The Experts below are selected from a list of 23259 Experts worldwide ranked by ideXlab platform
Stacey J. Winham - One of the best experts on this subject based on the ideXlab platform.
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Statistical methods for testing X Chromosome Variant associations: application to sex-specific characteristics of bipolar disorder
Biology of Sex Differences, 2019Co-Authors: William A. Jons, Colin L. Colby, Susan L. Mcelroy, Mark A. Frye, Joanna M. Biernacka, Stacey J. WinhamAbstract: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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Statistical methods for testing X Chromosome Variant associations: application to sex-specific characteristics of bipolar disorder
Biology of Sex Differences, 2019Co-Authors: William A. Jons, Colin L. Colby, Susan L. Mcelroy, Mark A. Frye, Joanna M. Biernacka, Stacey J. WinhamAbstract: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.
Frédéric Veyrunes - One of the best experts on this subject based on the ideXlab platform.
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Sex Chromosome quadrivalents in oocytes of the African pygmy mouse Mus minutoides that harbors non-conventional sex Chromosomes
Chromosoma, 2019Co-Authors: Frédéric Baudat, Bernard De Massy, Frédéric VeyrunesAbstract:Eutherian mammals have an extremely conserved sex-determining system controlled by highly differentiated sex Chromosomes. Females are XX and males XY, and any deviation generally leads to infertility, mainly due to meiosis disruption. The African pygmy mouse ( Mus minutoides ) presents an atypical sex determination system with three sex Chromosomes: the classical X and Y Chromosomes and a feminizing X Chromosome Variant, called X*. Thus, three types of females coexist (XX, XX*, and X*Y) that all show normal fertility. Moreover, the three Chromosomes (X and Y on one side and X* on the other side) are fused to different autosomes, which results in the inclusion of the sex Chromosomes in a quadrivalent in XX* and X*Y females at meiotic prophase. Here, we characterized the configurations adopted by these sex Chromosome quadrivalents during meiotic prophase. The XX* quadrivalent displayed a closed structure in which all homologous Chromosome arms were fully synapsed and with sufficient crossovers to ensure the reductional segregation of all Chromosomes at the first meiotic division. Conversely, the X*Y quadrivalents adopted either a closed configuration with non-homologous synapsis of the X* and Y Chromosomes or an open chain configuration in which X* and Y remained asynapsed and possibly transcriptionally silenced. Moreover, the number of crossovers was insufficient to ensure Chromosome segregation in a significant fraction of nuclei. Together, these findings raise questions about the mechanisms allowing X*Y females to have a level of fertility as good as that of XX and XX* females, if not higher.
William A. Jons - One of the best experts on this subject based on the ideXlab platform.
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Statistical methods for testing X Chromosome Variant associations: application to sex-specific characteristics of bipolar disorder
Biology of Sex Differences, 2019Co-Authors: William A. Jons, Colin L. Colby, Susan L. Mcelroy, Mark A. Frye, Joanna M. Biernacka, Stacey J. WinhamAbstract: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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Statistical methods for testing X Chromosome Variant associations: application to sex-specific characteristics of bipolar disorder
Biology of Sex Differences, 2019Co-Authors: William A. Jons, Colin L. Colby, Susan L. Mcelroy, Mark A. Frye, Joanna M. Biernacka, Stacey J. WinhamAbstract: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.
Frédéric Baudat - One of the best experts on this subject based on the ideXlab platform.
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Sex Chromosome quadrivalents in oocytes of the African pygmy mouse Mus minutoides that harbors non-conventional sex Chromosomes
Chromosoma, 2019Co-Authors: Frédéric Baudat, Bernard De Massy, Frédéric VeyrunesAbstract:Eutherian mammals have an extremely conserved sex-determining system controlled by highly differentiated sex Chromosomes. Females are XX and males XY, and any deviation generally leads to infertility, mainly due to meiosis disruption. The African pygmy mouse ( Mus minutoides ) presents an atypical sex determination system with three sex Chromosomes: the classical X and Y Chromosomes and a feminizing X Chromosome Variant, called X*. Thus, three types of females coexist (XX, XX*, and X*Y) that all show normal fertility. Moreover, the three Chromosomes (X and Y on one side and X* on the other side) are fused to different autosomes, which results in the inclusion of the sex Chromosomes in a quadrivalent in XX* and X*Y females at meiotic prophase. Here, we characterized the configurations adopted by these sex Chromosome quadrivalents during meiotic prophase. The XX* quadrivalent displayed a closed structure in which all homologous Chromosome arms were fully synapsed and with sufficient crossovers to ensure the reductional segregation of all Chromosomes at the first meiotic division. Conversely, the X*Y quadrivalents adopted either a closed configuration with non-homologous synapsis of the X* and Y Chromosomes or an open chain configuration in which X* and Y remained asynapsed and possibly transcriptionally silenced. Moreover, the number of crossovers was insufficient to ensure Chromosome segregation in a significant fraction of nuclei. Together, these findings raise questions about the mechanisms allowing X*Y females to have a level of fertility as good as that of XX and XX* females, if not higher.
Joanna M. Biernacka - One of the best experts on this subject based on the ideXlab platform.
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Statistical methods for testing X Chromosome Variant associations: application to sex-specific characteristics of bipolar disorder
Biology of Sex Differences, 2019Co-Authors: William A. Jons, Colin L. Colby, Susan L. Mcelroy, Mark A. Frye, Joanna M. Biernacka, Stacey J. WinhamAbstract: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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Statistical methods for testing X Chromosome Variant associations: application to sex-specific characteristics of bipolar disorder
Biology of Sex Differences, 2019Co-Authors: William A. Jons, Colin L. Colby, Susan L. Mcelroy, Mark A. Frye, Joanna M. Biernacka, Stacey J. WinhamAbstract: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.