Department of Biostatistics, University of Washington, Seattle, Washington 98195-7232, USA.
Genet Epidemiol. 2012 Jul;36(5):438-50. doi: 10.1002/gepi.21638. Epub 2012 May 2.
Genetic variants on the X-chromosome could potentially play an important role in some complex traits. However, development of methods for detecting association with X-linked markers has lagged behind that for autosomal markers. We propose methods for case-control association testing with X-chromosome markers in samples with related individuals. Our method, XM, appropriately adjusts for both correlation among relatives and male-female allele copy number differences. Features of XM include: (1) it is applicable to and computationally feasible for completely general combinations of family and case-control designs; (2) it allows for both unaffected controls and controls of unknown phenotype to be included in the same analysis; (3) it can incorporate phenotype information on relatives with missing genotype data; and (4) it adjusts for sex-specific trait prevalence values. We propose two other tests, Xχ and XW, which can also be useful in certain contexts. We derive the best linear unbiased estimator of allele frequency, and its variance, for X-linked markers. In simulation studies with related individuals, we demonstrate the power and validity of the proposed methods. We apply the methods to X-chromosome association analysis of (1) asthma in a Hutterite sample and (2) alcohol dependence in the GAW 14 COGA data. In analysis (1), we demonstrate computational feasibility of XM and the applicability of our robust variance estimator. In analysis (2), we detect significant association, after Bonferroni correction, between alcohol dependence and single nucleotide polymorphism rs979606 in the monoamine oxidases A gene, where this gene has previously been found to be associated with substance abuse and antisocial behavior.
X 染色体上的遗传变异可能在某些复杂特征中发挥重要作用。然而，用于检测与 X 连锁标记关联的方法的发展落后于常染色体标记。我们提出了在具有相关个体的样本中，使用 X 染色体标记进行病例对照关联测试的方法。我们的方法 XM 适当地调整了亲属之间的相关性和男女等位基因拷贝数差异。XM 的特点包括：（1）它适用于和计算上可行的完全通用的家族和病例对照设计组合；（2）它允许将未受影响的对照和未知表型的对照纳入同一分析；（3）它可以合并缺失基因型数据的亲属的表型信息；（4）它调整了特定性别特征的患病率值。我们提出了另外两种测试方法 Xχ 和 XW，它们在某些情况下也很有用。我们为 X 连锁标记推导了最佳线性无偏估计的等位基因频率及其方差。在具有相关个体的模拟研究中，我们证明了所提出方法的功效和有效性。我们将这些方法应用于（1）哈特派样本中的哮喘和（2）GAW 14 COGA 数据中的酒精依赖的 X 染色体关联分析。在分析（1）中，我们证明了 XM 的计算可行性和我们稳健方差估计器的适用性。在分析（2）中，我们在 Bonferroni 校正后检测到酒精依赖与单核苷酸多态性 rs979606 之间的显著关联，该基因先前已被发现与物质滥用和反社会行为有关。
