TY - JOUR
T1 - A genome-wide association study reveals ARL15, a novel non-HLA susceptibility gene for rheumatoid arthritis in North Indians
AU - Negi, Sapna
AU - Juyal, Garima
AU - Senapati, Sabyasachi
AU - Prasad, Pushplata
AU - Gupta, Aditi
AU - Singh, Shalini
AU - Kashyap, Sujit
AU - Kumar, Ashok
AU - Kumar, Uma
AU - Gupta, Rajiva
AU - Kaur, Satbir
AU - Agrawal, Suraksha
AU - Aggarwal, Amita
AU - Ott, Jurg
AU - Jain, Sanjay
AU - Juyal, Ramesh C.
AU - Thelma, B. K.
PY - 2013/12
Y1 - 2013/12
N2 - Objective: Genome-wide association studies (GWAS) and their subsequent meta-analyses have changed the landscape of genetics in rheumatoid arthritis (RA) by uncovering several novel genes. Such studies are heavily weighted by samples from Caucasian populations, but they explain only a small proportion of total heritability. Our previous studies in genetically distinct North Indian RA cohorts have demonstrated apparent allelic/genetic heterogeneity between North Indian and Western populations, warranting GWAS in non-European populations. We undertook this study to detect additional disease-associated loci that may be collectively important in the presence or absence of genes with a major effect. Methods: High-quality genotypes for >600,000 single-nucleotide polymorphisms (SNPs) in 706 RA patients and 761 controls from North India were generated in the discovery stage. Twelve SNPs showing suggestive association (P < 5 × 10-5) were then tested in an independent cohort of 927 RA patients and 1,148 controls. Additional disease-associated loci were determined using support vector machine (SVM) analyses. Fine-mapping of novel loci was performed by using imputation. Results: In addition to the expected association of the HLA locus with RA, we identified association with a novel intronic SNP of ARL15 (rs255758) on chromosome 5 (Pcombined = 6.57 × 10 -6; odds ratio 1.42). Genotype-phenotype correlation by assaying adiponectin levels demonstrated the functional significance of this novel gene in disease pathogenesis. SVM analysis confirmed this association along with that of a few more replication stage genes. Conclusion: In this first GWAS of RA among North Indians, ARL15 emerged as a novel genetic risk factor in addition to the classic HLA locus, which suggests that population-specific genetic loci as well as those shared between Asian and European populations contribute to RA etiology. Furthermore, our study reveals the potential of machine learning methods in unraveling gene-gene interactions using GWAS data.
AB - Objective: Genome-wide association studies (GWAS) and their subsequent meta-analyses have changed the landscape of genetics in rheumatoid arthritis (RA) by uncovering several novel genes. Such studies are heavily weighted by samples from Caucasian populations, but they explain only a small proportion of total heritability. Our previous studies in genetically distinct North Indian RA cohorts have demonstrated apparent allelic/genetic heterogeneity between North Indian and Western populations, warranting GWAS in non-European populations. We undertook this study to detect additional disease-associated loci that may be collectively important in the presence or absence of genes with a major effect. Methods: High-quality genotypes for >600,000 single-nucleotide polymorphisms (SNPs) in 706 RA patients and 761 controls from North India were generated in the discovery stage. Twelve SNPs showing suggestive association (P < 5 × 10-5) were then tested in an independent cohort of 927 RA patients and 1,148 controls. Additional disease-associated loci were determined using support vector machine (SVM) analyses. Fine-mapping of novel loci was performed by using imputation. Results: In addition to the expected association of the HLA locus with RA, we identified association with a novel intronic SNP of ARL15 (rs255758) on chromosome 5 (Pcombined = 6.57 × 10 -6; odds ratio 1.42). Genotype-phenotype correlation by assaying adiponectin levels demonstrated the functional significance of this novel gene in disease pathogenesis. SVM analysis confirmed this association along with that of a few more replication stage genes. Conclusion: In this first GWAS of RA among North Indians, ARL15 emerged as a novel genetic risk factor in addition to the classic HLA locus, which suggests that population-specific genetic loci as well as those shared between Asian and European populations contribute to RA etiology. Furthermore, our study reveals the potential of machine learning methods in unraveling gene-gene interactions using GWAS data.
UR - https://www.scopus.com/pages/publications/84889064165
UR - https://www.scopus.com/pages/publications/84889064165#tab=citedBy
U2 - 10.1002/art.38110
DO - 10.1002/art.38110
M3 - Article
C2 - 23918589
AN - SCOPUS:84889064165
SN - 0004-3591
VL - 65
SP - 3026
EP - 3035
JO - Arthritis and Rheumatism
JF - Arthritis and Rheumatism
IS - 12
ER -