Genetic linkage analysis in the age of whole-genome sequencing

Key Points Genetic linkage analysis can be used as a tool for estimating the genetic distance between two loci. In family data, a small recombination fraction between a hypothesized disease locus and a genetic marker is evidence of short distance between the two loci. Linkage analysis is contrasted with family-based association analysis, in which unaffected family members serve as control individuals (in family-based association tests). Single-nucleotide variants (SNVs) generated by whole-genome sequencing (WGS) can be used in linkage analysis. We describe various linkage algorithms and their properties, as well as their implementations. A detailed enumeration of the pertinent steps in linkage analysis provides a guideline for non-specialists on procedures and pitfalls. Before genome-wide association studies, linkage analysis was the primary approach used for genetic mapping of complex traits in humans. Now, with the widespread application of whole-genome sequencing (WGS), linkage analysis based on WGS data is emerging as a useful tool for the identification of susceptibility genes for human disease. This Review reiterates the main principles of linkage analysis and provides guidelines for performing linkage analysis on WGS data. For many years, linkage analysis was the primary tool used for the genetic mapping of Mendelian and complex traits with familial aggregation. Linkage analysis was largely supplanted by the wide adoption of genome-wide association studies (GWASs). However, with the recent increased use of whole-genome sequencing (WGS), linkage analysis is again emerging as an important and powerful analysis method for the identification of genes involved in disease aetiology, often in conjunction with WGS filtering approaches. Here, we review the principles of linkage analysis and provide practical guidelines for carrying out linkage studies using WGS data.