Association between cord blood metabolites in tryptophan pathway and childhood risk of autism spectrum disorder and attention-deficit hyperactivity disorder

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Abstract

Alterations in tryptophan and serotonin have been implicated in various mental disorders; but studies are limited on child neurodevelopmental disabilities such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). This prospective cohort study examined the associations between levels of tryptophan and select metabolites (5-methoxytryptophol (5-MTX), 5-hydroxytryptophan (5-HTP), serotonin, N-acetyltrytophan) in cord plasma (collected at birth) and physician-diagnosed ASD, ADHD and other developmental disabilities (DD) in childhood. The study sample ( n = 996) derived from the Boston Birth Cohort, which included 326 neurotypical children, 87 ASD, 269 ADHD, and 314 other DD children (mutually exclusive). These participants were enrolled at birth and followed-up prospectively (from October 1, 1998 to June 30, 2018) at the Boston Medical Center. Higher levels of cord 5-MTX was associated with a lower risk of ASD (aOR: 0.56, 95% CI: 0.41, 0.77) and ADHD (aOR: 0.79, 95% CI: 0.65, 0.96) per Z-score increase, after adjusting for potential confounders. Similarly, children with cord 5-MTX ≥ 25th percentile (vs. <25th percentile) had a reduction in ASD (aOR: 0.27, 95% CI: 0.14, 0.49) and ADHD risks (aOR: 0.45, 95% CI: 0.29, 0.70). In contrast, higher levels of cord tryptophan, 5-HTP and N-acetyltryptophan were associated with higher risk of ADHD, with aOR: 1.25, 95% CI: 1.03, 1.51; aOR: 1.32, 95% CI: 1.08, 1.61; and aOR: 1.27, 95% CI: 1.05, 1.53, respectively, but not with ASD and other DD. Cord serotonin was not associated with ASD, ADHD, and other DD. Most findings remained statistically significant in the sensitivity and subgroup analyses.

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Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level has been reported in individuals with autism spectrum disorders (ASD), but the underlying cause of this deficit was unknown. The ASMT gene, encoding the last enzyme of melatonin synthesis, is located on the pseudo-autosomal region 1 of the sex chromosomes, deleted in several individuals with ASD. In this study, we sequenced all ASMT exons and promoters in individuals with ASD (n=250) and compared the allelic frequencies with controls (n=255). Non-conservative variations of ASMT were identified, including a splicing mutation present in two families with ASD, but not in controls. Two polymorphisms located in the promoter (rs4446909 and rs5989681) were more frequent in ASD compared to controls (P=0.0006) and were associated with a dramatic decrease in ASMT transcripts in blood cell lines (P=2 x 10(-10)). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (P=2 x 10(-12)) and melatonin level (P=3 x 10(-11)) in individuals with ASD. These results indicate that a low melatonin level, caused by a primary deficit in ASMT activity, is a risk factor for ASD. They also support ASMT as a susceptibility gene for ASD and highlight the crucial role of melatonin in human cognition and behavior.

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Author and article information

Contributors

Xiaobin Wang:

ORCID: http://orcid.org/0000-0003-4451-302X

xwang82@jhu.edu

Journal

Journal ID (nlm-ta): Transl Psychiatry

Journal ID (iso-abbrev): Transl Psychiatry

Title: Translational Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2158-3188

Publication date (Electronic): 9 July 2022

Publication date PMC-release: 9 July 2022

Publication date Collection: 2022

Volume: 12

Electronic Location Identifier: 270

Affiliations

[1 ]GRID grid.21107.35, ISNI 0000 0001 2171 9311, Center on Early Life Origins of Disease, Department of Population, Family and Reproductive Health, , Johns Hopkins University Bloomberg School of Public Health, ; Baltimore, MD USA

[2 ]GRID grid.189504.1, ISNI 0000 0004 1936 7558, Department of Pediatrics, , Boston University School of Medicine and Boston Medical Center, ; Boston, MA USA

[3 ]Department of Biomedical Sciences & Pathobiology, Fralin Life Sciences Institute at Virginia Technology, Blacksburg, VA USA

[4 ]GRID grid.21107.35, ISNI 0000 0001 2171 9311, Department of Pediatrics, , Johns Hopkins University School of Medicine, ; Baltimore, MD USA

Author information

Xiaobin Wang http://orcid.org/0000-0003-4451-302X

Article

Publisher ID: 1992

DOI: 10.1038/s41398-022-01992-0

PMC ID: 9271093

PubMed ID: 35810183

SO-VID: f90804ed-1384-4623-b5f8-230446d8758b

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 11 January 2022

Date revision received : 20 May 2022

Date accepted : 25 May 2022

Funding

Funded by: FundRef https://doi.org/10.13039/100000102, U.S. Department of Health & Human Services | Health Resources and Services Administration (Health Resources & Services Administration);

Award ID: R40MC27443

Award ID: UJ2MC31074

Award Recipient : Xiaobin Wang

Funded by: U.S. Department of Health & Human Services | Health Resources and Services Administration (Health Resources & Services Administration)

Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);

Award ID: R21AI079872

Award ID: R01HD086013

Award Recipient : Xiaobin Wang

Funded by: U.S. Department of Health & Human Services | National Institutes of Health (NIH)