Multipoint linkage disequilibrium mapping for complex diseases

Linkage disequilibrium (LD) or association studies using case-parent trios have become a common approach to locate unobserved susceptibility genes underlying complex diseases. With the availability of ever more dense marker maps, how to utilize the information carried by multiple markers simultaneously remains challenging. Recently, Liang et al. ([2001a] Am. J. Hum. Genet. 68: 937-950) proposed a multipoint LD method to estimate the location of a susceptibility gene within a framework map along with its sampling uncertainty. Two important features of this method are that 1) it uses all trios whether parents are heterozygous for a given marker or not, and 2) it provides a single test statistic for the null hypothesis of no linkage or no LD to the region, avoiding the multiple testing problem encountered when performing individual transmission disequilibrium tests (TDT) for each marker individually. In this paper, we discuss how this method can be expanded to address important issues pertaining to complex diseases in a unified fashion. These issues include, among others, gene-gene and gene-environment interactions, genetic heterogeneity, phenotypic refinement, and paternal vs. maternal transmission. We applied this method to asthmatic case-parent trios from the Collaborative Study on the Genetics of Asthma (CSGA), and found that the previous evidence for linkage and LD in a 13.6 cM region of chromosome 11 can be attributed to maternal transmission, while there was no evidence of excess paternal transmission. Furthermore, such discrepancy in preferential transmission was most evident among probands with early onset age (6 years old or younger).