Fine mapping by linkage and association in nuclear family and case-control designs

This report summarizes the Genetic Analysis Workshop 14 contributions related to fine-mapping strategies, in which examining smaller regions by association with single-nucleotide polymorphisms (SNPs) can yield savings in genotyping and multiple-testing penalties. The aim of the analyses conducted in Group 7 contributions was to localize disease susceptibility loci from either the simulated or the Collaborative Study on the Genetics of Alcoholism (COGA) data within identified regions of linkage. Among the 10 contributions, most groups analyzed the simulated data, one group analyzed the COGA data only, and one group analyzed both data sets. The research questions included evaluation of new methods of analysis, as well as comparisons among alternative methods, analytic strategies, and study designs. Methods of interest included an algorithm for SNP marker ordering, a locally weighted transmission disequilibrium test statistic, a likelihood-ratio test statistic for family-based association in nuclear families, a robust test statistic for case-control association studies, and Bayesian spatial modeling methods for haplotype clustering and association. Evaluations included comparisons among confidence intervals for loci detected via linkage, effects of multiple testing adjustments and trade-offs between type I error and power, comparisons among haplotype-based (multilocus) and genotype-based (multilocus and single-locus) association analyses, and design of fine-mapping and replication studies. While several promising new approaches were identified, further development and evaluation of methods for multiple testing, regression modeling of association with multiple markers and haplotypes, and combined treatment of linkage and association data are necessary if we are to identify many of the genes that contribute to complex traits.