A genome-wide association study identifying RAP1A as a novel susceptibility gene for Crohn's disease in Japanese individuals.

Background and Aims: Genome-wide association studies (GWASs) of European populations have identified numerous susceptibility loci for Crohn's disease (CD). Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array (JPA) and subsequent imputation with the 1KJPN reference panel.

Methods: Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population followed by a meta-analysis. Two additional replication sets (254 + 516 CD patients and 287 + 565 controls) were analysed for top hit SNPs from novel genomic regions.

Results: Genotype data of 4,335,144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10-26, odds ratio [OR] = 2.10), HLA-DQB1 (rs184950714, Pmeta = 3.56 × 10-19, OR = 2.05), ZNF365 and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci (P < 1 × 10-6), and rs488200 located upstream of RAP1A was significantly associated with CD (Pcombined = 4.36 × 10-8, OR = 1.31). Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression.

Conclusion: RAP1A is a novel susceptibility locus for CD in the Japanese population.