Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus

Prithvi Raj, Ran Song, Honglin Zhu, Linley Riediger, Dong Jae Jun, Chaoying Liang, Carlos Arana, Bo Zhang, Yajing Gao, Benjamin E. Wakeland, Igor Dozmorov, Jinchun Zhou, Jennifer A. Kelly, Bernard R. Lauwerys, Joel M. Guthridge, Nancy J. Olsen, Swapan K. Nath, Chandrashekhar Pasare, Nicolai van Oers, Gary GilkesonBetty P. Tsao, Patrick M. Gaffney, Peter K. Gregersen, Judith A. James, Xiaoxia Zuo, David R. Karp, Quan Zhen Li, Edward K. Wakeland

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. Results: We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. Conclusions: We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.

Original languageEnglish (US)
Article number281
JournalGenome biology
Volume21
Issue number1
DOIs
StatePublished - Dec 2020

Keywords

  • Autophagy
  • DAP1
  • Haplotype
  • RNA-Seq
  • SLE
  • SNPs
  • Sequencing

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

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