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Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder
Metals are critical to neurodevelopment, and dysregulation in early life has been documented in autism spectrum disorder (ASD). However, underlying mechanisms and biochemical assays to distinguish ASD cases from controls remain elusive. In a nationwide study of twins in Sweden, we tested whether zin...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976276/ https://www.ncbi.nlm.nih.gov/pubmed/29854952 http://dx.doi.org/10.1126/sciadv.aat1293 |
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author | Curtin, Paul Austin, Christine Curtin, Austen Gennings, Chris Arora, Manish Tammimies, Kristiina Willfors, Charlotte Berggren, Steve Siper, Paige Rai, Dheeraj Meyering, Kristin Kolevzon, Alexander Mollon, Josephine David, Anthony S. Lewis, Glyn Zammit, Stanley Heilbrun, Lynne Palmer, Raymond F. Wright, Robert O. Bölte, Sven Reichenberg, Abraham |
author_facet | Curtin, Paul Austin, Christine Curtin, Austen Gennings, Chris Arora, Manish Tammimies, Kristiina Willfors, Charlotte Berggren, Steve Siper, Paige Rai, Dheeraj Meyering, Kristin Kolevzon, Alexander Mollon, Josephine David, Anthony S. Lewis, Glyn Zammit, Stanley Heilbrun, Lynne Palmer, Raymond F. Wright, Robert O. Bölte, Sven Reichenberg, Abraham |
author_sort | Curtin, Paul |
collection | PubMed |
description | Metals are critical to neurodevelopment, and dysregulation in early life has been documented in autism spectrum disorder (ASD). However, underlying mechanisms and biochemical assays to distinguish ASD cases from controls remain elusive. In a nationwide study of twins in Sweden, we tested whether zinc-copper cycles, which regulate metal metabolism, are disrupted in ASD. Using novel tooth-matrix biomarkers that provide direct measures of fetal elemental uptake, we developed a predictive model to distinguish participants who would be diagnosed with ASD in childhood from those who did not develop the disorder. We replicated our findings in three independent studies in the United States and the UK. We show that three quantifiable characteristics of fetal and postnatal zinc-copper rhythmicity are altered in ASD: the average duration of zinc-copper cycles, regularity with which the cycles recur, and the number of complex features within a cycle. In all independent study sets and in the pooled analysis, zinc-copper rhythmicity was disrupted in ASD cases. In contrast to controls, in ASD cases, the cycle duration was shorter (F = 52.25, P < 0.001), regularity was reduced (F = 47.99, P < 0.001), and complexity diminished (F = 57.30, P < 0.001). With two distinct classification models that used metal rhythmicity data, we achieved 90% accuracy in classifying cases and controls, with sensitivity to ASD diagnosis ranging from 85 to 100% and specificity ranging from 90 to 100%. These findings suggest that altered zinc-copper rhythmicity precedes the emergence of ASD, and quantitative biochemical measures of metal rhythmicity distinguish ASD cases from controls. |
format | Online Article Text |
id | pubmed-5976276 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-59762762018-05-31 Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder Curtin, Paul Austin, Christine Curtin, Austen Gennings, Chris Arora, Manish Tammimies, Kristiina Willfors, Charlotte Berggren, Steve Siper, Paige Rai, Dheeraj Meyering, Kristin Kolevzon, Alexander Mollon, Josephine David, Anthony S. Lewis, Glyn Zammit, Stanley Heilbrun, Lynne Palmer, Raymond F. Wright, Robert O. Bölte, Sven Reichenberg, Abraham Sci Adv Research Articles Metals are critical to neurodevelopment, and dysregulation in early life has been documented in autism spectrum disorder (ASD). However, underlying mechanisms and biochemical assays to distinguish ASD cases from controls remain elusive. In a nationwide study of twins in Sweden, we tested whether zinc-copper cycles, which regulate metal metabolism, are disrupted in ASD. Using novel tooth-matrix biomarkers that provide direct measures of fetal elemental uptake, we developed a predictive model to distinguish participants who would be diagnosed with ASD in childhood from those who did not develop the disorder. We replicated our findings in three independent studies in the United States and the UK. We show that three quantifiable characteristics of fetal and postnatal zinc-copper rhythmicity are altered in ASD: the average duration of zinc-copper cycles, regularity with which the cycles recur, and the number of complex features within a cycle. In all independent study sets and in the pooled analysis, zinc-copper rhythmicity was disrupted in ASD cases. In contrast to controls, in ASD cases, the cycle duration was shorter (F = 52.25, P < 0.001), regularity was reduced (F = 47.99, P < 0.001), and complexity diminished (F = 57.30, P < 0.001). With two distinct classification models that used metal rhythmicity data, we achieved 90% accuracy in classifying cases and controls, with sensitivity to ASD diagnosis ranging from 85 to 100% and specificity ranging from 90 to 100%. These findings suggest that altered zinc-copper rhythmicity precedes the emergence of ASD, and quantitative biochemical measures of metal rhythmicity distinguish ASD cases from controls. American Association for the Advancement of Science 2018-05-30 /pmc/articles/PMC5976276/ /pubmed/29854952 http://dx.doi.org/10.1126/sciadv.aat1293 Text en Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Curtin, Paul Austin, Christine Curtin, Austen Gennings, Chris Arora, Manish Tammimies, Kristiina Willfors, Charlotte Berggren, Steve Siper, Paige Rai, Dheeraj Meyering, Kristin Kolevzon, Alexander Mollon, Josephine David, Anthony S. Lewis, Glyn Zammit, Stanley Heilbrun, Lynne Palmer, Raymond F. Wright, Robert O. Bölte, Sven Reichenberg, Abraham Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder |
title | Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder |
title_full | Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder |
title_fullStr | Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder |
title_full_unstemmed | Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder |
title_short | Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder |
title_sort | dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976276/ https://www.ncbi.nlm.nih.gov/pubmed/29854952 http://dx.doi.org/10.1126/sciadv.aat1293 |
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