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- Guerreiro, R., et al.
(author)
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Heritability and genetic variance of dementia with Lewy bodies
- 2019
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In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 127, s. 492-501
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Journal article (peer-reviewed)abstract
- Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants. © 2019 Elsevier Inc.
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- Guerreiro, R., et al.
(author)
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Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study
- 2018
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In: Lancet Neurology. - 1474-4422. ; 17:1, s. 64-74
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Journal article (peer-reviewed)abstract
- Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2.40, 95% CI 2.14-2.70; p=1.05 x 10-48), SNCA (rs7681440; OR 0.73, 0.66-0.81; p=6.39 x 10(-10)), and GBA (rs35749011; OR 2.55, 1.88-3.46; p=1.78 x 10(-9)). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1.51, 1.27-1.79; p=2.32 x 10(-6)); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.
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- Springer, W, et al.
(author)
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Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)
- 2016
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In: Movement Disorders. - : Wiley. - 0885-3185. ; 31:Suppl. S2, s. 282-282
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Conference paper (peer-reviewed)abstract
- Objective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype.
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- Chisholm, J., et al.
(author)
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The far-ultraviolet continuum slope as a Lyman Continuum escape estimator at high redshift
- 2022
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 517:4, s. 5104-5120
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Journal article (peer-reviewed)abstract
- Most of the hydrogen in the intergalactic medium (IGM) was rapidly ionized at high redshifts. While observations have established that reionization occurred, observational constraints on the high-redshift ionizing emissivity remain elusive. Here, we present a new analysis of the Low-redshift Lyman Continuum Survey (LzLCS) and literature observations, a combined sample of 89 star-forming galaxies at redshifts near 0.3 with Hubble Space Telescope observations of their ionizing continua (or Lyman Continuum, LyC). We find a strong (6σ significant) inverse correlation between the continuum slope at 1550 Å (defined as Fλ ∝ λβ1550obs) and both the LyC escape fraction (fesc, LyC) and fesc, LyC times the ionizing photon production efficiency (ξion). On average, galaxies with redder continuum slopes have smaller fesc, LyC than galaxies with bluer slopes mainly due to higher dust attenuation. More than 5 per cent (20 per cent) of the LyC emission escapes galaxies with β1550obs <−2.1 (−2.6). We find strong correlations between β1550obs and the [O III]/[O II] flux ratio (at 7.5σ significance), galaxy stellar mass (at 5.9σ), the gas-phase metallicity (at 4.6σ), and the observed far-ultraviolet absolute magnitude (at 3.4σ). Using previous observations of β1550obs at high redshift, we estimate the evolution of fesc, LyC with both redshift and galaxy magnitude. The LzLCS observations suggest that fainter and lower mass galaxies dominate the ionizing photon budget at higher redshift, possibly due to their rapidly evolving metal and dust content. Finally, we use our correlation between β1550obs and fesc, LyC × ξion to predict the ionizing emissivity of galaxies during the epoch of reionization. Our estimated emissivities match IGM observations, and suggest that star-forming galaxies emit sufficient LyC photons into the IGM to exceed recombinations near redshifts of 7–8.
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- Marques-Chaves, R., et al.
(author)
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No correlation of the Lyman continuum escape fraction with spectral hardness
- 2022
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 663
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Journal article (peer-reviewed)abstract
- The properties that govern the production and escape of hydrogen-ionizing photons (Lyman continuum, LyC; with energies > 13.6 eV) in star-forming galaxies are still poorly understood, but they are key to identifying and characterizing the sources that reionized the Universe. Here we empirically explore the relation between the hardness of ionizing radiation and the LyC leakage in a large sample of low-z star-forming galaxies from the recent Hubble Space Telescope Low-z Lyman Continuum Survey. Using Sloan Digital Sky Survey stacks and deep X-shooter observations, we investigate the hardness of the ionizing spectra (QHe+/QH) between 54.4 eV (He+) and 13.6 eV (H) from the optical recombination lines He II 4686 Å and Hβ 4861 Å for galaxies with LyC escape fractions spanning a wide range, fesc(LyC) ≃ 0−90%. We find that the observed intensity of He II/Hβ is primarily driven by variations in the metallicity, but is not correlated with LyC leakage. Both very strong (esc(LyC)> ≃ 0.5) and nonleakers (esc(LyC)> ≃ 0) present similar observed intensities of He II and Hβ at comparable metallicity, between ≃0.01 and ≃0.02 for 12 + log(O/H)> 8.0 and < 8.0, respectively. Our results demonstrate that QHe+/QH does not correlate with fesc(LyC), which implies that strong LyC emitters do not show harder ionizing spectra than nonleakers at similar metallicity.
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| 10. |
- Soto-Ortolaza, A. I., et al.
(author)
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GWAS risk factors in Parkinson's disease : LRRK2 coding variation and genetic interaction with PARK16
- 2013
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In: American Journal of Neurodegenerative Disease. - 2165-591X. ; 2:4, s. 99-287
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Journal article (peer-reviewed)abstract
- Parkinson's disease (PD) is a multifactorial movement disorder characterized by progressive neurodegeneration. Genome-wide association studies (GWAS) have nominated over fifteen distinct loci associated with risk of PD, however the biological mechanisms by which these loci influence disease risk are mostly unknown. GWAS are only the first step in the identification of disease genes: the specific causal variants responsible for the risk within the associated loci and the interactions between them must be identified to fully comprehend their impact on the development of PD. In the present study, we first attempted to replicate the association signals of 17 PD GWAS loci in our series of 1381 patients with PD and 1328 controls. BST1, SNCA, HLA-DRA, CCDC62/HIP1R and MAPT all showed a significant association with PD under different models of inheritance and LRRK2 showed a suggestive association. We then examined the role of coding LRRK2 variants in the GWAS association signal for that gene. The previously identified LRRK2 risk mutant p.M1646T and protective haplotype p.N551K-R1398H-K1423K did not explain the association signal of LRRK2 in our series. Finally, we investigated the gene-gene interaction between PARK16 and LRRK2 that has previously been proposed. We observed no interaction between PARK16 and LRRK2 GWAS variants, but did observe a non-significant trend toward interaction between PARK16 and LRRK2 variants within the protective haplotype. Identification of causal variants and the interactions between them is the crucial next step in making biological sense of the massive amount of data generated by GWAS studies. Future studies combining larger sample sizes will undoubtedly shed light on the complex molecular interplay leading to the development of PD.
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