Skip to main content
Journal cover image

Early complement genes are associated with visual system degeneration in multiple sclerosis.

Publication ,  Journal Article
Fitzgerald, KC; Kim, K; Smith, MD; Aston, SA; Fioravante, N; Rothman, AM; Krieger, S; Cofield, SS; Kimbrough, DJ; Bhargava, P; Saidha, S ...
Published in: Brain
September 1, 2019

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Brain

DOI

EISSN

1460-2156

Publication Date

September 1, 2019

Volume

142

Issue

9

Start / End Page

2722 / 2736

Location

England

Related Subject Headings

  • Visual Pathways
  • Tomography, Optical Coherence
  • Retina
  • Randomized Controlled Trials as Topic
  • Prospective Studies
  • Proportional Hazards Models
  • Polymorphism, Single Nucleotide
  • Neurology & Neurosurgery
  • Nerve Degeneration
  • Multiple Sclerosis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Fitzgerald, K. C., Kim, K., Smith, M. D., Aston, S. A., Fioravante, N., Rothman, A. M., … Calabresi, P. A. (2019). Early complement genes are associated with visual system degeneration in multiple sclerosis. Brain, 142(9), 2722–2736. https://doi.org/10.1093/brain/awz188
Fitzgerald, Kathryn C., Kicheol Kim, Matthew D. Smith, Sean A. Aston, Nicholas Fioravante, Alissa M. Rothman, Stephen Krieger, et al. “Early complement genes are associated with visual system degeneration in multiple sclerosis.Brain 142, no. 9 (September 1, 2019): 2722–36. https://doi.org/10.1093/brain/awz188.
Fitzgerald KC, Kim K, Smith MD, Aston SA, Fioravante N, Rothman AM, et al. Early complement genes are associated with visual system degeneration in multiple sclerosis. Brain. 2019 Sep 1;142(9):2722–36.
Fitzgerald, Kathryn C., et al. “Early complement genes are associated with visual system degeneration in multiple sclerosis.Brain, vol. 142, no. 9, Sept. 2019, pp. 2722–36. Pubmed, doi:10.1093/brain/awz188.
Fitzgerald KC, Kim K, Smith MD, Aston SA, Fioravante N, Rothman AM, Krieger S, Cofield SS, Kimbrough DJ, Bhargava P, Saidha S, Whartenby KA, Green AJ, Mowry EM, Cutter GR, Lublin FD, Baranzini SE, De Jager PL, Calabresi PA. Early complement genes are associated with visual system degeneration in multiple sclerosis. Brain. 2019 Sep 1;142(9):2722–2736.
Journal cover image

Published In

Brain

DOI

EISSN

1460-2156

Publication Date

September 1, 2019

Volume

142

Issue

9

Start / End Page

2722 / 2736

Location

England

Related Subject Headings

  • Visual Pathways
  • Tomography, Optical Coherence
  • Retina
  • Randomized Controlled Trials as Topic
  • Prospective Studies
  • Proportional Hazards Models
  • Polymorphism, Single Nucleotide
  • Neurology & Neurosurgery
  • Nerve Degeneration
  • Multiple Sclerosis