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| 3. |
- van Es, Michael A, et al.
(författare)
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Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis
- 2009
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:10, s. 1083-1087
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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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| 4. |
- van Es, Michael A, et al.
(författare)
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Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis
- 2011
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Ingår i: Annals of Neurology. - : Wiley-Blackwell. - 0364-5134 .- 1531-8249. ; 70:6, s. 964-973
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios.RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD.INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.
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| 5. |
- van Es, Michael A, et al.
(författare)
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Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.
- 2008
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:1, s. 29-31
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Tidskriftsartikel (refereegranskat)abstract
- We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 x 10(-8) in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18-1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies.
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| 6. |
- Smith, Bradley N., et al.
(författare)
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The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder
- 2013
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Ingår i: European Journal of Human Genetics. - London : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 21:1, s. 102-108
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Tidskriftsartikel (refereegranskat)abstract
- A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n = 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n = 434) and controls (n = 856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.
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| 7. |
- Van Es, Michael A, et al.
(författare)
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Analysis of FGGY as a risk factor for sporadic amyotrophic lateral sclerosis
- 2009
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Ingår i: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders. - : Informa UK Limited. - 1466-0822 .- 1743-4483. ; 10:5-6, s. 441-447
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Tidskriftsartikel (refereegranskat)abstract
- A genome-wide association study (GWAS) using pooled DNA samples from 386 sporadic ALS patients and 542 controls from the USA, identified genetic variation in FGGY (FLJ10986) as a risk factor, as well as 66 additional candidate SNPs. Considering the large number of hypotheses that are tested in GWAS, independent replication of associations is crucial for identifying true-positive genetic risk factors for disease. The primary aim of this study was to study the association between FGGY and sporadic ALS in large, homogeneous populations from northern Europe. Genotyping experiments were performed using Illumina Beadchips, Sequenom iPLEX assays and Taqman technology on large case-control series from The Netherlands, Belgium, Sweden and Ireland (total: 1883 sporadic ALS patients and 2063 controls). No significant association between sporadic ALS and the six previously reported associated SNPs in FGGY was observed: rs6700125 (p =0.56), rs6690993 (p =0.30), rs10493256 (p =0.68), rs6587852 (p =0.64), rs1470407 (p =0.28) and rs333662 (p =0.44). Screening of the additional candidate loci did not yield significant associations either, with the lowest p-value in joint analysis for rs7772593 (p =0.14). We concluded that common genetic variation in FGGY is not associated with susceptibility to sporadic ALS in genetically homogeneous populations from northern Europe.
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| 10. |
- Liu, Xueping, et al.
(författare)
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Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P=3.96×10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
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| 12. |
- Diekstra, Frank P., et al.
(författare)
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UNC13A is a modifier of survival in amyotrophic lateral sclerosis
- 2012
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 33:3, s. 630.e3-630.e8
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Tidskriftsartikel (refereegranskat)abstract
- A large genome-wide screen in patients with sporadic amyotrophic lateral sclerosis (ALS) showed that the common variant rs12608932 in gene UNC13A was associated with disease susceptibility. UNC13A regulates the release of neurotransmitters, including glutamate. Genetic risk factors that, in addition, modify survival, provide promising therapeutic targets in ALS, a disease whose etiology remains largely elusive. We examined whether UNC13A was associated with survival of ALS patients in a cohort of 450 sporadic ALS patients and 524 unaffected controls from a population-based study of ALS in The Netherlands. Additionally, survival data were collected from individuals of Dutch, Belgian, or Swedish descent (1767 cases, 1817 controls) who had participated in a previously published genome-wide association study of ALS. We related survival to rs12608932 genotype. In both cohorts, the minor allele of rs12608932 in UNC13A was not only associated with susceptibility but also with shorter survival of ALS patients. Our results further corroborate the role of UNC13A in ALS pathogenesis. (C) 2012 Elsevier Inc. All rights reserved.
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| 18. |
- Suominen, EN, et al.
(författare)
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Health-related quality of life outcomes in adolescent Scheuermann's kyphosis patients treated with posterior spinal fusion: A comparison with age- and sex-matched controls
- 2022
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Ingår i: Journal of children's orthopaedics. - : SAGE Publications. - 1863-2521 .- 1863-2548. ; 16:4, s. 290-296
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Tidskriftsartikel (refereegranskat)abstract
- To assess the health-related quality of life and radiographic outcomes of surgically treated adolescent Scheuermann’s kyphosis patients after minimum of 2-year follow-up and to compare the health-related quality of life with age- and sex-matched healthy controls. Methods: Twenty-two consecutive adolescents (mean age = 16.7 years) undergoing posterior spinal fusion for Scheuermann’s kyphosis were included and matched by age and sex with two healthy controls. The health-related quality of life was evaluated using the Scoliosis Research Society-24 questionnaire. Radiographic parameters were measured for comparison preoperatively and at 6 months and 2-year follow-ups. The health-related quality of life parameters were compared with healthy controls at 2 years of follow-up. Results: The mean maximal thoracic kyphosis improved from 79° (range = 75°–90°) to 55° (range = 45°–75°) ( p < 0.001), and the mean lumbar lordosis was reduced from 71° (range = 51°–107°) to 52° (range = 34°–68°) ( p < 0.001) after 2 years postoperatively. Incidence of proximal junctional kyphosis (PJK) was 18%. The scores of the Scoliosis Research Society-24 improved, with statistical significance observed in pain and self-image domains from preoperative to 2-year follow-up ( p = 0.002 in both domains). The self-image and function were significantly lower in the operated patients at their 2-year follow-up visit compared to controls ( p = 0.023 for self-image and p < 0.001 for function). Conclusion: Instrumented posterior spinal fusion improves the health-related quality of life of Scheuermann’s kyphosis patients during the 2-year follow-up. The greatest improvement is observed in pain and self-image domains. The health-related quality of life in pain and activity domains reaches the level of healthy individuals, while function and self-image remain at a statistically lower level.
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| 19. |
- Svensson, Maria A., et al.
(författare)
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A comparative study of ERG status assessment on DNA-, mRNA-, and proteinlevels using unique samples from a Swedish biopsy cohort
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The ERG rearrangement is identified in approximately 50% of prostate cancer (PCa) screened cohorts and is known to be highly specific. This genetic aberration, most commonly leading to the TMPRSS2-ERG fusion, but also SLC45A3-ERG or NDRG1- ERG fusions, all leading to an over expression of a truncated ERG protein. Most studies have applied in situ hybridization (FISH) methods or mRNA based assays to investigate the ERG status. Recently, studies showed that ERG protein levels assessed by ERG antibodies can be used as a surrogate marker for ERG rearrangement. In the current study we investigate ERG status on a series of diagnostic biopsies using DNA-, mRNA- and protein based assays. We formally compare three assay results (i.e. FISH, fusion mRNA and immunohistochemistry) to identify which method could be most appropriate to use when having limited amount of tissue. ERG rearrangement was found in 56% of the cases. Comparing ERG rearrangement status by FISH with ERG over expression and TMPRSS2-ERG fusion transcript we found 95.1% (154/162, Fisher’s exact test 9.50E-36) and 85.2% (138/162, Fisher’s exact test 7.26E-22) concordance, respectively. We show that the ERG antibody highly correlates with the ERG rearrangement with high sensitivity and specificity. We also identified the most common TMPRSS2-ERG isoform in the majority of ERG rearranged cases. These results provide compelling evidence that the ERG antibody can be used to further investigate the role of ERG in PCa.
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| 21. |
- van Es, Michael A, et al.
(författare)
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ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis : a genome-wide association study.
- 2007
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 6:10, s. 869-77
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS. METHODS: We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study. FINDINGS: A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0.012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3.28x10(-6), odds ratio 1.58, 95% CI 1.30-1.91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0.00016). INTERPRETATION: Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis.
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| 22. |
- Albacete, Javier L., et al.
(författare)
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Predictions for p + Pb Collisions at sN N = √5 TeV : Comparison with Data
- 2016
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Ingår i: International Journal of Modern Physics E. - 0218-3013. ; 25:9
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Forskningsöversikt (refereegranskat)abstract
- Predictions made in Albacete et al. [Int. J. Mod. Phys. E 22 (2013) 1330007] prior to the LHC p+Pb run at sNN = 5 TeV are compared to currently available data. Some predictions shown here have been updated by including the same experimental cuts as the data. Some additional predictions are also presented, especially for quarkonia, that were provided to the experiments before the data were made public but were too late for the original publication.
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| 25. |
- Cisneros, David A., et al.
(författare)
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Transducer binding establishes localized interactions to tune sensory rhodopsin II
- 2008
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Ingår i: Structure. - : Elsevier BV. - 0969-2126 .- 1878-4186. ; 16:8, s. 1206-1213
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Tidskriftsartikel (refereegranskat)abstract
- In haloarchaea, sensory rhodopsin II (SRII) mediates a photophobic response to avoid photo-oxidative damage in bright light. Upon light activation the receptor undergoes a conformational change that activates a tightly bound transducer molecule (HtrII), which in turn by a chain of homologous reactions transmits the signal to the chemotactic eubacterial two-component system. Here, using single-molecule force spectroscopy, we localize and quantify changes to the intramolecular interactions within SRII of Natronomonas pharaonis (NpSRII) upon NpHtrII binding. Transducer binding affected the interactions at transmembrane alpha helices F and G of NpSRII to which the transducer was in contact. Remarkably, the interactions were distributed asymmetrically and significantly stabilized alpha helix G entirely but alpha helix F only at its extracellular tip. These findings provide unique insights into molecular mechanisms that "prime" the complex for signaling, and guide the receptor toward transmitting light-activated structural changes to its cognate transducer.
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