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...
Ausführliche Beschreibung
Autor*in: |
Jons, William A. [verfasserIn] |
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Englisch |
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2019 |
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Anmerkung: |
© The Author(s). 2019 |
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Übergeordnetes Werk: |
Enthalten in: Biology of sex differences - London : BioMed Central, 2010, 10(2019), 1 vom: 09. Dez. |
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Übergeordnetes Werk: |
volume:10 ; year:2019 ; number:1 ; day:09 ; month:12 |
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DOI / URN: |
10.1186/s13293-019-0272-4 |
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SPR031237584 |
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520 | |a 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. | ||
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10.1186/s13293-019-0272-4 doi (DE-627)SPR031237584 (SPR)s13293-019-0272-4-e DE-627 ger DE-627 rakwb eng Jons, William A. verfasserin aut Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 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. Bipolar disorder (dpeaa)DE-He213 X chromosome (dpeaa)DE-He213 Genetic association (dpeaa)DE-He213 Rapid cycling (dpeaa)DE-He213 Binge eating (dpeaa)DE-He213 Alcohol use disorder (dpeaa)DE-He213 Suicidality (dpeaa)DE-He213 X chromosome inactivation (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 X chromosome statistical analysis (dpeaa)DE-He213 Colby, Colin L. aut McElroy, Susan L. aut Frye, Mark A. aut Biernacka, Joanna M. aut Winham, Stacey J. (orcid)0000-0002-8492-9102 aut Enthalten in Biology of sex differences London : BioMed Central, 2010 10(2019), 1 vom: 09. Dez. (DE-627)642889368 (DE-600)2587352-0 2042-6410 nnns volume:10 year:2019 number:1 day:09 month:12 https://dx.doi.org/10.1186/s13293-019-0272-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2086 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019 1 09 12 |
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10.1186/s13293-019-0272-4 doi (DE-627)SPR031237584 (SPR)s13293-019-0272-4-e DE-627 ger DE-627 rakwb eng Jons, William A. verfasserin aut Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 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. Bipolar disorder (dpeaa)DE-He213 X chromosome (dpeaa)DE-He213 Genetic association (dpeaa)DE-He213 Rapid cycling (dpeaa)DE-He213 Binge eating (dpeaa)DE-He213 Alcohol use disorder (dpeaa)DE-He213 Suicidality (dpeaa)DE-He213 X chromosome inactivation (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 X chromosome statistical analysis (dpeaa)DE-He213 Colby, Colin L. aut McElroy, Susan L. aut Frye, Mark A. aut Biernacka, Joanna M. aut Winham, Stacey J. (orcid)0000-0002-8492-9102 aut Enthalten in Biology of sex differences London : BioMed Central, 2010 10(2019), 1 vom: 09. Dez. (DE-627)642889368 (DE-600)2587352-0 2042-6410 nnns volume:10 year:2019 number:1 day:09 month:12 https://dx.doi.org/10.1186/s13293-019-0272-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2086 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019 1 09 12 |
allfields_unstemmed |
10.1186/s13293-019-0272-4 doi (DE-627)SPR031237584 (SPR)s13293-019-0272-4-e DE-627 ger DE-627 rakwb eng Jons, William A. verfasserin aut Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 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. Bipolar disorder (dpeaa)DE-He213 X chromosome (dpeaa)DE-He213 Genetic association (dpeaa)DE-He213 Rapid cycling (dpeaa)DE-He213 Binge eating (dpeaa)DE-He213 Alcohol use disorder (dpeaa)DE-He213 Suicidality (dpeaa)DE-He213 X chromosome inactivation (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 X chromosome statistical analysis (dpeaa)DE-He213 Colby, Colin L. aut McElroy, Susan L. aut Frye, Mark A. aut Biernacka, Joanna M. aut Winham, Stacey J. (orcid)0000-0002-8492-9102 aut Enthalten in Biology of sex differences London : BioMed Central, 2010 10(2019), 1 vom: 09. Dez. (DE-627)642889368 (DE-600)2587352-0 2042-6410 nnns volume:10 year:2019 number:1 day:09 month:12 https://dx.doi.org/10.1186/s13293-019-0272-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2086 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019 1 09 12 |
allfieldsGer |
10.1186/s13293-019-0272-4 doi (DE-627)SPR031237584 (SPR)s13293-019-0272-4-e DE-627 ger DE-627 rakwb eng Jons, William A. verfasserin aut Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 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. Bipolar disorder (dpeaa)DE-He213 X chromosome (dpeaa)DE-He213 Genetic association (dpeaa)DE-He213 Rapid cycling (dpeaa)DE-He213 Binge eating (dpeaa)DE-He213 Alcohol use disorder (dpeaa)DE-He213 Suicidality (dpeaa)DE-He213 X chromosome inactivation (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 X chromosome statistical analysis (dpeaa)DE-He213 Colby, Colin L. aut McElroy, Susan L. aut Frye, Mark A. aut Biernacka, Joanna M. aut Winham, Stacey J. (orcid)0000-0002-8492-9102 aut Enthalten in Biology of sex differences London : BioMed Central, 2010 10(2019), 1 vom: 09. Dez. (DE-627)642889368 (DE-600)2587352-0 2042-6410 nnns volume:10 year:2019 number:1 day:09 month:12 https://dx.doi.org/10.1186/s13293-019-0272-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2086 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019 1 09 12 |
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10.1186/s13293-019-0272-4 doi (DE-627)SPR031237584 (SPR)s13293-019-0272-4-e DE-627 ger DE-627 rakwb eng Jons, William A. verfasserin aut Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 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. Bipolar disorder (dpeaa)DE-He213 X chromosome (dpeaa)DE-He213 Genetic association (dpeaa)DE-He213 Rapid cycling (dpeaa)DE-He213 Binge eating (dpeaa)DE-He213 Alcohol use disorder (dpeaa)DE-He213 Suicidality (dpeaa)DE-He213 X chromosome inactivation (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 X chromosome statistical analysis (dpeaa)DE-He213 Colby, Colin L. aut McElroy, Susan L. aut Frye, Mark A. aut Biernacka, Joanna M. aut Winham, Stacey J. (orcid)0000-0002-8492-9102 aut Enthalten in Biology of sex differences London : BioMed Central, 2010 10(2019), 1 vom: 09. Dez. (DE-627)642889368 (DE-600)2587352-0 2042-6410 nnns volume:10 year:2019 number:1 day:09 month:12 https://dx.doi.org/10.1186/s13293-019-0272-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2086 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019 1 09 12 |
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Jons, William A. misc Bipolar disorder misc X chromosome misc Genetic association misc Rapid cycling misc Binge eating misc Alcohol use disorder misc Suicidality misc X chromosome inactivation misc Sex differences misc X chromosome statistical analysis Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
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Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder Bipolar disorder (dpeaa)DE-He213 X chromosome (dpeaa)DE-He213 Genetic association (dpeaa)DE-He213 Rapid cycling (dpeaa)DE-He213 Binge eating (dpeaa)DE-He213 Alcohol use disorder (dpeaa)DE-He213 Suicidality (dpeaa)DE-He213 X chromosome inactivation (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 X chromosome statistical analysis (dpeaa)DE-He213 |
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misc Bipolar disorder misc X chromosome misc Genetic association misc Rapid cycling misc Binge eating misc Alcohol use disorder misc Suicidality misc X chromosome inactivation misc Sex differences misc X chromosome statistical analysis |
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Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
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Jons, William A. |
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Biology of sex differences |
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2019 |
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Jons, William A. Colby, Colin L. McElroy, Susan L. Frye, Mark A. Biernacka, Joanna M. Winham, Stacey J. |
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Elektronische Aufsätze |
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Jons, William A. |
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10.1186/s13293-019-0272-4 |
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title_sort |
statistical methods for testing x chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
title_auth |
Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
abstract |
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. © The Author(s). 2019 |
abstractGer |
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. © The Author(s). 2019 |
abstract_unstemmed |
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. © The Author(s). 2019 |
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title_short |
Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder |
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Colby, Colin L. McElroy, Susan L. Frye, Mark A. Biernacka, Joanna M. Winham, Stacey J. |
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