Association of polygenic risk score with multiple sclerosis susceptibility and phenotype in Europeans

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Brain. March 7, 2022: awac092. doi:10.1093/brain/awac092. Online ahead of print.

ABSTRACT

Polygenic inheritance plays a central role in driving susceptibility to multiple sclerosis, an inflammatory demyelinating disease of the central nervous system. We developed polygenic risk scores (PRS) for multiple sclerosis and assessed associations with disease status and severity in cohorts of European descent. The largest genome-wide association dataset for multiple sclerosis to date (n=41,505) was leveraged to generate PRS scores, serving as an informative susceptibility marker, tested in two sets of independent data, UK Biobank [UKBB, area under the curve (AUC) = 0.73, 95% CI: 0.72-0.74, P = 6.41e-146] and Kaiser Permanente in Northern California (KPNC, AUC=0.8, 95% CI: 0.76-0.82, P=1.5e-53). Individuals in the top 10% of SRPs had a more than five-fold increased risk in UK Biobank (95% CI: 4.7-6, P=2.8e-45) and a fifteen-fold increased risk in KPNC (95% CI: 10.4-24, P=3.7e-11), relative to the middle decile. The cumulative absolute risk of developing multiple sclerosis from the age of 20 was significantly higher in genetically predisposed individuals according to the PRS. Additionally, the inclusion of PRS increased risk discrimination from 13% to 26% compared to models based solely on conventional risk factors for multiple sclerosis, such as smoking and mononucleosis infection. , in UKBB and KPNC, respectively. Stratification of disease risk by sets of genes representative of selected cell signaling cascades has named promising candidate genetic programs for functional characterization. These pathways include the mediation of inflammatory signaling, viral infection response, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression among major contributors to multiple sclerosis susceptibility. . This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multi-case families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P

PMID:35253861 | DOI: 10.1093/brain/awac092

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