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Sökning: WFRF:(Wolf Christiane)

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  • Adams, Hieab H. H., et al. (författare)
  • Novel genetic loci underlying human intracranial volume identified through genome-wide association
  • 2016
  • Ingår i: Nature Neuroscience. - 1097-6256 .- 1546-1726. ; 19:12, s. 1569-1582
  • Tidskriftsartikel (refereegranskat)abstract
    • Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
  • Debette, Stéphanie, et al. (författare)
  • Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection
  • 2015
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 47, s. 78-83
  • Tidskriftsartikel (refereegranskat)abstract
    • Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year)1. Minor cervical traumas, infection, migraine and hypertension are putative risk factors1–3, and inverse associations with obesity and hypercholesterolemia are described3,4. No confirmed genetic susceptibility factors have been identified using candidate gene approaches5. We performed genome-wide association studies (GWAS) in 1 1,393 CeAD cases and 1 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69–0.82; P = 4.46 × 1 10−10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 1 × 1 10−3; combined P = 1 1.00 × 1 10−1111). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction6–9. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.
  • Hibar, Derrek P., et al. (författare)
  • Common genetic variants influence human subcortical brain structures
  • 2015
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 520:7546, s. 224-U216
  • Tidskriftsartikel (refereegranskat)abstract
    • The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume(5) and intracranial volume(6). These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 X 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
  • Hibar, Derrek P., et al. (författare)
  • Novel genetic loci associated with hippocampal volume
  • 2017
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
  • Jeglinski, Jana W. E., et al. (författare)
  • Differences in foraging ecology align with genetically divergent ecotypes of a highly mobile marine top predator
  • 2015
  • Ingår i: Oecologia. - 0029-8549 .- 1432-1939. ; 179:4, s. 1041-1052
  • Tidskriftsartikel (refereegranskat)abstract
    • Foraging differentiation within a species can contribute to restricted gene flow between ecologically different groups, promoting ecological speciation. Galapagos sea lions (Zalophus wollebaeki) show genetic and morphological divergence between the western and central archipelago, possibly as a result of an ecologically mediated contrast in the marine habitat. We use global positioning system (GPS) data, time-depth recordings (TDR), stable isotope and scat data to compare foraging habitat characteristics, diving behaviour and diet composition of Galapagos sea lions from a western and a central colony. We consider both juvenile and adult life stages to assess the potential role of ontogenetic shifts that can be crucial in shaping foraging behaviour and habitat choice for life. We found differences in foraging habitat use, foraging style and diet composition that aligned with genetic differentiation. These differences were consistent between juvenile and adult sea lions from the same colony, overriding age-specific behavioural differences. Our study contributes to an understanding of the complex interaction of ecological condition, plastic behavioural response and genetic make-up of interconnected populations.
  • Mishra, Laxmi S., 1983- (författare)
  • FtsH metalloproteases and their pseudo-proteases in the chloroplast envelope of Arabidopsis thaliana
  • 2021
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • By cleaving peptide bonds, proteases either activate or degrade proteins and maintain protein quality control in response to various developmental stimuli and environmental factors. My work has focused on elucidating the role of the filamentation temperature sensitive protein H (FtsH) proteases. FtsHs belong to a membrane-embedded class of proteases found in eubacteria, animals and plants, which are located in the organelles of endosymbiosis (mitochondria and chloroplasts). They possess an AAA+ (ATPase associated with various cellular activities) and a peptidase M41 domain containing the HEXXH consensus sequence in the Zn2+ metalloprotease domain. FtsH proteases are known to form ring-like homo- or hetero-hexameric complexes. Arabidopsis thaliana, the model plant used in this study, contains seventeen AtFtsH proteases, of which twelve are presumably proteolytically active and five presumably proteolytic inactive members, known as AtFtsHi (i for inactive). In AtFtsHi members, the HEXXH motif is either deleted (AtFtsHi3) or mutated (AtFtsHi1, 2, 4, 5). Twelve AtFtsHs (AtFtsH 1, 2, 5–9, 11, 12 and AtFtsHi 1-5) are targeted to the chloroplast, whereas the remaining three (AtFtsH 3, 4 and 10) are mitochondrial. In Paper I, we demonstrate that AtFtsH12 interacts with AtFtsHi1, 2, 4, 5 to form a heteromeric complex. Abundance of these AtFtsH12-AtFtsHi complexes alters the accumulation of TIC (translocon on the inner chloroplast membrane) complexes. Transgenic mi12 (miRNA) knockdown plants that express lower amounts of AtFtsH12 displayed a pale-seedling and an aberrant chloroplast phenotype. mi12 plants displayed lowered total chlorophyll (Chla+Chlb) amount compared to wild type (WT), complementation lines and native AtFtsH12 promoter overexpressor (ox12) lines. Our biochemical studies identified drastic modifications in the total proteome of mi12 seedlings. N-terminome analyses of mi12 seedlings showed undisturbed plastidic protein maturation. In Paper II, we have shown that single mutants depleted in AtFTSHI1, 2, 4 or 5 are embryo-lethal, suggesting the pseudo-proteases to have an indispensable role in seed germination. This study further identified “weak” Atftshi1, Atftshi4, Atftshi3-1(kd) and Atftshi3-2 homozygous mutants, which develop into plants with altered photosynthetic efficiency. Field experiments were performed to determine the Darwinian fitness of these homozygous as well as heterozygous AtFtsHi mutants. The results suggested AtFtsHi enzymes to be critical during early developmental stages. A complete Atftshi3 knockdown mutant (Atftshi3-1(kd)) was identified (described in Paper III), which is not embryo-lethal and tolerates drought better than WT plants. Atftshi3-1(kd) leaves were smaller with fewer and smaller stomatal aperture. Above ground, Atftshi3-1(kd) leaves displayed lowered stomatal conductance and increased WUEi (intrinsic water-use efficiency), while below ground, the root-associated bacterial community showed a typical drought stress response. Upregulated transcripts of the ABA-responsive genes in leaves of Atftshi3-1(kd) compared to WT indicate the drought tolerance to be controlled independently of ABA. To conclude, AtFtsHi pseudo-proteases affect various stages of plant development and abiotic stress management, especially drought.
  • Polonis, Katarzyna, et al. (författare)
  • A multilocus genetic risk score is associated with arterial stiffness in hypertensive patients : The CARE NORTH study
  • 2018
  • Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352. ; 36:9, s. 1882-1888
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Arterial stiffness is recognized as an intermediate phenotype and predictor of cardiovascular disease. Arterial stiffness is complex in origin with contributions from lifestyle and genetic factors. However, the association between single nucleotide polymorphisms (SNPs) and arterial stiffness remains unclear. Objective: The aim is to assess whether a multilocus genetic risk score (GRS), composed of selected SNPs linked to cardiovascular traits and outcomes, is associated with arterial stiffness in patients with hypertension. Design and methods: This study included 730 participants derived from the CARE NORTH study. The arterial stiffness was evaluated by carotid-femoral pulse wave velocity (cfPWV). An adjusted linear regression was used to evaluate the association between cfPWV and each individual SNP using multiple genetic models. The association between a constructed GRS and cfPWV was tested in an unadjusted and adjusted model. Results: We selected 13 SNPs found to be associated with cfPWV (P<.05): 6 SNPs in additive, 4 SNPs in recessive and 3 SNPs in dominant mode of inheritance. The GRS based on these SNPs was positively associated with cfPWV both in unadjusted and adjusted models (β = 0.2m/s, 95% CI 0.11-0.29, P - 7.6 × 10-6 and β = 0.22 m/s, 95% CI 0.15-0.28, P=1.4 × 10-10, respectively). The GRS explained an additional 3.6% cfPWV variance above clinical covariates. Conclusion: We demonstrate that the GRS composed of 13 SNPs related to cardiovascular phenotypes is associated with an increased arterial stiffness in hypertensive patients. Our findings may help to clarify genetic basis of arterial stiffening and provide insight into mechanisms underlying this phenotype.
  • Satizabal, Claudia L., et al. (författare)
  • Genetic architecture of subcortical brain structures in 38,851 individuals
  • 2019
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
  • Tidskriftsartikel (refereegranskat)abstract
    • Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
  • Thompson, Paul M., et al. (författare)
  • The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
  • 2014
  • Ingår i: BRAIN IMAGING BEHAV. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
  • Tidskriftsartikel (refereegranskat)abstract
    • The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
  • Ådén, Jörgen, 1980-, et al. (författare)
  • Arabidopsis thaliana peroxiredoxin Q is extraordinarily dynamic on the μs-ms timescale
  • Annan publikation (övrigt vetenskapligt)abstract
    • Peroxiredoxin Q (PrxQ) isolated from Arabidopsis thaliana belongs to a family of redox enzymes called peroxiredoxins, which are thioredoxin- or glutaredoxin dependent peroxidases acting to reduce peroxides and in particular hydrogen peroxide. PrxQ cycles between an active reduced state and an inactive oxidized state during its catalytic cycle. The catalytic mechanism involves a nucleophilic attack of the catalytic cysteine on hydrogen peroxide to generate a sulfonic acid intermediate with a concerted release of a water molecule. This intermediate is subsequently relaxed by the reaction of a second cysteine, denoted as the resolving cysteine, generating an intermolecular disulphide bond to expel a second water molecule into solution. PrxQ is finally recycled to the active state by a thioredoxin dependent reduction. Previous structural studies of PrxQ homologues have provided the structural basis for the switch between reduced and oxidized conformations. Here we have performed a detailed study of the structure and dynamics of PrxQ in both the oxidized and reduced state. Reliable and experimentally validated structural models of PrxQ in both oxidation states were generated using homology based modeling. Model-free analyses of NMR spin relaxation show that PrxQ is monomeric in both oxidation states. As evident from fast R2 relaxation rates the reduced form of PrxQ undergoes unprecedented dynamics on the slow μs-ms timescale. The ground state of the conformational dynamics is likely the stably folded reduced state as implied by circular dichroism spectroscopy. We speculate that the extensive dynamics is intimately related to the catalytic function of PrxQ.
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