An efficient, robust and unified method for mapping complex traits (III): combined linkage/linkage-disequilibrium analysis.

Extending the method for linkage analysis [Zhao et al., 1998a: Am. J. Med. Genet. 77:366-383; 1998b: Am. J. Med. Genet. 79:49-61], this article describes a method for the linkage-disequilibrium analysis, and for combining linkage and linkage-disequilibrium analyses. As highly dense markers are increasingly used in genome scans, one or more markers are not only linked with the disease genes if they exist, but also likely in linkage-disequilibrium with those putative genes. Hence, linkage-disequilibrium analysis potentially offers additional information about positions of putative disease genes. Combining both linkage and linkage-disequilibrium signals, this approach is able to improve positional signals. As before, the proposed method is a model-based approach, but semiparametric via the estimating equation technique. Under the assumptions of penetrance and allele frequency, this method efficiently estimates recombination fractions for linkage analysis and odds ratios for linkage-disequilibrium analysis. As described in two previous papers, this method is relatively more robust than the lod score methods, since it requires weaker assumption than conditional independence. While the estimated recombination fractions are used for inference as part of linkage analysis, the estimated odds ratios are used for linkage-disequilibrium inference and combined linkage, and linkage-disequilibrium parameters can be used to test combined linkage/linkage-disequilibrium analysis. This approach has been implemented, named gSCAN, and its compiled version is available for trial on request via the web site (http:/lynx.fhcrc.org/qge). We applied this new approach to affected sib-pair data collected for the genome scan to localize type 1 diabetes genes. Under an assumed autosomal dominant gene model, the linkage analysis confirms an earlier suggestion of one major gene around D6S281. Interestingly, the linkage-disequilibrium analysis suggests several additional signals around D6S250, GATA30, D6S311, D6S441, D6S442, D6S415, D6S411, D6S305, and a290xh9. The linkage analysis, on the other hand, suggests a signal around D6S281, while providing supporting evidence for several other marker loci. However, the combined analysis did not provide strong support for any of the findings, implying that linkage and linkage-disequilibrium findings are not consistent.

Zhao LP ，Quiaoit F ，Aragaki C ，Hsu L ... -  《american journal of medical genetics》

Combined linkage and linkage disequilibrium mapping for genome screens.

Linkage analysis and association studies, two major approaches for genetic studies of human diseases, are useful for mapping genes that are highly penetrant, but both use only part of the information that is available for mapping disease genes. Therefore, they provide limited utility when used alone. In this report, we present combined linkage and linkage disequilibrium mapping that simultaneously utilizes linkage and linkage disequilibrium information for mapping human disease genes. Compared with the existing linkage analysis and association study methods, this method has several advantages: 1) it has high statistical power by a joint analysis of linkage and linkage disequilibrium for localizing disease susceptibility loci: 2) it unifies the theory of linkage analysis and linkage disequilibrium mapping, 3) it retains the general framework for linkage analysis and, hence, can be easily incorporated into the existing software for the linkage analysis. The proposed LLDM is applied to familial hemophagocytic lymphohistiocytosis (FHL) disease.

Xiong M ，Jin L 《GENETIC EPIDEMIOLOGY》

Combined high resolution linkage and association mapping of quantitative trait loci.

In this paper, we investigate variance component models of both linkage analysis and high resolution linkage disequilibrium (LD) mapping for quantitative trait loci (QTL). The models are based on both family pedigree and population data. We consider likelihoods which utilize flanking marker information, and carry out an analysis of model building and parameter estimations. The likelihoods jointly include recombination fractions, LD coefficients, the average allele substitution effect and allele dominant effect as parameters. Hence, the model simultaneously takes care of the linkage, LD or association and the effects of the putative trait locus. The models clearly demonstrate that linkage analysis and LD mapping are complementary, not exclusive, methods for QTL mapping. By power calculations and comparisons, we show the advantages of the proposed method: (1) population data can provide information for LD mapping, and family pedigree data can provide information for both linkage analysis and LD mapping; (2) using family pedigree data and a sparse marker map, one may investigate the prior suggestive linkage between trait locus and markers to obtain low resolution of the trait loci, because linkage analysis can locate a broad candidate region; (3) with the prior knowledge of suggestive linkage from linkage analysis, both population and family pedigree data can be used simultaneously in high resolution LD mapping based on a dense marker map, since LD mapping can increase the resolution for candidate regions; (4) models of high resolution LD mappings using two flanking markers have higher power than that of models of using only one marker in the analysis; (5) excluding the dominant variance from the analysis when it does exist would lose power; (6) by performing linkage interval mappings, one may get higher power than by using only one marker in the analysis.

Fan R ，Xiong M 《EUROPEAN JOURNAL OF HUMAN GENETICS》

Multipoint linkage disequilibrium mapping using multilocus allele frequency data.

Johnson T 《ANNALS OF HUMAN GENETICS》

Transmission/disequilibrium tests for quantitative traits.

Spielman et al. [1993] proposed a transmission-disequilibrium test (TDT), based on marker data collected on affected offspring and their parents, to test for linkage between a genetic marker and a binary trait provided there is allelic association. It has been shown that this TDT is powerful and is not affected by allelic association due to population stratification in the absence of linkage. For quantitative traits, George and Elston [1987] proposed a likelihood method to detect the effect of a candidate gene in pedigree data when familial correlations are present. This test will detect allelic association but will do so in the absence of linkage. In this paper, we investigate two new likelihood-ratio test statistics for multi-generational quantitative traits to test either for linkage in the presence of allelic association or for allelic association in the presence of linkage, such as may be due to linkage disequilibrium. We compare these two tests analytically and by simulation with respect to 1) the sample size required for the asymptotic null distributions to be valid and 2) their power to detect association in those cases in which they are not sensitive to population stratification unless linkage is present. In general, 80 nuclear families with two children each and at least one heterozygous parent, or the equivalent number of children in large pedigrees, are enough for the asymptotic null distribution of the proposed conditional and TDT methods to be valid. The theoretical power is close to the simulated power except for the case of a recessive allele with low frequency. A sampling strategy is proposed that dramatically improves power.

Zhu X ，Elston RC 《GENETIC EPIDEMIOLOGY》