title: A genome-wide association study reveals ARL15, a novel non-HLA susceptibility gene for rheumatoid arthritis in North Indians.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National Institute of Immunology, New Delhi, India.
authors.forename: Sapna
authors.initials: S
authors.lastname: Negi
authors.forename: Garima
authors.initials: G
authors.lastname: Juyal
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Senapati
authors.forename: Pushplata
authors.initials: P
authors.lastname: Prasad
authors.forename: Aditi
authors.initials: A
authors.lastname: Gupta
authors.forename: Shalini
authors.initials: S
authors.lastname: Singh
authors.forename: Sujit
authors.initials: S
authors.lastname: Kashyap
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Uma
authors.initials: U
authors.lastname: Kumar
authors.forename: Rajiva
authors.initials: R
authors.lastname: Gupta
authors.forename: Satbir
authors.initials: S
authors.lastname: Kaur
authors.forename: Suraksha
authors.initials: S
authors.lastname: Agrawal
authors.forename: Amita
authors.initials: A
authors.lastname: Aggarwal
authors.forename: Jurg
authors.initials: J
authors.lastname: Ott
authors.forename: Sanjay
authors.initials: S
authors.lastname: Jain
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Juyal
authors.forename: B K
authors.initials: BK
authors.lastname: Thelma
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics*
chemical_list: D020727:ADP-Ribosylation Factors; C585870:ARL15 protein, human