Exome sequencing studies (Ng et al., 2009), which interrogate the protein coding portion of the genome, can detect rare variants, but the AD studies performed to date used arrays and have not detected any significant rare variants (Vrieze et al., 2014, Zuo et al., 2013a). One possibility for this finding is that the risk variants for AD may lie outside exons, potentially in regions of the genome which regulate gene expression (Buhler et al., 2015). Indeed, the vast majority (~88%) of GWAS findings for complex diseases are not in exons (Hindorff). The implication is that entire genes will need to be sequenced, thereby capturing variants both within and outside exons. In the past, it has been difficult to understand how risk variants located outside exons could influence disease. However, large-scale efforts have been undertaken to map the location of and better understand the role of regulatory elements in the human genome, such as the Roadmap Epigenomics Project(Kundaje et al., 2015) and the Encyclopedia of DNA Elements (ENCODE) (2012).
