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Genome-Wide Association Studies (GWAS) correlate the genotype with the phenotype, identifying the genetic variants that are linked to any particular trait or disease. In 2005, a ground-breaking successful GWAS in humans associated the complement factor H gene with age-related macular degeneration (Klein et al., 2005). Since then, many successful GWAS using genotyping arrays have been published (Manolio, 2017), but due to the lowering cost of DNA sequencing, whole genome sequencing GWAS are becoming more frequent. However, the usefulness of classical GWAS has recently been questioned in a Cell publication (Boyle et al., 2017). The authors explain that genetic variants causing a disease should be part of a pathway connected with the etiology or prognosis of the disease, and moreover, they describe the benefits of linking GWAS with cell specific gene expression data. Still, many GWAS fail to correlate a specific genetic variant with a gene or a pathway leading to disease. This is partially due to the loose definition of how to establish an association between each genetic variant (frequently in non-coding regions) and the causal gene. In addition, the size of the effect of each genetic variant in polygenic traits and low penetrance genetic diseases is difficult to accurately establish due to confounding factors such as population stratification.

One of the main weaknesses of whole genome sequencing GWAS is the fact that for every diploid (or polyploid) organism we only obtain the “haploid genome.” Due to the prevalent shortreads technology, we merge both gene copies of every chromosome into one, losing physical connections …