Genome-wide study of longitudinal brain imaging measures of multiple sclerosis progression across six clinical trials

Abstract

Abstract While the genetics of MS risk susceptibility are well-described, 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=3,401) and change in T2LV (N=3,513) across six randomized clinical trials from Biogen and Roche/Genentech: ADVANCE, ASCEND, DECIDE, and OPERA I & II, and ORATORIO. Analyses were adjusted for age, sex, ancestry, and treatment. Results were pooled for 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=3.9x10-7) for BV change, and NEDD4L (rs11398377-GC/G, p=9.3x10-8) 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. Trial registry name and numbers: ASCEND (NCT01416181), ADVANCE (NCT00906399), DECIDE (NCT01064401), OPERA1 (NCT 01247324), OPERA2 (NCT 01412333), ORATORIO (NCT 01194570)