After a genomewide screen in the Hutterites was completed, the IL4RA gene was examined as the 16p-linked susceptibility locus for asthma and atopy. Seven known variants and one novel variant, representing all nonsynonymous substitutions in the mature protein, were examined in the Hutterites; on the basis of studies in the Hutterites, outbred white, black, and Hispanic families were genotyped for selected markers. All population samples showed evidence of association to atopy or to asthma (P values.039-.0044 for atopy and. 029-.0000061 for asthma), but the alleles or haplotypes showing the strongest evidence differed between the groups. Overall, these data suggest that the IL4RA gene is an atopy- and asthma-susceptibility locus but that variation outside the coding region of the gene influences susceptibility.
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.
Most common diseases, such as asthma, type 2 diabetes, bipolar disorder, and cardiovascular disease, are known to have genetic components, but the susceptibility genes have been notoriously difficult to localize and to identify. These complex diseases likely have a large number of genetic and nongenetic risk factors that together have varying effects on phenotype. Many investigators have recommended founder populations for complex-trait mapping, with the expectation that fewer susceptibility alleles will be segregating in these restricted gene pools (Lander and Schork 1994; Wright et al. 1999; Shifman and Darvasi 2001). Some or all individuals in these populations are inbred, but often the exact relationships between all members are either unknown or not taken into account. It is tempting to use such populations for their presumed homogeneity, even in the absence of accurate pedigree information. The failure to take full pedigree information into account can either reduce the power to detect linkage (Dyer et al., in press) or inflate LOD scores (Miano et al. 2000). The failure to account for relatedness among individuals will also affect association studies. In particular, many statistical tests of association are not strictly valid, owing to the lack of true independence between individuals. Nonetheless, such populations have been used widely in association studies (e.g.,
Serotonin has been implicated in common disorders involving the central nervous, gastrointestinal, cardiovascular, and pulmonary systems. We describe the first genome-wide screen to identify quantitative trait loci (QTLs) influencing whole blood serotonin in 567 members of a single large pedigree, using a novel association-based mapping approach. We identified an association between the b3 integrin (ITGB3) Leu33Pro polymorphism on 17q21 and whole blood serotonin levels (P-value ¼ 9.8 Â 10 À5). This variant explained the evidence for linkage in this region when included as a covariate in the linkage analysis (change in LOD from 1.87 to 0.16), indicating that ITGB3 may be an important serotonin QTL.
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