Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

Am J Hum Genet. 2014 Jan 2;94(1):47-61. doi: 10.1016/j.ajhg.2013.12.002.

Abstract

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Autophagy-Related Protein 5
  • Carrier Proteins / genetics
  • Case-Control Studies
  • Chromosomes, Human, Pair 11 / genetics*
  • Chromosomes, Human, Pair 3 / genetics*
  • DEAD-box RNA Helicases / genetics
  • Endodeoxyribonucleases / genetics
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genotype
  • HLA Antigens / genetics
  • Humans
  • Interleukin-12 Subunit p35 / genetics
  • Linkage Disequilibrium
  • Logistic Models
  • Male
  • Microchip Analytical Procedures
  • Microtubule-Associated Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins / genetics
  • Risk Factors
  • Scleroderma, Systemic / genetics*

Substances

  • ATG5 protein, human
  • Autophagy-Related Protein 5
  • Carrier Proteins
  • HLA Antigens
  • IL12A protein, human
  • Interleukin-12 Subunit p35
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins
  • SCHIP1 protein, human
  • DNASE1L3 protein, human
  • Endodeoxyribonucleases
  • DDX6 protein, human
  • DEAD-box RNA Helicases