in girls. Models did not change appreciably upon adjustment for maternal conditions, medication use, or emotional distress ratings. Findings were corroborated using machine learning approaches, with area under the receiver operating characteristic curve values in the test sets ranging from 0.771 to 0.965. Our results are consistent with gestational immunopathology in ASD, may provide insights into sex-specific differences, and have the potential to lead to biomarkers for early diagnosis.

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Fig. 1
Fig. 2: Autism spectrum disorders (ASDs) predictive modeling.

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Acknowledgements

We dedicate this paper to the memory of Sir Michael (Mike) Rutter, a dear friend and pioneer in autism and child psychiatry research, who helped build the ABC. We thank Wai Hung Wong, Nina Deoras, Parisa Zolfaghari, and Shobun Baile for laboratory analyses, Joy Ukaigwe for data preparation, Meredith Eddy for project coordination, and Kelly Magnus for assistance with manuscript preparation. We are grateful to the families in Norway participating in MoBa and the ABC study. This work was supported by National Institutes of Health grants NS047537 and NS086122, the Jane Botsford Johnson foundation, the Korein Foundation, the Simons Foundation Autism Research Initiative, the Norwegian Ministry of Health and Care Services, the Norwegian Ministry of Education and Research, and Research Council of Norway grants 189457, 190694, and 196452. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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  1. These authors contributed equally: Xiaoyu Che, Mady Hornig.

Authors and Affiliations

  1. Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA

    Xiaoyu Che & W. Ian Lipkin

  2. Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA

    Xiaoyu Che

  3. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

    Mady Hornig, Michaeline Bresnahan, Ezra Susser & W. Ian Lipkin

  4. New York State Psychiatric Institute, New York, NY, USA

    Michaeline Bresnahan & Ezra Susser

  5. Norwegian Institute of Public Health, Oslo, Norway

    Camilla Stoltenberg, Per Magnus, Pål Surén, Siri Mjaaland & Ted Reichborn-Kjennerud

  6. Department of Global Public Health, University of Bergen, Bergen, Norway

    Camilla Stoltenberg

  7. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Ted Reichborn-Kjennerud

  8. Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA

    W. Ian Lipkin

  9. Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA

    W. Ian Lipkin

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Contributions

CS, ES, MB, MH, PM, and WIL developed the experimental design. MH directed cytokine assays. XC directed statistical analyses. WIL and XC wrote the manuscript. CS, ES, MB, MH, PM, PS, SM, TR-K, and WIL contributed to the data analysis, edited, and approved the manuscript.

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Correspondence to Ezra Susser or W. Ian Lipkin.

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Che, X., Hornig, M., Bresnahan, M. et al. Maternal mid-gestational and child cord blood immune signatures are strongly associated with offspring risk of ASD. Mol Psychiatry 27, 1527–1541 (2022). https://doi.org/10.1038/s41380-021-01415-4

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