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Sökning: WFRF:(Birve Anna) > Meyer Thomas

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1.
  • Blauw, Hylke M, et al. (författare)
  • A large genome scan for rare CNVs in amyotrophic lateral sclerosis
  • 2010
  • Ingår i: Human Molecular Genetics. - : Oxford Journals. - 0964-6906 .- 1460-2083. ; 19:20, s. 4091-4099
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
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2.
  • Eschbach, Judith, et al. (författare)
  • PGC-1 is a male-specific disease modifier of human and experimental amyotrophic lateral sclerosis
  • 2013
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:17, s. 3477-3484
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyotrophic lateral sclerosis (ALS) is a devastating, adult-onset neurodegenerative disorder of the upper and lower motor systems. It leads to paresis, muscle wasting and inevitably to death, typically within 35 years. However, disease onset and survival vary considerably ranging in extreme cases from a few months to several decades. The genetic and environmental factors underlying this variability are of great interest as potential therapeutic targets. In ALS, men are affected more often and have an earlier age of onset than women. This gender difference is recapitulated in transgenic rodent models, but no underlying mechanism has been elucidated. Here we report that SNPs in the brain-specific promoter region of the transcriptional co-activator PGC-1, a master regulator of metabolism, modulate age of onset and survival in two large and independent ALS populations and this occurs in a strictly male-specific manner. In complementary animal studies, we show that deficiency of full-length (FL) Pgc-1 leads to a significantly earlier age of onset and a borderline shortened survival in male, but not in female ALS-transgenic mice. In the animal model, FL Pgc-1-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1 as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1 in this neurodegenerative disorder.
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4.
  • van Es, Michael A, et al. (författare)
  • Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis
  • 2009
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:10, s. 1083-1087
  • Tidskriftsartikel (refereegranskat)abstract
    • We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.
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5.
  • Weishaupt, Jochen H, et al. (författare)
  • A novel optineurin truncating mutation and three glaucoma-associated missense variants in patients with familial amyotrophic lateral sclerosis in Germany
  • 2013
  • Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 34:5, s. 1516.e9-1516.e15
  • Tidskriftsartikel (refereegranskat)abstract
    • Mutations in the optineurin (OPTN) gene have been associated with normal tension glaucoma and with amyotrophic lateral sclerosis (ALS). Here, we screened German familial ALS cases for OPTN mutations to gain additional insight into the spectrum and pathogenic relevance of this gene for ALS. One hundred familial German ALS cases and 148 control subjects were screened for OPTN mutations by sequence analysis of the complete OPTN coding sequence, and phenotypes of OPTN mutant patients were described. We identified a novel heterozygous truncating OPTN mutation p.Lys440Asnfs*8 in 1 ALS family with an aggressive ALS disease phenotype. This mutation abolishes protein domains crucial for nuclear factor kappa B signaling. Moreover, we detected 3 different nonsynonymous sequence variants, which have been described previously as risk factors for primary retinal ganglion cell degeneration in normal tension glaucoma. Two of them were detected on the same allele in a family that also carries a p.Asn352Ser disease mutation in the ALS gene TARDBP. All OPTN mutant patients presented with typical spinal onset ALS. Taken together, we detected a novel truncating OPTN mutation associated with an aggressive form of ALS and confirmed that OPTN mutations are a rare cause of ALS. In addition our data suggest that in some cases plausibly more than 1 mutation in OPTN or another ALS gene might be needed to cause ALS. Finally, our findings show that motoneurons and retinal ganglion cells, which are both projecting central nervous system neurons, might share common susceptibility factors. (C) 2013 Elsevier Inc. All rights reserved.
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