Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci

Nat Commun. 2015 Jan 22:6:5966. doi: 10.1038/ncomms6966.

Abstract

Alopecia areata (AA) is a prevalent autoimmune disease with 10 known susceptibility loci. Here we perform the first meta-analysis of research on AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the major histocompatibility complex, where we fine-map four independent effects, all implicating human leukocyte antigen-DR as a key aetiologic driver. Outside the major histocompatibility complex, we identify two novel loci that exceed the threshold of statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, transforming growth factor beta/Tregs and JAK kinase signalling, and support the causal role of aberrant immune processes in AA.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Alleles
  • Alopecia Areata / genetics*
  • Animals
  • Apoptosis Regulatory Proteins / genetics*
  • Ataxin-2 / genetics*
  • Bcl-2-Like Protein 11
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • HLA Antigens / genetics*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins / genetics*
  • Mice
  • Microscopy, Fluorescence
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Principal Component Analysis
  • Protein Conformation
  • Proteins / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Skin / metabolism

Substances

  • ATXN2 protein, human
  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Ataxin-2
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • HLA Antigens
  • Intracellular Signaling Peptides and Proteins
  • LRRC32 protein, human
  • Membrane Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • SH2B3 protein, human