Abstract
Genome-wide association studies (GWAS) underscore the genetic basis of multiple sclerosis (MS); however, only few of the newly reported genetic variations relevant in MS have been replicated or correlated for clinical/paraclinical phenotypes such as spinal cord atrophy in independent patient cohorts. We genotyped 141 MS patients for 58 variations reported to reach significance in GWAS. Expanded disability status scale (EDSS) and disease duration (DD) are available from regular clinical examinations. MRI included sagittal high-resolution 3D T1-weighted magnetization-prepared rapid acquisition gradient echo of the cervical cord region used for volumetry. Due dependency of mean upper cervical cord area (MUCCA) with EDSS and/or DD, correction operations were performed compensating for EDSS/DD. We assessed each MS risk locus for possible MUCCA association. We identified twelve risk loci that significantly correlated with MUCCA. For nine loci—BATF, CYP27B1, IL12B, NFKB1, IL7, PLEK, EVI5, TAGAP and nrs669607—patients revealed significantly higher degree of atrophy; TYK2, RGS1 and CLEC16A revealed inverse effects. The weighted genetic risk score over the twelve loci showed significant correlation with MUCCA. Our data reveal a risk gene depending paraclinical/clinical phenotype. Since MUCCA clearly correlates with disability, the candidates identified here may serve as prognostic markers for disability progression.
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Acknowledgments
We thank the Faculty of Medicine of the Ruhr-University Bochum for the financial support (FoRUM reference number F762N-2012).
Conflict of interest
Dr. Akkad, Dr. Bellenberg, Ms. Esser, Mr. Weiler, Dr. Epplen and Dr. Haghikia report no disclosures. Dr. Gold has received payments for consultancy from Biogen and Teva and speaker honoraria and research grants from Biogen Idec Germany, Teva, Sanofi Aventis, Novartis, Bayer Healthcare and Merck Serono. Dr. Lukas has received limited research grants from Glaxo Smith Kline; payments for consultancy from Biogen Idec, Novartis and Sanofi-Aventis; and speaker honoraria from Teva Pharma, Biogen Indec, Genzyme and Novartis. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
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DAA and BB contributed equally to this work.
CL and AH contributed equally to this work.
Denis A. Akkad, Barbara Bellenberg, Carsten Lukas and Aiden Haghikia contributed equally to this work.
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Akkad, D.A., Bellenberg, B., Esser, S. et al. Multiple sclerosis risk loci correlate with cervical cord atrophy and may explain the course of disability. Neurogenetics 16, 161–168 (2015). https://doi.org/10.1007/s10048-015-0438-0
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DOI: https://doi.org/10.1007/s10048-015-0438-0