Bourgain Catherine, Hoffjan Sabine, Nicolae Raluca, Newman Dina, Steiner Lori, Walker Karen, Reynolds Rebecca, Ober Carole, McPeek Mary Sara
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
Am J Hum Genet. 2003 Sep;73(3):612-26. doi: 10.1086/378208. Epub 2003 Aug 15.
To avoid problems related to unknown population substructure, association studies may be conducted in founder populations. In such populations, however, the relatedness among individuals may be considerable. Neglecting such correlations among individuals can lead to seriously spurious associations. Here, we propose a method for case-control association studies of binary traits that is suitable for any set of related individuals, provided that their genealogy is known. Although we focus here on large inbred pedigrees, this method may also be used in outbred populations for case-control studies in which some individuals are relatives. We base inference on a quasi-likelihood score (QLS) function and construct a QLS test for allelic association. This approach can be used even when the pedigree structure is far too complex to use an exact-likelihood calculation. We also present an alternative approach to this test, in which we use the known genealogy to derive a correction factor for the case-control association chi2 test. We perform analytical power calculations for each of the two tests by deriving their respective noncentrality parameters. The QLS test is more powerful than the corrected chi2 test in every situation considered. Indeed, under certain regularity conditions, the QLS test is asymptotically the locally most powerful test in a general class of linear tests that includes the corrected chi2 test. The two methods are used to test for associations between three asthma-associated phenotypes and 48 SNPs in 35 candidate genes in the Hutterites. We report a highly significant novel association (P=2.10-6) between atopy and an amino acid polymorphism in the P-selectin gene, detected with the QLS test and also, but less significantly (P=.0014), with the transmission/disequilibrium test.
为避免与未知群体亚结构相关的问题，关联研究可在奠基者群体中进行。然而，在这类群体中，个体之间的亲缘关系可能相当显著。忽视个体间的这种相关性可能导致严重的虚假关联。在此，我们提出一种用于二元性状病例对照关联研究的方法，该方法适用于任何一组已知谱系的相关个体。尽管我们在此重点关注大型近亲家系，但此方法也可用于远交群体中存在部分个体为亲属的病例对照研究。我们基于拟似然得分（QLS）函数进行推断，并构建用于等位基因关联的QLS检验。即使家系结构过于复杂而无法进行精确似然计算，这种方法也可使用。我们还提出了该检验的另一种方法，即利用已知谱系推导病例对照关联卡方检验的校正因子。我们通过推导各自的非中心参数对两种检验分别进行分析效能计算。在所考虑的每种情况下，QLS检验都比校正后的卡方检验更具效能。实际上，在某些正则条件下，QLS检验在包括校正后的卡方检验在内的一般线性检验类别中渐近地是局部最具效能的检验。这两种方法用于检验哈特派人群中三种哮喘相关表型与35个候选基因中的48个单核苷酸多态性（SNP）之间的关联。我们报告了特应性与P - 选择素基因中的一个氨基酸多态性之间存在高度显著的新型关联（P = 2.1×10⁻⁶），该关联通过QLS检验检测到，同时也通过传递/不平衡检验检测到，但显著性稍低（P = 0.0014）。
