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Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations
Genome-wide association studies have confirmed the polygenic nature of schizophrenia and suggest that there are hundreds or thousands of alleles associated with increased liability for the disorder. However, the generalizability of any one allelic marker of liability is remarkably low and has bred t...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438037/ https://www.ncbi.nlm.nih.gov/pubmed/28221366 http://dx.doi.org/10.1038/tp.2017.8 |
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author | Liu, C Bousman, C A Pantelis, C Skafidas, E Zhang, D Yue, W Everall, I P |
author_facet | Liu, C Bousman, C A Pantelis, C Skafidas, E Zhang, D Yue, W Everall, I P |
author_sort | Liu, C |
collection | PubMed |
description | Genome-wide association studies have confirmed the polygenic nature of schizophrenia and suggest that there are hundreds or thousands of alleles associated with increased liability for the disorder. However, the generalizability of any one allelic marker of liability is remarkably low and has bred the notion that schizophrenia may be better conceptualized as a pathway(s) disorder. Here, we empirically tested this notion by conducting a pathway-wide association study (PWAS) encompassing 255 experimentally validated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways among 5033 individuals diagnosed with schizophrenia and 5332 unrelated healthy controls across three distinct ethnic populations; European-American (EA), African-American (AA) and Han Chinese (CH). We identified 103, 74 and 87 pathways associated with schizophrenia liability in the EA, CH and AA populations, respectively. About half of these pathways were uniquely associated with schizophrenia liability in each of the three populations. Five pathways (serotonergic synapse, ubiquitin mediated proteolysis, hedgehog signaling, adipocytokine signaling and renin secretion) were shared across all three populations and the single-nucleotide polymorphism sets representing these five pathways were enriched for single-nucleotide polymorphisms with regulatory function. Our findings provide empirical support for schizophrenia as a pathway disorder and suggest schizophrenia is not only a polygenic but likely also a poly-pathway disorder characterized by both genetic and pathway heterogeneity. |
format | Online Article Text |
id | pubmed-5438037 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-54380372017-06-01 Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations Liu, C Bousman, C A Pantelis, C Skafidas, E Zhang, D Yue, W Everall, I P Transl Psychiatry Original Article Genome-wide association studies have confirmed the polygenic nature of schizophrenia and suggest that there are hundreds or thousands of alleles associated with increased liability for the disorder. However, the generalizability of any one allelic marker of liability is remarkably low and has bred the notion that schizophrenia may be better conceptualized as a pathway(s) disorder. Here, we empirically tested this notion by conducting a pathway-wide association study (PWAS) encompassing 255 experimentally validated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways among 5033 individuals diagnosed with schizophrenia and 5332 unrelated healthy controls across three distinct ethnic populations; European-American (EA), African-American (AA) and Han Chinese (CH). We identified 103, 74 and 87 pathways associated with schizophrenia liability in the EA, CH and AA populations, respectively. About half of these pathways were uniquely associated with schizophrenia liability in each of the three populations. Five pathways (serotonergic synapse, ubiquitin mediated proteolysis, hedgehog signaling, adipocytokine signaling and renin secretion) were shared across all three populations and the single-nucleotide polymorphism sets representing these five pathways were enriched for single-nucleotide polymorphisms with regulatory function. Our findings provide empirical support for schizophrenia as a pathway disorder and suggest schizophrenia is not only a polygenic but likely also a poly-pathway disorder characterized by both genetic and pathway heterogeneity. Nature Publishing Group 2017-02 2017-02-21 /pmc/articles/PMC5438037/ /pubmed/28221366 http://dx.doi.org/10.1038/tp.2017.8 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Liu, C Bousman, C A Pantelis, C Skafidas, E Zhang, D Yue, W Everall, I P Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations |
title | Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations |
title_full | Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations |
title_fullStr | Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations |
title_full_unstemmed | Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations |
title_short | Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations |
title_sort | pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438037/ https://www.ncbi.nlm.nih.gov/pubmed/28221366 http://dx.doi.org/10.1038/tp.2017.8 |
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