Linkage analysis was the predominant statistical genetic mapping approach used for the genetic mapping of Mendelian and complex traits with familial aggregation. With the recent increased availability of exome and whole-genome sequence data, linkage analysis has been once again brought to the forefront owing to the development of power­ful methods to detect rare variants involved in disease aetiology using family-based data; such an approach has many advantages over simply using filter methods to identify causal variants.

Prof. OTT Jürg and Prof. WANG Jing from Institute of Psychology, together with LEAL Suzanne M. from Baylor College of Medicine, review the principles of linkage analysis and provide practical guidelines for carrying out linkage studies using WGS data.

This Review provides the reader with a practical guide for performing linkage analysis to identify variants that are responsible for Mendelian trait aetiology. After briefly mentioning the relative merits of linkage and association analysis, they discuss linkage algorithms and their implementations in computer programs, with a special emphasis on the use of sequence data. They then outline a step-by-step approach to successful linkage analysis using WGS data. For example, they provide general guidelines on which pedigree members to select for sequencing, as usually, for cost reasons, only a small subset of family members are sequenced. For several offspring affected with a recessive trait whose parents are related, it is best to sequence offspring before parents. However, to detect compound heterozygosity, parents need to have known genotypes. In general family pedigrees, a good rule is to sequence distantly related individuals affected with the trait of interest, but it is generally unnecessary to sequence unaffected family members.