@misc{10481/106832,
year = {2025},
month = {9},
url = {https://hdl.handle.net/10481/106832},
abstract = {The “omnigenic” hypothesis postulates that the polygenic effects of common variants on a typical complex trait coalesce on
relatively few core genes through trans-effects on their expression. Our aim was to identify core genes for systemic lupus
erythematosus (SLE) by testing for association with genome-wide aggregated trans-effects (GATE) scores for gene expression in a
large genetic dataset (5267/4909 SLE cases/controls). SLE was strongly associated with upregulation of expression of eight
interferon-stimulated genes driven by shared trans-effects. We estimate that trans-effects on interferon signaling account for 9% of
the total genetic effect on SLE risk. Outside this pathway, GATE analysis detected twenty putative core genes for SLE. Direct protein
measurements for these genes were strongly associated with SLE in UK Biobank. Two putative core genes (TNFRSF17, TNFRSF13B)
encode receptors (BCMA, TACI) expressed on B cells; their ligands (BAFF, APRIL) are targeted by drugs licensed or in development
for SLE. Four genes (PDCD1, LAG3, TNFRSF9, CD27) encode receptors that have been characterized as immune checkpoints, and
three (CD5L, SIGLEC1, CXCL13) are biomarkers of SLE disease activity. These results provide genetic support for existing drug targets
in SLE (interferon signaling, BAFF/APRIL signaling) and identify other possible therapeutic targets including immune checkpoint
receptors.},
organization = {UK Biobank Resource
(Application No. 23652)},
organization = {Academy of Medical Sciences, Wellcome Trust, UK Government Department of Business, Energy and Industrial Strategy, British Heart Foundation, y Diabetes UK
(Springboard Award SBF006/1109)},
organization = {Medical Research Council (MRC)
(Cross Disciplinary Fellowship Programme - MC_FE_00035)},
organization = {Consejería de Universidad, Investigación e Innovación — Junta de Andalucía
(EMERGIA Grant 30BM280101)},
organization = {EU/EFPIA Innovative Medicines Initiative Joint Undertaking
(PRECISESADS, Grant No. 115565)},
publisher = {Springer},
title = {Discovery of core genes for systemic lupus erythematosus via genome-wide aggregated trans-effects analysis},
doi = {10.1038/s41435-025-00352-4},
author = {Iakovliev, Andrii and Castellini-Pérez, Olivia and Erabadda, Buddhiprabha and PRECISESADS Clinical Consortium, / and Martín, Javier and Barturen, Guillermo and McKeigue, Paul M. and Carnero Montoro, Elena and Alarcón-Riquelme, Marta E. and Spiliopoulou, Athina},
}