# The genetic basis of progression in multiple sclerosis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $442,964

## Abstract

This proposal will seek to identify and characterize the genetic factors that modulate disease activity and
progression in multiple sclerosis (MS). The project builds on the hypothesis that allelic variants affecting
disease trajectory are eminently identifiable through adequately powered unbiased genetic screens, and will
thus employ a multi-dimensional statistical analysis to identify key gene networks and biological processes
underlying disease progression. In order to minimize the confounding influence of the temporary fluctuations in
disability that result from the relapsing inflammatory activity that characterizes the early stages of MS the
discovery phase of this project will focus exclusively on older subjects (aged at least 55) with a long disease
duration (>10 years). Since typically less than 1 in 7 patients satisfy these criteria this approach is only
possible because of the enormous bio-specimen resource available to the International Multiple Sclerosis
Genetics Consortium (IMSGC) (>62,000 cases). We will use the Multiple Sclerosis Severity Score (MSSS) as
our measure of progression; an ordinal decile score that indicates how a patient's Expanded Disability Status
Scale (EDSS) ranks in comparison with other patients with the same duration of disease. The IMSGC has DNA
from almost 9,000 older long disease duration patients that have at least one MSSS measure. For maximal
efficiency we will screen these 9,000 cases in collaboration with our colleagues from the Karolinska Institute in
Sweden. Replicated results will be immediately analyzed in the context of cell-specific pathways and top
candidates will be subsequently explored for genetic interactions, including their functional validation.
Specifically, in Aim 1 we will conduct a GWAS on 4,000 patients using the latest generation of genotyping
chips, which through imputation will allow us to assess more than 70 million variants. In Specific Aim 2 we will
then replicate the most associated markers identified in aim 1 in the remaining 5,000 samples, conduct
additional replications in at least two more independent sample populations, a meta-analysis, and perform
bioinformatics and experimental validation of the most promising associations. Combining the data across both
efforts will provide power to identify variants accounting for as little as 0.5% of variances in MSSS. The
identification of genetic modifiers of disease expression will have profound translational implications for the
understanding and management of MS, and in particular for progressive MS, the most disabling and currently
untreatable form of the disease.

## Key facts

- **NIH application ID:** 9737736
- **Project number:** 5R01NS099240-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** SERGIO E BARANZINI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,964
- **Award type:** 5
- **Project period:** 2017-09-30 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9737736

## Citation

> US National Institutes of Health, RePORTER application 9737736, The genetic basis of progression in multiple sclerosis (5R01NS099240-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9737736. Licensed CC0.

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