Genome-wide study of longitudinal brain imaging measures of multiple sclerosis progression across six clinical trials
While the genetics of MS risk susceptibility are well-described, and recent progress has been made on the genetics of disease severity, the genetics of disease progression remain elusive. We therefore investigated the genetic determinants of MS progression on longitudinal brain MRI: change in brain...
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Published in | Scientific reports Vol. 13; no. 1; p. 14313 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
31.08.2023
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | While the genetics of MS risk susceptibility are well-described, and recent progress has been made on the genetics of disease severity, the genetics of disease progression remain elusive. We therefore investigated the genetic determinants of MS progression on longitudinal brain MRI: change in brain volume (BV) and change in T2 lesion volume (T2LV), reflecting progressive tissue loss and increasing disease burden, respectively. We performed genome-wide association studies of change in BV (N = 3401) and change in T2LV (N = 3513) across six randomized clinical trials from Biogen and Roche/Genentech: ADVANCE, ASCEND, DECIDE, OPERA I & II, and ORATORIO. Analyses were adjusted for randomized treatment arm, age, sex, and ancestry. Results were pooled in a meta-analysis, and were evaluated for enrichment of MS risk variants. Variant colocalization and cell-specific expression analyses were performed using published cohorts. The strongest peaks were in
PTPRD
(rs77321193-C/A, p = 3.9 × 10
–7
) for BV change, and
NEDD4L
(rs11398377-GC/G, p = 9.3 × 10
–8
) for T2LV change. Evidence of colocalization was observed for
NEDD4L
, and both genes showed increased expression in neuronal and/or glial populations. No association between MS risk variants and MRI outcomes was observed. In this unique, precompetitive industry partnership, we report putative regions of interest in the neurodevelopmental gene
PTPRD
, and the ubiquitin ligase gene
NEDD4L
. These findings are distinct from known MS risk genetics, indicating an added role for genetic progression analyses and informing drug discovery. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-023-41099-0 |