Finally, traditional family-based linkage analyses consider the consistency of within-family sharing of specific transmitted chromosomal segments among affected family members rather than the consistency or similarity of the nucleotide content of those segments across different families. As a result, such methods are fairly robust to allelic heterogeneity.68 However, not all approaches to linkage analysis are very powerful, and this is especially true for non-parametric approaches involving small families69, 70, although transmission/disequilibrium tests may have merit in the analysis of rare variants.71 In addition, linkage analysis approaches not only come with the often difficult and expensive need to sample family members, but many phenotypes may not exhibit familial aggregation, undermining the motivation to consider family-based studies10.
