Transancestral mapping and genetic load in systemic lupus erythematosus

Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

Publication types

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

MeSH terms

  • African Continental Ancestry Group / genetics*
  • Age of Onset
  • American Native Continental Ancestry Group / genetics*
  • Case-Control Studies
  • European Continental Ancestry Group / genetics*
  • Genetic Load*
  • HLA Antigens / genetics*
  • Hispanic Americans / genetics
  • Humans
  • Logistic Models
  • Lupus Erythematosus, Systemic / genetics*
  • Multifactorial Inheritance
  • Mutagenesis, Insertional
  • Polymorphism, Single Nucleotide
  • Sequence Deletion

Substances

  • HLA Antigens