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- Stolk, Lisette, et al.
(författare)
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Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:3, s. 260-268
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Tidskriftsartikel (refereegranskat)abstract
- To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
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- Lunetta, Kathryn L., et al.
(författare)
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Rare coding variants and X-linked loci associated with age at menarche
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P = 2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
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- Zygmunt, S C, et al.
(författare)
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Realignment and surgical fixation of atlanto-axial and subaxial dislocations in rheumatoid arthritis (RA) patients
- 1988
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Ingår i: Acta Neurochirurgica. Supplementum. - 0065-1419. ; 43, s. 79-84
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Tidskriftsartikel (refereegranskat)abstract
- One hundred consecutive patients with atlanto-axial dislocation(s) were subjected to posterior occipito-cervical fusion and followed up to 16 1/2 years postoperatively (mean: 4 1/2 years). The mean age at surgery was 60.3 years. At the time of follow-up, 45 patients had died, mostly due to cardiopulmonary disease. Out of the 100 patients, 67% showed a major improvement and in an additional 14% there was a slight or moderate improvement. Some patients with a stable fusion later developed subaxial dislocation(s) necessitating an anterior fusion which in patients with RA is difficult due to poor bone quality. MRI revealed pannus formation around the odontoid peg in many patients, in several to such a degree that cord compression was evident. Following the posterior fixation, the pannus disappeared or was reduced which may at least partly explain the generally favourable operative outcome following the fixation procedure. Early occipito-cervical fusion appears to prevent further vertical dislocation or upwards migration of the odontoid which is a more severe condition, and does not appear to result in increased incidence of subsequent subaxial dislocation(s). Such luxation(s) pose a technically difficult problem since the quality of the patients' own bone usually does not permit a common anterior fusion procedure with autologous graft. In such cases with cord compression, acrylic cement may be used to obtain a normalized realignment.
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