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 (ORM) = 1.13, odds ratio in females for a change of two allele copies (ORW2) = 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.

中文翻译：

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测试X染色体变异关联的统计方法：应用于躁郁症的性别特征。

背景技术躁郁症（BD）影响男女，但是就其症状和合并症而言存在重要的性别差异。例如，快速循环（RC）在女性中更为普遍，而酒精使用障碍（AUD）在男性中更为普遍。我们假设X染色体变异可能与BD的性别特异性特征有关。很少有研究探索X染色体在BD中的作用，而BD由于X染色体失活（XCI）而变得复杂。此过程通过沉默雌性的两个拷贝之一来实现许多X染色体基因的“剂量补偿”，并且大多数统计方法要么忽略XCI发生，要么错误地假定一个拷贝在所有位点均被灭活。我们介绍了没有做出这些假设的新统计方法。方法我们在遗传协会信息网络（GAIN）的1001名BD患者和梅奥诊所的双相情感障碍生物库中的957名BD患者中研究了这一假设。我们使用两种统计方法来检查超过14,000个X染色体单核苷酸多态性（SNP）与性别相关的BD性状的关联，这两种统计方法都说明了SNP是否正在经历或逃脱XCI。在“ XCI知悉方法”中，我们拟合了性别调整的逻辑回归模型，该模型假设了附加的遗传效应，其中我们根据关于哪些区域被灭活的先验知识对SNP进行了编码，或者假设一个副本被表达或两个副本被表达。在“ XCI稳健方法”中，我们将性别，SNP，SNP-性别相互作用效应对于该区域是灭活还是逃避XCI具有灵活性。结果使用“ XCI信息分析法”，该方法仅考虑SNP的主要作用，不允许SNP的作用因性别而异，因此未发现任何表型之间的显着相关性。使用“ XCI稳健方法”，基因间SNP rs5932307与BD（P = 8.3×10-8）相关，对女性的影响更大（男性的优势比（ORM）= 1.13，女性的优势比发生变化）两个等位基因副本（ORW2）= 3.86）。结论X染色体关联研究应采用能说明其独特生物学特性的方法。需要做进一步的工作来验证已确定的与BD的关联，以正式评估这两种方法在不同真实遗传结构下的效果，