DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Interferon alpha levels in systemic lupus erythematosus. The EFO term interferon alpha measurement, systemic lupus erythematosus was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: interferon alpha measurement, systemic lupus erythematosus

SCORE TYPE:

P-Value

DATE ADDED:

2017-05-02

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

SN Kariuki, Y Ghodke-Puranik, JM Dorschner, BS Chrabot, JA Kelly, BP Tsao, RP Kimberly, ME Alarcón-Riquelme, CO Jacob, LA Criswell, KL Sivils, CD Langefeld, JB Harley, AD Skol, TB Niewold

TITLE:

Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus.

JOURNAL:

Genes and immunity None None, Vol 16, pp. 15-23

ABSTRACT:

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, greatly reducing the power of case-control studies in SLE. Elevated circulating interferon-alpha (IFN-α) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. About 40-50% of patients have high IFN-α, and high levels correspond with clinical differences. To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high vs low IFN-α in over 1550 SLE cases, including genome-wide association study and replication cohorts. In meta-analysis, the top associations in European ancestry were protein kinase, cyclic GMP-dependent, type I (PRKG1) rs7897633 (P(Meta) = 2.75 × 10(-8)) and purine nucleoside phosphorylase (PNP) rs1049564 (P(Meta) = 1.24 × 10(-7)). We also found evidence for cross-ancestral background associations with the ankyrin repeat domain 44 (ANKRD44) and pleckstrin homology domain containing, family F member 2 gene (PLEKHF2) loci. These loci have not been previously identified in case-control SLE genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN-α production in SLE. As case-control studies of heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic sub-phenotypes becomes an attractive strategy for genetic discovery in complex disease. PUBMED: 25338677
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