Contributions
Abstract: 61
Type: Oral
Abstract Category: Clinical aspects of MS - MS Variants
Background: Genome-wide association studies (GWAS) have been successful in identifying over 100 variants associated with risk of multiple sclerosis (MS). However, in comparison, genetic correlates of MS severity are much less well understood. Optical Coherence Tomography (OCT) imaging provides reproducible quantification of retinal thinning in MS and correlates longitudinally with brain atrophy and visual dysfunction, and, thus, could serve as sensitive measure to relate genetic factors to MS disease severity and course.
Goals: To assess genetic predictors of GCIP thinning in MS patients
Methods: 382 Caucasian patients with longitudinal OCT measurements (mean follow-up of 3.5 years) were recruited from the Johns Hopkins Multiple Sclerosis clinic population and genotyped on a customized array. We modeled measures of ganglion cell/inner plexiform layer (GCIP) thickness in a mixed model framework, adjusting for intra-eye correlation and estimated individual trajectories of GCIP changes. From this model, we extracted the residual, person-specific slopes (adjusting for age, gender and history optic neuritis) for use in SNP-based analyses. Independent variants (based on patterns of linkage disequilibrium from a reference panel) were annotated to genes and we calculated gene-based association statistics using an adapted sequence kernel association test (SKAT) to allow for common and rare variants. We then applied the recently developed HotNet2 algorithm to extract high-weight, novel biologically-relevant subnetworks by mapping the gene-based p-values to a consensus protein-protein interaction matrix including information from 3 large reference networks (Multinet, HINT+HI2012, iRefIndex9). We performed sensitivity analyses where we excluded the major histocompatibility complex gene region.
Results: From the results of our network analyses, the largest novel sub-network was highly-connected and composed of 18 genes that were significantly enriched for the complement pathway with involvement of 7 of the included genes (q-value for enrichment =3.92x10-11). Of the included genes, C3 (P=0.001) was the most strongly associated with changes in GCIP thickness occurring over follow-up.
Conclusions: These results suggest potentially a novel role of the complement pathway that may underlie changes in the retina of MS patients and are supported by existing knowledge of the function of complement genes in retinal ganglion cell pathology and in other neurodegenerative diseases.
Disclosure: Kathryn Fitzgerald: nothing to disclose
Julia Button: nothing to disclose
Omar Al-Louzi: nothing to disclose
Dorlan Kimbrough: nothing to disclose
Charles White: nothing to disclose
Marieme Demberle: nothing to disclose
Elias Sotirchos: nothing to disclose
Nikolaos Patsopoulos: has received research support from Intel Corp
Ellen Mowry: has received funding from an investigator-initiated trial from Biogen, is a site PI of trials from Biogen and Sun Pharma, and received free medication for a trial from Teva Neuroscience.
Shiv Saidha: has received consulting fees from Medical Logix for the development of CME programs in neurology, consulting fees from Axon Advisors LLC, Educational Grant Support from Novartis & Teva Neurosciences, speaking honoraria from the National Association of Managed Care Physicians, Advanced Studies in Medicine and the Family Medicine Foundation of West Virginia, and served on scientific advisory boards for Biogen-Idec, Genzyme & Novartis. He is a researcher in the OCTIMS study. He receives research funding from the Race to Erase MS and Genentech Corporation.
Peter Calabresi: has received grants to Johns Hopkins from Biogen, Novartis, and MedImmune, and has received honoraria for consulting from Vertex.
Philip DeJager: is on the scientific advisory board for Teva and Genzyme/Sanofi; received speaker honoraria from Biogen-Idec, Source Healthcare Analytics, Pfizer, and Teva; is on the editorial board for Journal of Neuroimmunology and Multiple Sclerosis Journal; is an associate editor for Neuroepigenetics; and received research support from Biogen-Idec, GSK, Vertex, Genzyme/Sanofi, and National MS Society.
Abstract: 61
Type: Oral
Abstract Category: Clinical aspects of MS - MS Variants
Background: Genome-wide association studies (GWAS) have been successful in identifying over 100 variants associated with risk of multiple sclerosis (MS). However, in comparison, genetic correlates of MS severity are much less well understood. Optical Coherence Tomography (OCT) imaging provides reproducible quantification of retinal thinning in MS and correlates longitudinally with brain atrophy and visual dysfunction, and, thus, could serve as sensitive measure to relate genetic factors to MS disease severity and course.
Goals: To assess genetic predictors of GCIP thinning in MS patients
Methods: 382 Caucasian patients with longitudinal OCT measurements (mean follow-up of 3.5 years) were recruited from the Johns Hopkins Multiple Sclerosis clinic population and genotyped on a customized array. We modeled measures of ganglion cell/inner plexiform layer (GCIP) thickness in a mixed model framework, adjusting for intra-eye correlation and estimated individual trajectories of GCIP changes. From this model, we extracted the residual, person-specific slopes (adjusting for age, gender and history optic neuritis) for use in SNP-based analyses. Independent variants (based on patterns of linkage disequilibrium from a reference panel) were annotated to genes and we calculated gene-based association statistics using an adapted sequence kernel association test (SKAT) to allow for common and rare variants. We then applied the recently developed HotNet2 algorithm to extract high-weight, novel biologically-relevant subnetworks by mapping the gene-based p-values to a consensus protein-protein interaction matrix including information from 3 large reference networks (Multinet, HINT+HI2012, iRefIndex9). We performed sensitivity analyses where we excluded the major histocompatibility complex gene region.
Results: From the results of our network analyses, the largest novel sub-network was highly-connected and composed of 18 genes that were significantly enriched for the complement pathway with involvement of 7 of the included genes (q-value for enrichment =3.92x10-11). Of the included genes, C3 (P=0.001) was the most strongly associated with changes in GCIP thickness occurring over follow-up.
Conclusions: These results suggest potentially a novel role of the complement pathway that may underlie changes in the retina of MS patients and are supported by existing knowledge of the function of complement genes in retinal ganglion cell pathology and in other neurodegenerative diseases.
Disclosure: Kathryn Fitzgerald: nothing to disclose
Julia Button: nothing to disclose
Omar Al-Louzi: nothing to disclose
Dorlan Kimbrough: nothing to disclose
Charles White: nothing to disclose
Marieme Demberle: nothing to disclose
Elias Sotirchos: nothing to disclose
Nikolaos Patsopoulos: has received research support from Intel Corp
Ellen Mowry: has received funding from an investigator-initiated trial from Biogen, is a site PI of trials from Biogen and Sun Pharma, and received free medication for a trial from Teva Neuroscience.
Shiv Saidha: has received consulting fees from Medical Logix for the development of CME programs in neurology, consulting fees from Axon Advisors LLC, Educational Grant Support from Novartis & Teva Neurosciences, speaking honoraria from the National Association of Managed Care Physicians, Advanced Studies in Medicine and the Family Medicine Foundation of West Virginia, and served on scientific advisory boards for Biogen-Idec, Genzyme & Novartis. He is a researcher in the OCTIMS study. He receives research funding from the Race to Erase MS and Genentech Corporation.
Peter Calabresi: has received grants to Johns Hopkins from Biogen, Novartis, and MedImmune, and has received honoraria for consulting from Vertex.
Philip DeJager: is on the scientific advisory board for Teva and Genzyme/Sanofi; received speaker honoraria from Biogen-Idec, Source Healthcare Analytics, Pfizer, and Teva; is on the editorial board for Journal of Neuroimmunology and Multiple Sclerosis Journal; is an associate editor for Neuroepigenetics; and received research support from Biogen-Idec, GSK, Vertex, Genzyme/Sanofi, and National MS Society.