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Unraveling the metabolomic architecture of autism in a large Danish population-based cohort

Ottosson, Filip ; Russo, Francesco ; Abrahamsson, Anna ; MacSween, Nadia ; Courraud, Julie ; Skogstrand, Kristin ; Melander, Olle LU orcid ; Ericson, Ulrika LU ; Orho-Melander, Marju LU and Cohen, Arieh S. , et al. (2024) In BMC Medicine 22(1).
Abstract

Background: The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth. Methods: We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass... (More)

Background: The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth. Methods: We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features. Results: We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p < 0.05) and with variants near SLC22A4 and SLC22A5 (p < 5.0e − 8), coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. Conclusions: Cyclo-leucine-proline and 5-AVAB are associated with future diagnosis of autism in Danish neonates, both representing novel early biomarkers for autism. 5-AVAB is potentially modifiable and may influence carnitine homeostasis.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
5-Aminovaleric acid betaine, Autism, Cyclo-leucine-proline, Dried blood spot, Metabolome, Metabolomics, Neonatal
in
BMC Medicine
volume
22
issue
1
article number
302
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85199040789
  • pmid:39026322
ISSN
1741-7015
DOI
10.1186/s12916-024-03516-7
language
English
LU publication?
yes
id
44928dfe-99c1-4a32-9730-46e00ce7dfb2
date added to LUP
2024-08-26 13:47:02
date last changed
2024-08-27 03:00:04
@article{44928dfe-99c1-4a32-9730-46e00ce7dfb2,
  abstract     = {{<p>Background: The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth. Methods: We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features. Results: We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p &lt; 0.05) and with variants near SLC22A4 and SLC22A5 (p &lt; 5.0e − 8), coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. Conclusions: Cyclo-leucine-proline and 5-AVAB are associated with future diagnosis of autism in Danish neonates, both representing novel early biomarkers for autism. 5-AVAB is potentially modifiable and may influence carnitine homeostasis.</p>}},
  author       = {{Ottosson, Filip and Russo, Francesco and Abrahamsson, Anna and MacSween, Nadia and Courraud, Julie and Skogstrand, Kristin and Melander, Olle and Ericson, Ulrika and Orho-Melander, Marju and Cohen, Arieh S. and Grove, Jakob and Mortensen, Preben Bo and Hougaard, David M. and Ernst, Madeleine}},
  issn         = {{1741-7015}},
  keywords     = {{5-Aminovaleric acid betaine; Autism; Cyclo-leucine-proline; Dried blood spot; Metabolome; Metabolomics; Neonatal}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{BMC Medicine}},
  title        = {{Unraveling the metabolomic architecture of autism in a large Danish population-based cohort}},
  url          = {{http://dx.doi.org/10.1186/s12916-024-03516-7}},
  doi          = {{10.1186/s12916-024-03516-7}},
  volume       = {{22}},
  year         = {{2024}},
}