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Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder
BACKGROUND: Bipolar disorder (BD) affects both sexes, but important sex differences exist with respect to its symptoms and comorbidities. For example, rapid cycling (RC) is more prevalent in females, and alcohol use disorder (AUD) is more prevalent in males. We hypothesize that X chromosome variants...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902568/ https://www.ncbi.nlm.nih.gov/pubmed/31818333 http://dx.doi.org/10.1186/s13293-019-0272-4 |
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author | Jons, William A. Colby, Colin L. McElroy, Susan L. Frye, Mark A. Biernacka, Joanna M. Winham, Stacey J. |
author_facet | Jons, William A. Colby, Colin L. McElroy, Susan L. Frye, Mark A. Biernacka, Joanna M. Winham, Stacey J. |
author_sort | Jons, William A. |
collection | PubMed |
description | BACKGROUND: Bipolar disorder (BD) affects both sexes, but important sex differences exist with respect to its symptoms and comorbidities. For example, rapid cycling (RC) is more prevalent in females, and alcohol use disorder (AUD) is more prevalent in males. We hypothesize that X chromosome variants may be associated with sex-specific characteristics of BD. Few studies have explored the role of the X chromosome in BD, which is complicated by X chromosome inactivation (XCI). This process achieves “dosage compensation” for many X chromosome genes by silencing one of the two copies in females, and most statistical methods either ignore that XCI occurs or falsely assume that one copy is inactivated at all loci. We introduce new statistical methods that do not make these assumptions. METHODS: We investigated this hypothesis in 1001 BD patients from the Genetic Association Information Network (GAIN) and 957 BD patients from the Mayo Clinic Bipolar Disorder Biobank. We examined the association of over 14,000 X chromosome single nucleotide polymorphisms (SNPs) with sex-associated BD traits using two statistical approaches that account for whether a SNP may be undergoing or escaping XCI. In the “XCI-informed approach,” we fit a sex-adjusted logistic regression model assuming additive genetic effects where we coded the SNP either assuming one copy is expressed or two copies are expressed based on prior knowledge about which regions are inactivated. In the “XCI-robust approach,” we fit a logistic regression model with sex, SNP, and SNP-sex interaction effects that is flexible to whether the region is inactivated or escaping XCI. RESULTS: Using the “XCI-informed approach,” which considers only the main effect of SNP and does not allow the SNP effect to differ by sex, no significant associations were identified for any of the phenotypes. Using the “XCI-robust approach,” intergenic SNP rs5932307 was associated with BD (P = 8.3 × 10(−8)), with a stronger effect in females (odds ratio in males (OR(M)) = 1.13, odds ratio in females for a change of two allele copies (OR(W2)) = 3.86). CONCLUSION: X chromosome association studies should employ methods which account for its unique biology. Future work is needed to validate the identified associations with BD, to formally assess the performance of both approaches under different true genetic architectures, and to apply these approaches to study sex differences in other conditions. |
format | Online Article Text |
id | pubmed-6902568 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-69025682019-12-11 Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder Jons, William A. Colby, Colin L. McElroy, Susan L. Frye, Mark A. Biernacka, Joanna M. Winham, Stacey J. Biol Sex Differ Research BACKGROUND: Bipolar disorder (BD) affects both sexes, but important sex differences exist with respect to its symptoms and comorbidities. For example, rapid cycling (RC) is more prevalent in females, and alcohol use disorder (AUD) is more prevalent in males. We hypothesize that X chromosome variants may be associated with sex-specific characteristics of BD. Few studies have explored the role of the X chromosome in BD, which is complicated by X chromosome inactivation (XCI). This process achieves “dosage compensation” for many X chromosome genes by silencing one of the two copies in females, and most statistical methods either ignore that XCI occurs or falsely assume that one copy is inactivated at all loci. We introduce new statistical methods that do not make these assumptions. METHODS: We investigated this hypothesis in 1001 BD patients from the Genetic Association Information Network (GAIN) and 957 BD patients from the Mayo Clinic Bipolar Disorder Biobank. We examined the association of over 14,000 X chromosome single nucleotide polymorphisms (SNPs) with sex-associated BD traits using two statistical approaches that account for whether a SNP may be undergoing or escaping XCI. In the “XCI-informed approach,” we fit a sex-adjusted logistic regression model assuming additive genetic effects where we coded the SNP either assuming one copy is expressed or two copies are expressed based on prior knowledge about which regions are inactivated. In the “XCI-robust approach,” we fit a logistic regression model with sex, SNP, and SNP-sex interaction effects that is flexible to whether the region is inactivated or escaping XCI. RESULTS: Using the “XCI-informed approach,” which considers only the main effect of SNP and does not allow the SNP effect to differ by sex, no significant associations were identified for any of the phenotypes. Using the “XCI-robust approach,” intergenic SNP rs5932307 was associated with BD (P = 8.3 × 10(−8)), with a stronger effect in females (odds ratio in males (OR(M)) = 1.13, odds ratio in females for a change of two allele copies (OR(W2)) = 3.86). CONCLUSION: X chromosome association studies should employ methods which account for its unique biology. Future work is needed to validate the identified associations with BD, to formally assess the performance of both approaches under different true genetic architectures, and to apply these approaches to study sex differences in other conditions. BioMed Central 2019-12-09 /pmc/articles/PMC6902568/ /pubmed/31818333 http://dx.doi.org/10.1186/s13293-019-0272-4 Text en © The Author(s). 2019 Open Access This 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 Jons, William A. Colby, Colin L. McElroy, Susan L. Frye, Mark A. Biernacka, Joanna M. Winham, Stacey J. Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
title | Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
title_full | Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
title_fullStr | Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
title_full_unstemmed | Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
title_short | Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
title_sort | statistical methods for testing x chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902568/ https://www.ncbi.nlm.nih.gov/pubmed/31818333 http://dx.doi.org/10.1186/s13293-019-0272-4 |
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