Identification of epistatic SNP combinations in rheumatoid arthritis using LAMPLINK and Japanese cohorts

Genome-wide association studies have enabled the identification of important genetic factors in many trait studies. However, only a fraction of the heritability can be explained by known genetic factors, even in the most common diseases. Genetic loci combinations, or epistatic contributions expressed by combinations of single nucleotide polymorphisms (SNPs), have been argued to be one of the critical factors explaining some of the missing heritability, especially in oligogenic/polygenic diseases. Rheumatoid arthritis (RA) is a complex disease with more than 100 reported SNP associations, as well as various HLAhaplotypes and amino acids; however, many associations between RA and inter-chromosomal SNP combinations are unknown. To discover novel associations of epistatic interactions with high odds ratios in RA, we applied the LAMPLINK method, a systematic enumerative procedure for identifying high-order SNP combinations, to a Japanese RA cohort (discovery cohort; 4024 patients with RA and 7731 controls). We validated the identified associations in a different Japanese cohort (validation cohort; 810 RA patients and 6303 controls). In this study, we identified 90 significant genetic associations in the discovery cohort. Among these, 74 (82.2%) associations were replicated in the validation cohort, and eight combinations were inter-chromosomal, all of which comprised rs7765379 or rs35265698 located in the HLA region. These two SNPs exhibited strong correlations with valine at amino acid position 11 in HLA-DRB1 (HLA-DRB1-11-Val). Finally, we discovered that rs9624 showed an association with RA through an epistatic interaction with HLA-DRB1-11-Val. Overall, LAMPLINK showed high reliability for identifying epistatic genetic contributions hidden in complex traits.