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COVID-19 and systemic lupus erythematosus genetics: A balance between autoimmune disease risk and protection against infection

Research output: Contribution to journalArticlepeer-review

Yuxuan Wang, Suri Guga, Kejia Wu, Zoe Khaw, Konstantinos Tzoumkas, Phil Tombleson, Mary E. Comeau, Carl D. Langefeld, Deborah S. Cunninghame graham, David L. Morris, Timothy J. Vyse, Giorgio Sirugo (Editor)

Original languageEnglish
Article numbere1010253
Pages (from-to)e1010253
JournalPLoS genetics
Volume18
Issue number11
Early online date3 Nov 2022
DOIs
Accepted/In press18 Sep 2022
E-pub ahead of print3 Nov 2022
Published3 Nov 2022

Bibliographical note

Funding Information: signal-BcomprisesevidencefortwofunctionaleffectswithrespecttoCOVID-19riskalleles, oneofwhichincreasesfunctionofTYK2throughalteredsplicing(rs2304256(V362F))and onethatiscorrelatedwithincreasedexpressionofTYK2(rs11085727).Itmaybethattheover-allreductionofTYK2activitycausedbytheCOVID-19riskallelesinsignal-Aevokesacom-pensatoryeffectonoverallgeneexpression,whichisdesignedtomitigatethedeleteriouseffect ofthemissensevariants–anexampleofregulatoryvariantsmodifyingthepenetranceofcoding variants [15,22]. This conjecture is supported by the lack of epigenetic marks in the signal-B regionofTYK2. Publisher Copyright: Copyright: © 2022 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

King's Authors

Abstract

Genome wide association studies show there is a genetic component to severe COVID-19. We find evidence that the genome-wide genetic association signal with severe COVID-19 is correlated with that of systemic lupus erythematosus (SLE), having formally tested this using genetic correlation analysis by LD score regression. To identify the shared associated loci and gain insight into the shared genetic effects, using summary level data we performed meta-analyses, a local genetic correlation analysis and fine-mapping using stepwise regression and functional annotation. This identified multiple loci shared between the two traits, some of which exert opposing effects. The locus with most evidence of shared association is TYK2, a gene critical to the type I interferon pathway, where the local genetic correlation is negative. Another shared locus is CLEC1A, where the direction of effects is aligned, that encodes a lectin involved in cell signaling, and the anti-fungal immune response. Our analyses suggest that several loci with reciprocal effects between the two traits have a role in the defense response pathway, adding to the evidence that SLE risk alleles are protective against infection.

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