GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

• Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

Nyckelord

c terminal src kinase

centromere antibody

cluster of differentiation 247

complexin 3

diacylglycerol kinase theta

gasdermin A

histone 3 lysine 27

interferon consensus sequence binding protein

interleukin 12 receptor subunit beta 1

interleukin 12 receptor subunit beta 2

lectin, mannose binding 1 like

mitochondrial ribosomal protein s7

nucleoporin 85

ORMDL sphingolipid biosynthesis regulator 3

phosphopantothenoylcysteine decarboxylase

post GPI attachment to proteins 3

proteasome 26S subunit, non-ATPase 3

Rho GTPase activating protein 31

ribonuclease P and MRP subunit p25

STAT4 protein

TNFAIP3 interacting protein 1

transcription factor

unclassified drug

zona pellucida binding protein 2

cell

cell component

disease incidence

genetic analysis

genome

meta-analysis

mortality

Article

Bayesian network

CD4+ T lymphocyte

cell expansion

cohort analysis

controlled study

epigenetics

fibrosis

gene identification

gene locus

genome-wide association study

human

immune response

major clinical study

molecular genetics

protein acetylation

rheumatic disease

risk factor

single nucleotide polymorphism

systemic sclerosis

T lymphocyte

vascular disease

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)