Novel risk genes for systemic lupus erythematosus predicted by random forest classification

Research output: Contribution to journalArticle

Abstract

Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individual's SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity. Random forest classification also allowed prediction of patients at risk for lupus nephritis with an area under the curve of 0.94. By allele-specific gene expression analysis we detected cis-regulatory SNPs that affect the expression levels of six of the top 40 genes designed by the random forest analysis, indicating a regulatory role for the identified risk variants. The 40 top genes from the prediction were overrepresented for differential expression in B and T cells according to RNA-sequencing of samples from five healthy donors, with more frequent over-expression in B cells compared to T cells.

Details

Authors
  • Jonas Carlsson Almlöf
  • Andrei Alexsson
  • Juliana Imgenberg-Kreuz
  • Lina Sylwan
  • Christofer Bäcklin
  • Dag Leonard
  • Gunnel Nordmark
  • Karolina Tandre
  • Maija-Leena Eloranta
  • Leonid Padyukov
  • Christine Bengtsson
  • Andreas Jönsen
  • Solbritt Rantapää Dahlqvist
  • Christopher Sjöwall
  • Anders A. Bengtsson
  • Iva Gunnarsson
  • Elisabet Svenungsson
  • Lars Rönnblom
  • Johanna K. Sandling
  • Ann-Christine Syvänen
Organisations
External organisations
  • Uppsala University
  • Karolinska Institutet
  • Karolinska University Hospital
  • Umeå University
  • Skåne University Hospital
  • Linköping University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Rheumatology and Autoimmunity
  • Medical Genetics
Original languageEnglish
Article number6236
JournalScientific Reports
Volume7
Issue number1
Publication statusPublished - 2017 Dec 1
Publication categoryResearch
Peer-reviewedYes