adverse drug reaction; epilepsy; genome wide association study; polygenic risk score; retina; Neuroscience (all); General Neuroscience
Abstract :
[en] [en] BACKGROUND: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug.
METHODS: Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants.
RESULTS: The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing.
CONCLUSION: We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Boothman, Isabelle; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland ; The SFI Futureneuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland ; The SFI Centre for Research Training in Genomics Data Science, Galway, Ireland
Clayton, Lisa M; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom ; Chalfont Centre for Epilepsy, Bucks, United Kingdom
McCormack, Mark; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Driscoll, Alexandra McKibben; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Stevelink, Remi; Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
Moloney, Patrick; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
KRAUSE, Roland ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Kunz, Wolfram S; Division of Neurochemistry, Department of Epileptology, University Bonn Medical Center, Bonn, Germany
Peter, Sarah; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
O'Brien, Terence J; Departments of Neuroscience and Neurology, Central Clinical School, The Alfred Hospital, Monash University, Melbourne, VIC, Australia
Sills, Graeme J; School of Life Sciences, University of Glasgow, Glasgow, United Kingdom
de Haan, Gerrit-Jan; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands
Zara, Federico; "IRCCS"G. Gaslini" Institute, Genova, Italy ; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy
Koeleman, Bobby P; Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
Depondt, Chantal; Department of Neurology, Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
Marson, Anthony G; Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
Craig, John; Department of Neurology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, United Kingdom
Johnson, Michael R; Division of Brain Sciences, Imperial College Faculty of Medicine, London, United Kingdom
Striano, Pasquale; "IRCCS"G. Gaslini" Institute, Genova, Italy ; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy
Lerche, Holger; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Furney, Simon J; Genomic Oncology Research Group, Deptartment of Physiology and Medical Physics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
Delanty, Norman; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Consortium EpiPGX
Sisodiya, Sanjay M; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom ; Chalfont Centre for Epilepsy, Bucks, United Kingdom
Cavalleri, Gianpiero L; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland ; The SFI Futureneuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland ; The SFI Centre for Research Training in Genomics Data Science, Galway, Ireland
FP7 - 279062 - EPIPGX - Epilepsy Pharmacogenomics: delivering biomarkers for clinical use
Funders :
Union Européenne
Funding text :
This work was supported by a grant from the European Commission (7th Framework Programme Grant 279062, EpiPGX) and in part by a research grant from Science Foundation Ireland (SFI) under grant numbers 16/RC/3948 and co-funded under the European Regional Development Fund and by FutureNeuro industry partners and by Science Foundation Ireland through the SFI Centre for Research Training in Genomics Data Science under grant number 18/CRT/6214. Research supported by PNRR-MUR-M4C2 PE0000006 Research Program “MNESYS”—A multiscale integrated approach to the study of the nervous system in health and disease. IRCCS ‘G. Gaslini’ is a member of ERN-Epicare. This work was also supported by the Epilepsy Society, United Kingdom.
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