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 language | English (US) |
|---|---|
| Pages (from-to) | 2722-2736 |
| Number of pages | 15 |
| Journal | Brain : a journal of neurology |
| Volume | 142 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2019 |
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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 journal › Article
}
TY - JOUR
T1 - Early complement genes are associated with visual system degeneration in multiple sclerosis
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
Y1 - 2019/9/1
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.
KW - early complement pathway genes
KW - genome-wide association studies
KW - multiple sclerosis
KW - optical coherence tomography
UR - http://www.scopus.com/inward/record.url?scp=85071899374&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071899374&partnerID=8YFLogxK
U2 - 10.1093/brain/awz188
DO - 10.1093/brain/awz188
M3 - Article
C2 - 31289819
AN - SCOPUS:85071899374
VL - 142
SP - 2722
EP - 2736
JO - Brain
JF - Brain
SN - 0006-8950
IS - 9
ER -