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

Kathryn Fitzgerald, Kicheol Kim, Matthew D. Smith, Sean A. Aston, Nicholas Fioravante, Alissa M. Rothman, Stephen Krieger, Stacey S. Cofield, Dorlan J. Kimbrough, Pavan Bhargava, Shiv Saidha, Katharine Whartenby, Ari J. Green, Ellen Mahar Mowry, Gary R. Cutter, Fred D. Lublin, Sergio E. Baranzini, Philip L. De Jager, Peter Calabresi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2722-2736
Number of pages15
JournalBrain : a journal of neurology
Volume142
Issue number9
DOIs
StatePublished - Sep 1 2019

Fingerprint

Multiple Sclerosis
Genes
Ganglia
Atrophy
Confidence Intervals
Phenotype
Optic Neuritis
Inborn Genetic Diseases
Visual Pathways
Complement Activation
Genome-Wide Association Study
Optical Coherence Tomography
Proportional Hazards Models
Disease Progression
Retina
Meta-Analysis

Keywords

  • early complement pathway genes
  • genome-wide association studies
  • multiple sclerosis
  • optical coherence tomography

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Early complement genes are associated with visual system degeneration in multiple sclerosis. / Fitzgerald, Kathryn; Kim, Kicheol; Smith, Matthew D.; Aston, Sean A.; Fioravante, Nicholas; Rothman, Alissa M.; Krieger, Stephen; Cofield, Stacey S.; Kimbrough, Dorlan J.; Bhargava, Pavan; Saidha, Shiv; Whartenby, Katharine; Green, Ari J.; Mowry, Ellen Mahar; Cutter, Gary R.; Lublin, Fred D.; Baranzini, Sergio E.; De Jager, Philip L.; Calabresi, Peter.

In: Brain : a journal of neurology, Vol. 142, No. 9, 01.09.2019, p. 2722-2736.

Research output: Contribution to journalArticle

Fitzgerald, K, Kim, K, Smith, MD, Aston, SA, Fioravante, N, Rothman, AM, Krieger, S, Cofield, SS, Kimbrough, DJ, Bhargava, P, Saidha, S, Whartenby, K, Green, AJ, Mowry, EM, Cutter, GR, Lublin, FD, Baranzini, SE, De Jager, PL & Calabresi, P 2019, 'Early complement genes are associated with visual system degeneration in multiple sclerosis', Brain : a journal of neurology, vol. 142, no. 9, pp. 2722-2736. https://doi.org/10.1093/brain/awz188
Fitzgerald, Kathryn ; Kim, Kicheol ; Smith, Matthew D. ; Aston, Sean A. ; Fioravante, Nicholas ; Rothman, Alissa M. ; Krieger, Stephen ; Cofield, Stacey S. ; Kimbrough, Dorlan J. ; Bhargava, Pavan ; Saidha, Shiv ; Whartenby, Katharine ; Green, Ari J. ; Mowry, Ellen Mahar ; Cutter, Gary R. ; Lublin, Fred D. ; Baranzini, Sergio E. ; De Jager, Philip L. ; Calabresi, Peter. / Early complement genes are associated with visual system degeneration in multiple sclerosis. In: Brain : a journal of neurology. 2019 ; Vol. 142, No. 9. pp. 2722-2736.
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AU - Fitzgerald, Kathryn

AU - Kim, Kicheol

AU - Smith, Matthew D.

AU - Aston, Sean A.

AU - Fioravante, Nicholas

AU - Rothman, Alissa M.

AU - Krieger, Stephen

AU - Cofield, Stacey S.

AU - Kimbrough, Dorlan J.

AU - Bhargava, Pavan

AU - Saidha, Shiv

AU - Whartenby, Katharine

AU - Green, Ari J.

AU - Mowry, Ellen Mahar

AU - Cutter, Gary R.

AU - Lublin, Fred D.

AU - Baranzini, Sergio E.

AU - De Jager, Philip L.

AU - Calabresi, Peter

PY - 2019/9/1

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N2 - 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.

AB - 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.

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