Supplementary Material for: Deviations from Hardy-Weinberg Equilibrium in Parental and Unaffected Sibling Genotype Data

<i>Background:</i> Genotyping error can increase both type I and II errors. In order to elucidate potential genotyping errors, data quality control often includes testing genotype data for deviations from Hardy-Weinberg Equilibrium (HWE). <i>Methods:</i> The Hardy-Weinberg Disequilibrium (HWD) coefficient and the ability to reject the null hypothesis of HWE were calculated analytically for genotype data from parents and unaffected siblings of affected probands. <i>Results:</i> Genotype data from parents and unaffected siblings display deviations from HWE when functional or markers in LD with functional locus are tested. For the parental genotype data all deviations from HWE are negative, indicating an excess of heterozygous genotypes with the strongest deviations from HWE observed for the multiplicative model. In contrast, for affected proband genotype data, there is no deviation from HWE under the multiplicative model and the deviations from HWE for the recessive model are positive. For the unaffected sibling data, patterns of deviation from HWE are similar to those observed in the proband data with the exception of the multiplicative model where the HWD coefficient although close to 0 can be either positive or negative depending on the allele frequency. <i>Conclusion:</i> Deviations from HWE in parental and unaffected sibling genotype data could be due to an association with the functional locus. However these deviations for genotypic relative risk ≤2.0 are not large and therefore the power to detect them is usually low. Testing for deviations from HWE in parental and unaffected sibling genotype data is still beneficial for quality control even though functional loci, in parental and unaffected sibling genotype data, can produce an association signal.

背景：基因分型错误可能同时增加I型错误与II型错误的发生概率。为了排查潜在的基因分型错误，数据质量控制环节通常会检测基因型数据是否偏离哈迪-温伯格平衡（Hardy-Weinberg Equilibrium, HWE）。
方法：本研究针对患病先证者的父母及其未受累同胞的基因型数据，通过解析计算得到了哈迪-温伯格不平衡（Hardy-Weinberg Disequilibrium, HWD）系数，以及拒绝HWE原假设的检验效能。
结果：当检测功能位点或与功能位点存在连锁不平衡（Linkage Disequilibrium, LD）的遗传标记时，先证者父母及未受累同胞的基因型数据会呈现出HWE偏离现象。就父母基因型数据而言，所有HWE偏离均为负值，表明杂合基因型过量；其中乘法模型下的HWE偏离程度最为显著。与之相对，患病先证者的基因型数据在乘法模型下未出现HWE偏离，而隐性模型下的HWE偏离则为正值。就未受累同胞的基因型数据而言，其HWE偏离模式与先证者数据基本一致，但乘法模型除外：尽管HWD系数接近0，但其正负性取决于等位基因频率。
结论：先证者父母及未受累同胞的基因型数据出现HWE偏离，可能源于与功能位点的关联。但当基因型相对风险≤2.0时，此类偏离幅度较小，因此检出效能通常较低。尽管先证者父母及未受累同胞的基因型数据中的功能位点可产生关联信号，但对该群体的基因型数据进行HWE偏离检测，仍有助于数据质量控制。