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Meta-Analysis
. 2016 Oct 20;11(10):e0163877.
doi: 10.1371/journal.pone.0163877. eCollection 2016.

Genome-Wide Meta-Analysis of Sciatica in Finnish Population

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Free PMC article
Meta-Analysis

Genome-Wide Meta-Analysis of Sciatica in Finnish Population

Susanna Lemmelä et al. PLoS One. .
Free PMC article

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.

Conflict of interest statement

The authors have declared that no competing interests exists.

Figures

Fig 1
Fig 1. Study design.
Two discovery GWAS were conducted in Finnish population-based cohorts, the Young Finns Study (YFS) and the Health 2000 Study (H2000). Meta-analysis was carried out across the discovery GWAS. The most promising variants in meta-analysis (p<1x10-6) were replicated in a subsample of the FINRISK Study.
Fig 2
Fig 2. Manhattan plot for meta-analysis of adjusted genome-wide association results.
Variants with p-values below the genome-wide significance level (p < 5x10-8) are shown in red.
Fig 3
Fig 3. Regional association plots for associated loci in the GWAS meta-analysis of sciatica.
The associations along with recombination rates and genes on the region are shown in 2 Mb windows surrounding the lead SNP, to provide a graphical view of the associated region. SNPs are plotted by position on chromosome (x-axis) against association with sciatica (-log10 –p-value, y-axis). The lead SNP is shown with a purple diamond. Color intensity of each dot depicting a SNP reflects the extent of LD with the lead SNP, colored red (r2<0.8) through blue (r2<0.2). The LD has been estimated using 1000 Genomes, Mar2012 release, European population (see URLs). Physical positions are based on of the human genome build 37 (NCBI). 9p22.3: (NFIB) represented by rs71321981 (chr9:14344410:I, p = 1.30x10-8). No usable LD information was available for this SNP. 15q21.2: (MYO5A) represented by rs145901849 (p = 1.34x10-8). The associated region harbor SNPs in the MYO5A (p < 5x10-8) (red circle) and SNPs in the surrounding genes MYO5C, LYSMD2, ARPP19, and FAM214A (p<1.0x10-6) (blue circles). 6p21.32: (HLA-DRB5) represented by rs115488695 (p = 3.58x10-7). The HLA gene region (6p21.32) has previously been associated with musculoskeletal disorders; SNPs (rs2187689, rs7767277) nearby TAP1 (violet circle) were associated with lumbar disc degeneration in the meta-analysis of Northern European individuals [26], two SNPs (rs7775228, rs10947262) within BTNL2 and nearby HLA-DQB1 genes (green circles) were associated with knee osteoarthritis in a Japanese GWAS [27), and two SNPs (rs2076311 and rs1799907) within COL11A2 (blue circle) were associated with magnetic resonance-determined disc signal intensity [28], and with degenerative lumbar spinal stenosis with radicular pain in Finnish individuals [29].
Fig 4
Fig 4. Sequence of the insertion chr9:14344410:I (rs71321981) within the regulatory region of the NFIB gene (9p22.3).
The chr9:14344410:I (rs71321981) was sequenced in 184 individuals belonging to the YFS and 184 individuals included in the H2000 discovery cohort. Upper panel: heterozygous insertion/frameshift (-/G); Middle panel: homozygous insertion (G/G); Lower panel: wild type (-/-). The nucleotide sequences generated were compared to the reference sequence at 1000 Genomes browser (see URLs).

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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.
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