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

Filip Ottosson; Francesco Russo; Anna Abrahamsson; Nadia MacSween; Julie Courraud; Kristin Skogstrand; Olle Melander; Ulrika Ericson; Marju Orho-Melander; Arieh S. Cohen; Jakob Grove; Preben Bo Mortensen; David M. Hougaard; Madeleine Ernst

doi:10.1186/s12916-024-03516-7

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

Filip Ottosson^*, Francesco Russo, Anna Abrahamsson, Nadia MacSween, Julie Courraud, Kristin Skogstrand, Olle Melander, Ulrika Ericson, Marju Orho-Melander, Arieh S. Cohen, Jakob Grove, Preben Bo Mortensen, David M. Hougaard, Madeleine Ernst^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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 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.

Originalsprog	Engelsk
Artikelnummer	302
Tidsskrift	BMC Medicine
Vol/bind	22
Nummer	1
ISSN	1741-7015
DOI	https://doi.org/10.1186/s12916-024-03516-7
Status	Udgivet - dec. 2024

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10.1186/s12916-024-03516-7Licens: CC BY

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Ottosson, F., Russo, F., Abrahamsson, A., MacSween, N., Courraud, J., Skogstrand, K., Melander, O., Ericson, U., Orho-Melander, M., Cohen, A. S., Grove, J., Mortensen, P. B., Hougaard, D. M., & Ernst, M. (2024). Unraveling the metabolomic architecture of autism in a large Danish population-based cohort. BMC Medicine, 22(1), Artikel 302. https://doi.org/10.1186/s12916-024-03516-7

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title = "Unraveling the metabolomic architecture of autism in a large Danish population-based cohort",

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 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.",

keywords = "5-Aminovaleric acid betaine, Autism, Cyclo-leucine-proline, Dried blood spot, Metabolome, Metabolomics, Neonatal",

author = "Filip Ottosson and Francesco Russo and Anna Abrahamsson and Nadia MacSween and Julie Courraud and Kristin Skogstrand and Olle Melander and Ulrika Ericson and Marju Orho-Melander and Cohen, {Arieh S.} and Jakob Grove and Mortensen, {Preben Bo} and Hougaard, {David M.} and Madeleine Ernst",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1186/s12916-024-03516-7",

language = "English",

volume = "22",

journal = "BMC Medicine",

issn = "1741-7015",

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TY - JOUR

T1 - Unraveling the metabolomic architecture of autism in a large Danish population-based cohort

AU - Ottosson, Filip

AU - Russo, Francesco

AU - Abrahamsson, Anna

AU - MacSween, Nadia

AU - Courraud, Julie

AU - Skogstrand, Kristin

AU - Melander, Olle

AU - Ericson, Ulrika

AU - Orho-Melander, Marju

AU - Cohen, Arieh S.

AU - Grove, Jakob

AU - Mortensen, Preben Bo

AU - Hougaard, David M.

AU - Ernst, Madeleine

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

KW - 5-Aminovaleric acid betaine

KW - Autism

KW - Cyclo-leucine-proline

KW - Dried blood spot

KW - Metabolome

KW - Metabolomics

KW - Neonatal

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U2 - 10.1186/s12916-024-03516-7

DO - 10.1186/s12916-024-03516-7

M3 - Journal article

C2 - 39026322

AN - SCOPUS:85199040789

SN - 1741-7015

VL - 22

JO - BMC Medicine

JF - BMC Medicine

IS - 1

M1 - 302

ER -

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

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