| Title: | Polygenic risk score association with multiple sclerosis susceptibility and phenotype in Europeans |
| Journal: | Brain |
| Published: | 7 Mar 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35253861/ |
| DOI: | https://doi.org/10.1093/brain/awac092 |
| URL: | https://academic.oup.com/brain/article-pdf/146/2/645/50496690/awac092.pdf |
| Citations: | 27 (21 in last 2 years) as of 8 Aug 2024 |
Publication 12488
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Abstract
Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the CNS. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both 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 independent datasets, UK Biobank [area under the curve (AUC) = 0.73, 95% confidence interval (CI): 0.72-0.74, P = 6.41 × 10-146] and Kaiser Permanente in Northern California (KPNC, AUC = 0.8, 95% CI: 0.76-0.82, P = 1.5 × 10-53). Individuals within the top 10% of PRS were at higher than 5-fold increased risk in UK Biobank (95% CI: 4.7-6, P = 2.8 × 10-45) and 15-fold higher risk in KPNC (95% CI: 10.4-24, P = 3.7 × 10-11), relative to the median decile. The cumulative absolute risk of developing multiple sclerosis from age 20 onwards was significantly higher in genetically predisposed individuals according to PRS. Furthermore, inclusion of PRS in clinical risk models increased the risk discrimination by 13% to 26% over models based only on conventional risk factors in UK Biobank and KPNC, respectively. Stratifying disease risk by gene sets representative of curated cellular signalling cascades, nominated promising genetic candidate programmes for functional characterization. These pathways include inflammatory signalling mediation, response to viral infection, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression to be among significant contributors to multiple sclerosis susceptibility. This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multicase families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P < 0.001), consistent with a partial overlap between the genetics of susceptibility and end-organ tissue injury. Mendelian randomization analysis suggested an effect of multiple sclerosis susceptibility on thalamic volume, which was further indicated to be through horizontal pleiotropy rather than a causal effect. In summary, this study indicates important, replicable associations of PRS with enhanced risk assessment and radiographic outcomes of tissue injury, potentially informing targeted screening and prevention strategies.</p>
9 Keywords
- Epigenesis, Genetic
- European People
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Multifactorial Inheritance
- Multiple Sclerosis
- Phenotype
- Risk Factors
45 Authors
- Hengameh Shams
- Xiaorong Shao
- Adam Santaniello
- Gina Kirkish
- Adil Harroud
- Qin Ma
- Noriko Isobe
- Jessa Alexander
- Riley Bove
- Sergio Baranzini
- Bruce A C Cree
- Eduardo Caverzasi
- Richard Cuneo
- Stacy J Caillier
- Tiffany Cooper
- Ari J Green
- Chu-Yueh Guo
- Jeffrey M Gelfand
- Refujia Gomez-O'shea
- Sasha Gupta
- Jill Hollenbach
- Meagan Harms
- Roland G Henry
- Stephen L Hauser
- Myra Mendoza
- Jorge R Oksenberg
- Nico Papinutto
- Sam Pleasure
- Kyra Powers
- Adam Renschen
- Adam Santaniello
- Joseph J Sabatino
- William A Stern
- Michael R Wilson
- Scott S Zamvil
- Catherine A Schaefer
- Jacob L McCauley
- Bruce A C Cree
- Alessandro Didonna
- Sergio E Baranzini
- Nikolaos A Patsopoulos
- Stephen L Hauser
- Lisa F Barcellos
- Roland G Henry
- Jorge R Oksenberg
1 Application
| Application ID | Title |
|---|---|
| 59309 | Polygenic Prediction of Susceptibility and Progression in Multiple Sclerosis |
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