Genotype-stratified variance of a quantitative trait could differ in the presence of gene-gene or gene-environment interactions. Genetic markers associated with phenotypic variance are thus considered promising candidates for follow-up interaction or joint location-scale analyses. However, as in studies of main effects, the X-chromosome is routinely excluded from "whole-genome" scans due to analytical challenges. Specifically, as males carry only one copy of the X-chromosome, the inherent sex-genotype dependency could bias the trait-genotype association, through sexual dimorphism in quantitative traits with sex-specific means or variances. Here we investigate phenotypic variance heterogeneity associated with X-chromosome single nucleotide polymorphisms (SNPs) and propose valid and powerful strategies. Among those, a generalized Levene's test has adequate power and remains robust to sexual dimorphism. An alternative approach is a sex-stratified analysis but at the cost of slightly reduced power and modeling flexibility. We applied both methods to an Estonian study of gene expression quantitative trait loci (eQTL; n = 841), and two complex trait studies of height, hip, and waist circumferences, and body mass index from Multi-Ethnic Study of Atherosclerosis (MESA; n = 2,073) and UK Biobank (UKB; n = 327,393). Consistent with previous eQTL findings on mean, we found some but no conclusive evidence for cis regulators being enriched for variance association. SNP rs2681646 is associated with variance of waist circumference (p = 9.5E-07) at X-chromosome-wide significance in UKB, with a suggestive female-specific effect in MESA (p = 0.048). Collectively, an enrichment analysis using permutated UKB (p < 0.1) and MESA (p < 0.01) datasets, suggests a possible polygenic structure for the variance of human height.

中文翻译：

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包括X染色体方差异质性分析的分析策略：性状特异性多基因方差结构的证据。

在存在基因-基因或基因-环境相互作用的情况下，数量性状的基因型分层方差可能会有所不同。因此，与表型变异相关的遗传标记被认为是有希望的后续相互作用或联合位置量表分析的候选者。但是，正如对主要作用的研究一样，由于分析上的挑战，X染色体通常被排除在“整个基因组”扫描之外。具体而言，由于雄性仅携带一个X染色体拷贝，因此固有的性别基因型依赖性可能会通过具有性别特定方式或变异的定量性状中的性别二态性来偏向性状-基因型关联。在这里，我们调查与X染色体单核苷酸多态性（SNPs）相关的表型方差异质性，并提出有效且有力的策略。在这些，广义Levene检验具有足够的功效，并且对于性二态性仍然很强健。另一种方法是按性别进行分析，但要以稍微降低功能和建模灵活性为代价。我们将这两种方法应用于爱沙尼亚的基因表达定量性状基因座研究（eQTL； n = 841），以及来自多民族动脉粥样硬化研究（MESA; Ms）的两项关于身高，臀部和腰围以及体重指数的复杂性状研究。 n = 2,073）和UK Biobank（UKB; n = 327,393）。与以往关于eQTL的均值一致，我们发现了一些但没有确凿的证据表明顺式调节剂可丰富变异关联。SNP rs2681646与UKB中在X染色体范围内具有显着意义的腰围差异（p = 9.5E-07）相关，在MESA中具有暗示的女性特异性作用（p = 0.048）。总的来说，