1. Sequence variant at 8q24.21 associates with sciatica caused by lumbar disc herniation
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Ingileif Jonsdottir, Olafur Th Magnusson, Stefania Benonisdottir, Michael L. Frigge, G. Bragi Walters, Thorunn Rafnar, Aron H. Bjornsson, Gisli Masson, Unnur Styrkarsdottir, Thorgeir E. Thorgeirsson, Daniel F. Gudbjartsson, Tomas Gudbjartsson, Ingvar Hakon Olafsson, Elfar Ulfarsson, Karl Orn Karlsson, Patrick Sulem, Arnor Vikingsson, Gudmar Thorleifsson, Augustine Kong, Gyda Bjornsdottir, Hreinn Stefansson, Asmundur Oddsson, Kari Stefansson, Gardar Sveinbjornsson, Ragnheidur Hansdottir, Unnur Thorsteinsdottir, Læknadeild (HÍ), Faculty of Medicine (UI), Tannlæknadeild (HÍ), Faculty of Odontology (UI), Raunvísindastofnun (HÍ), Science Institute (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland
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0301 basic medicine ,Male ,Áhættuþættir ,General Physics and Astronomy ,Genome-wide association study ,Intervertebral Disc Degeneration ,Bioinformatics ,Gastroenterology ,Genome-wide association studies ,Sciatica ,0302 clinical medicine ,Risk Factors ,education.field_of_study ,Multidisciplinary ,Musculoskeletal system ,Lumbar Vertebrae ,Mendelian Randomization Analysis ,Middle Aged ,3. Good health ,Phenotype ,Stoðkerfi (líffærafræði) ,Female ,medicine.symptom ,Intervertebral Disc Displacement ,Chromosomes, Human, Pair 8 ,musculoskeletal diseases ,Adult ,medicine.medical_specialty ,Science ,Population ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Lumbar ,Internal medicine ,medicine ,Erfðafræði ,Humans ,Genetic Predisposition to Disease ,education ,Sequence (medicine) ,Demography ,Base Sequence ,business.industry ,Genetic Variation ,General Chemistry ,Rannsóknir ,Body Height ,030104 developmental biology ,Risk factors ,Genetic Loci ,Polygenic risk score ,Lumbar disc herniation ,business ,030217 neurology & neurosurgery - Abstract
Data supporting the findings of this study are available within the article and its Supplementary Information files. Summary level data of markers tested for association is described in Scientific data as of 2015 with the identifier http://dx.doi.org/10.1038/sdata.2015.11 (ref. 64). Whole-genome sequencing summary data are available at the European Variant Archive (EVA, https://www.ebi.ac.uk/eva/) under the accession code PRJEB8636. GTEx data (http://www.gtexportal.org) accessed 8 August 2016; LD Score Database (ftp://atguftp.mgh.harvard.edu/brendan/1k_eur_r2_hm3snps_se_weights.RDS) accessed 23 June 2015; GWAS catalogue (https://www.ebi.ac.u/gwas/home) accessed 8 September 2016., Lumbar disc herniation (LDH) is common and often debilitating. Microdiscectomy of herniated lumbar discs (LDHsurg) is performed on the most severe cases to resolve the resulting sciatica. Here we perform a genome-wide association study on 4,748 LDHsurg cases and 282,590 population controls and discover 37 highly correlated markers associating with LDHsurg at 8q24.21 (between CCDC26 and GSDMC), represented by rs6651255[C] (OR=0.81; P=5.6 × 10−12) with a stronger effect among younger patients than older. As rs6651255[C] also associates with height, we performed a Mendelian randomization analysis using height polygenic risk scores as instruments to estimate the effect of height on LDHsurg risk, and found that the marker's association with LDHsurg is much greater than predicted by its effect on height. In light of presented findings, we speculate that the effect of rs6651255 on LDHsurg is driven by susceptibility to developing severe and persistent sciatica upon LDH., The financial support from the European Commission to the NeuroPain project (FP7#HEALTH-2013-602891-2) and the National Institutes of Health (R01DE022905) is acknowledged.
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- 2017