Data from: Genome-wide meta-analysis of sciatica in Finnish population

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.

坐骨神经痛（sciatica）或称坐骨神经综合征，是劳动年龄人群中常见且常导致失能的下背部疾病。该病遗传力相对较高，但分子机制尚不明确。芬兰人群属于遗传隔离群体，其起源群体规模较小且经历过瓶颈事件，导致部分罕见和低频变异富集。本研究首次开展了坐骨神经痛的全基因组关联研究（Genome-Wide Association Study, GWAS）与荟萃分析。本次荟萃分析纳入两项GWAS研究，覆盖291名芬兰坐骨神经痛病例与3671名对照，共对770万常染色体变异进行了基因分型与基因型填充。我们在776名芬兰坐骨神经痛患者与18489名对照中，对p值小于1×10⁻⁶的最具潜力位点开展了重复验证。本研究在两个全新位点上鉴定出5个低频基因内变异，达到坐骨神经痛的全基因组显著性关联水平。其中包括位于9p22.3区域NFIB基因内的chr9:14344410:I（rs71321981，p=1.30×10⁻⁸，次要等位基因频率（Minor Allele Frequency，MAF）=0.08），以及位于15q21.2区域的4个变异：rs145901849、rs80035109、rs190200374与rs117458827（对应MYO5A基因，依次为p=1.34×10⁻⁸，MAF=0.06；p=2.32×10⁻⁸，MAF=0.07；p=3.85×10⁻⁸，MAF=0.06；p=4.78×10⁻⁸，MAF=0.07）。荟萃分析中最显著的关联为转录因子NFIB调控区域内的单碱基插入变异rs71321981，该变异在独立芬兰人群样本中得到验证（p=0.04）。尽管我们将15q21.2鉴定为潜力位点，但未能完成重复验证。值得注意的是，15q21.2区域的先导变异在芬兰人群中的频率为6%~7%，高于其他欧洲人群的1%~2%。本研究通过基因分型验证了3个显著关联变异（chr9:14344410:I、rs190200374与rs80035109）的基因型填充准确率。综上，本研究结果提示9p22.3（NFIB）为一个全新的坐骨神经痛易感位点。此外，15q21.2虽被鉴定为潜力位点，但未能通过重复验证。