Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut and VA CT Healthcare Center 116A2, 950 Campbell Avenue, West Haven, CT, USA.
Hum Genet. 2013 Apr;132(4):397-403. doi: 10.1007/s00439-012-1255-2. Epub 2012 Dec 13.
Genetic heterogeneity could reduce the power of linkage analysis to detect risk loci for complex traits such as alcohol dependence (AD). Previously, we performed a genomewide linkage analysis for AD in African-Americans (AAs) (Biol Psychiatry 65:111-115, 2009). The power of that linkage analysis could have been reduced by the presence of genetic heterogeneity owing to differences in admixture among AA families. We hypothesized that by examining a study sample whose genetic ancestry was more homogeneous, we could increase the power to detect linkage. To test this hypothesis, we performed ordered subset linkage analysis in 384 AA families using admixture proportion as a covariate to identify a more homogeneous subset of families and determine whether there is increased evidence for linkage with AD. Statistically significant increases in lod scores in subsets relative to the overall sample were identified on chromosomes 4 (P = 0.0001), 12 (P = 0.021), 15 (P = 0.026) and 22 (P = 0.0069). In a subset of 44 families with African ancestry proportions ranging from 0.858 to 0.996, we observed a genomewide significant linkage at 180 cM on chromosome 4 (lod = 4.24, pointwise P < 0.00001, empirical genomewide P = 0.008). A promising candidate gene located there, GLRA3, which encodes a subunit of the glycine neurotransmitter receptor. Our results demonstrate that admixture proportion can be used as a covariate to reduce genetic heterogeneity and enhance the detection of linkage for AD in an admixed population such as AAs. This approach could be applied to any linkage analysis for complex traits conducted in an admixed population.
遗传异质性可能会降低连锁分析检测复杂性状（如酒精依赖症（AD））风险基因座的能力。此前，我们对非洲裔美国人（AA）的 AD 进行了全基因组连锁分析（Biol Psychiatry 65:111-115, 2009）。由于 AA 家族之间的混合差异，这种连锁分析的效力可能会降低遗传异质性。我们假设通过检查遗传背景更同质的研究样本，可以提高检测连锁的能力。为了验证这一假设，我们使用混合比例作为协变量，对 384 个 AA 家族进行有序子集连锁分析，以确定更同质的家族子集，并确定 AD 与连锁的关联是否有增加的证据。与总体样本相比，在染色体 4（P = 0.0001）、12（P = 0.021）、15（P = 0.026）和 22（P = 0.0069）上，亚组的 lod 评分有统计学意义的增加。在非洲裔祖先比例范围为 0.858 至 0.996 的 44 个家族的子集中，我们观察到染色体 4 上 180 cM 处存在全基因组显著连锁（lod = 4.24，单点 P < 0.00001，经验全基因组 P = 0.008）。位于该处的一个有希望的候选基因 GLRA3，它编码甘氨酸神经递质受体的一个亚基。我们的结果表明，混合比例可以作为协变量来降低遗传异质性，并增强在混合人群（如 AA）中 AD 的连锁检测。这种方法可应用于在混合人群中进行的任何复杂性状的连锁分析。
