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Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism

BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogene...

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Autores principales: Chen, Rui, Davis, Lea K., Guter, Stephen, Wei, Qiang, Jacob, Suma, Potter, Melissa H., Cox, Nancy J., Cook, Edwin H., Sutcliffe, James S., Li, Bingshan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361831/
https://www.ncbi.nlm.nih.gov/pubmed/28344757
http://dx.doi.org/10.1186/s13229-017-0130-3
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author Chen, Rui
Davis, Lea K.
Guter, Stephen
Wei, Qiang
Jacob, Suma
Potter, Melissa H.
Cox, Nancy J.
Cook, Edwin H.
Sutcliffe, James S.
Li, Bingshan
author_facet Chen, Rui
Davis, Lea K.
Guter, Stephen
Wei, Qiang
Jacob, Suma
Potter, Melissa H.
Cox, Nancy J.
Cook, Edwin H.
Sutcliffe, James S.
Li, Bingshan
author_sort Chen, Rui
collection PubMed
description BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-β pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13229-017-0130-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-53618312017-03-24 Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism Chen, Rui Davis, Lea K. Guter, Stephen Wei, Qiang Jacob, Suma Potter, Melissa H. Cox, Nancy J. Cook, Edwin H. Sutcliffe, James S. Li, Bingshan Mol Autism Research BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-β pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13229-017-0130-3) contains supplementary material, which is available to authorized users. BioMed Central 2017-03-21 /pmc/articles/PMC5361831/ /pubmed/28344757 http://dx.doi.org/10.1186/s13229-017-0130-3 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Chen, Rui
Davis, Lea K.
Guter, Stephen
Wei, Qiang
Jacob, Suma
Potter, Melissa H.
Cox, Nancy J.
Cook, Edwin H.
Sutcliffe, James S.
Li, Bingshan
Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism
title Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism
title_full Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism
title_fullStr Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism
title_full_unstemmed Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism
title_short Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism
title_sort leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361831/
https://www.ncbi.nlm.nih.gov/pubmed/28344757
http://dx.doi.org/10.1186/s13229-017-0130-3
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