Genome-Wide Meta-Analysis of Sciatica in Finnish Population

PLoS One. 2016 Oct 20;11(10):e0163877. doi: 10.1371/journal.pone.0163877. eCollection 2016.

Abstract

Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p<1x10-6) were replicated in 776 Finnish sciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:I (rs71321981) at 9p22.3 (NFIB gene; p = 1.30x10-8, MAF = 0.08) and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10-8, MAF = 0.06; p = 2.32x10-8, MAF = 0.07; p = 3.85x10-8, MAF = 0.06; p = 4.78x10-8, MAF = 0.07, respectively). The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04). Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6-7%) than in other European populations (1-2%). Imputation accuracies of the three significantly associated variants (chr9:14344410:I, rs190200374, and rs80035109) were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB), which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate.

Publication types

  • Meta-Analysis

MeSH terms

  • Case-Control Studies
  • Chromosomes, Human, Pair 15
  • Chromosomes, Human, Pair 6
  • Chromosomes, Human, Pair 9
  • Databases, Factual
  • Disease Susceptibility
  • European Continental Ancestry Group / genetics*
  • Finland
  • Gene Frequency
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • NFI Transcription Factors / genetics
  • Polymorphism, Single Nucleotide
  • Sciatica / genetics*
  • Sciatica / pathology

Substances

  • NFI Transcription Factors
  • NFIB protein, human

Grant support

The study was supported by the Academy of Finland, Responding to Public Health ChallengesResearch Programme (129364 to EVJ) and the Finnish Work Environment Fund (113077 to KHP). Financial support from the Academy of Finland was also received through grants 283045 to JK; 126925, 124282, 129378, 117797, and 141071 to OTR; 121584 to JV; 134309 to MK; 139635 to VS; 251217 and 285380 to SR; 251704 to A.P. In addition, the study was supported by the Orion Farmos Research Foundation to VA; Sigrid Juselius Foundation (to SR and AP), Finnish Foundation for Cardiovascular Research (to SR); Biocentrum Helsinki (to SR); NordForsk e-Science NIASC (62721 to SR); EU-7th FP (The SynSys Project and EU FP7-242167 to AP), the Wellcome Trust (098051 to AP). The Young Finns Study has also received financial support from the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds, Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.