title: Genome-Wide Meta-Analysis of Sciatica in Finnish Population.
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.
authors.affiliation: Health and Work Ability, Finnish Institute of Occupational Health, 00250 Helsinki, Finland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Lemmelä
authors.affiliation: Health and Work Ability, Finnish Institute of Occupational Health, 00250 Helsinki, Finland.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Solovieva
authors.affiliation: Health and Work Ability, Finnish Institute of Occupational Health, 00250 Helsinki, Finland.
authors.forename: Rahman
authors.initials: R
authors.lastname: Shiri
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), 00014 University of Helsinki, Helsinki, Finland.|Department of Public Health, 00014 University of Helsinki, Helsinki, Finland.
authors.forename: Christian
authors.initials: C
authors.lastname: Benner
authors.affiliation: Population Health Unit, National Institute for Health and Welfare, 00251 Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Heliövaara
authors.affiliation: Faculty of Medicine, Institute of Health Sciences, University of Oulu, 90220 Oulu, Finland.|NMR Metabolomics Laboratory, University of Eastern Finland, Kuopio, Finland.|National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kettunen
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, United States of America.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States of America.
authors.forename: Verneri
authors.initials: V
authors.lastname: Anttila
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), 00014 University of Helsinki, Helsinki, Finland.|Department of Public Health, 00014 University of Helsinki, Helsinki, Finland.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, United Kingdom.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), 00014 University of Helsinki, Helsinki, Finland.|Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, 00271 Helsinki, Finland.|The Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia.
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, 33520 Tampere, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Seppälä
authors.affiliation: Division of Medicine, Turku University Hospital, 20521 Turku, Finland.|Department of Medicine, University of Turku, 20521 Turku, Finland.
authors.forename: Markus
authors.initials: M
authors.lastname: Juonala
authors.affiliation: Department of Clinical Physiology, Tampere University Hospital, 33521 Tampere, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.affiliation: Department of Health, National Institute for Health and Welfare, 00251 Helsinki, Finland.
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.affiliation: Division of Medicine, Turku University Hospital, 20521 Turku, Finland.|Department of Medicine, University of Turku, 20521 Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Viikari
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20520 Turku, Finland.|Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, 20521 Turku, Finland.
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, 33520 Tampere, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), 00014 University of Helsinki, Helsinki, Finland.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, United States of America.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States of America.|Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, United States of America.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: Disability Prevention Centre, Finnish Institute of Occupational Health, 00250 Helsinki, Finland.
authors.forename: Eira
authors.initials: E
authors.lastname: Viikari-Juntura
authors.affiliation: Health and Work Ability, Finnish Institute of Occupational Health, 00250 Helsinki, Finland.
authors.forename: Kirsti
authors.initials: K
authors.lastname: Husgafvel-Pursiainen
mesh_terms: D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15; D002896:Chromosomes, Human, Pair 6; D002899:Chromosomes, Human, Pair 9; D016208:Databases, Factual; D004198:Disease Susceptibility; D005387:Finland; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051839:NFI Transcription Factors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012585:Sciatica / Q000235:genetics* / Q000473:pathology; D044465:White People / Q000235:genetics*
chemical_list: D051839:NFI Transcription Factors; C110754:NFIB protein, human