The quest for genetic risk factors for Crohn\u27s disease in the post-GWAS era

Multiple genome-wide association studies (GWASs) and two large scale meta-analyses have been performed for Crohn\u27s disease and have identified 71 susceptibility loci. These findings have contributed greatly to our current understanding of the disease pathogenesis. Yet, these loci only explain approximately 23% of the disease heritability. One of the future challenges inthis post-GWAS era is to identify potential sources of the remaining heritability. Such sources may include common variants with limited effect size, rare variants with higher effect sizes, structural variations, or even more complicated mechanisms such as epistatic, gene-environment and epigeneticinteractions. Here, we outline potential sources of this hidden heritability, focusing on Crohn\u27s disease and the currently available data. Wealso discuss future strategies to determine more about the heritabilitythese strategies include expanding current GWAS, fine-mapping, whole genome sequencing or exome sequencing, and using family-based approaches. Despite thecurrent limitations, such strategies may help to transfer research achievements into clinical practice and guide the improvement of preventive and therapeutic measures