Evolutionary Insights into the “Population-Specificity” of the Genetic Factors Associated with Inflammatory Bowel Diseases

Inflammatory bowel disease (IBD) – a generic term for Crohn’s disease (CD) and ulcerative colitis (UC) – represents great risks for inheritance, such as high sibling recurrent risks (┣s in CD and UC: 20-35 and 8-15) and high monozygotic concordance rates (50% to 60%). Recent genome-wide association studies (GWAS) have successfully identified many causative genes (risk variants) for IBD. These discoveries highlight the importance of autophagy and innate immunity as determinants of dysregulated host-commensal bacteria interactions in the intestine. Some of the risk-variants are shared between CD and UC, indicating both similarities and differences in their etiologies. Most of the IBD risk-variants, however, have been reported in European-ancestry populations, and these associations are not always reproduced in non-European ancestry populations, suggesting a population-specific susceptibility to IBD. In fact, some of the IBD risk variants showed no association with CD and UC in East Asians. Hence, IBD’s causative factors should be defined as genetically different between Europeans and East Asians; it is essential that we expand GWAS into nonEuropean populations so as to unravel the causes of its population-specific susceptibility and identify IBD risk variants in each geographic population. It is widely an accepted idea that the risk variants of complex diseases, including IBD, are retained not only in patients, but also in healthy controls. Because the risk variants spread prevalently into geographically diverse populations, it is plausible that their origins could be dated before Homo sapiens’ expansion out of Africa; that is, the fate of risk variants must be affected by human population history, such as demography, migration and natural selection. Here, we suggest that an evolutionary perspective of IBD genomics could provide essential clues for resolving significant questions: (1) Do the risk-variants have similar allele frequencies in different populations? (2) How are the risk-variants prevalent in human populations? (3) What factors can cause the inconsistency of GWAS-results across geographic populations? In this chapter, we first provide an overview of the evolutionary characteristics of disease-causative variants in Mendelian diseases and complex diseases. Secondly, we review the recent progress of IBD genetic/genomic studies among both European and East Asian populations. Finally, we discuss the evolutionary consequences of population-specific susceptibility to IBD and the importance of its use for diverse human populations in the future of GWAS.