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

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)