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Sökning: WFRF:(McEvoy Linda K)

  • Resultat 1-9 av 9
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1.
  • Pattaro, Cristian, et al. (författare)
  • Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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2.
  • Desikan, Rahul S, et al. (författare)
  • Amyloid-β associated volume loss occurs only in the presence of phospho-tau.
  • 2011
  • Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 70:4, s. 657-61
  • Tidskriftsartikel (refereegranskat)abstract
    • The relationship between neurodegeneration and the 2 hallmark proteins of Alzheimer's disease, amyloid-β (Aβ) and tau, is still unclear. Here, we examined 286 nondemented participants (107 cognitively normal older adults and 179 memory impaired individuals) who underwent longitudinal magnetic resonance (MR) imaging and lumbar puncture. Using mixed effects models, we investigated the relationship between longitudinal entorhinal cortex atrophy rate, cerebrospinal fluid (CSF) p-tau(181p) and CSF Aβ(1-42) . We found a significant relationship between elevated entorhinal cortex atrophy rate and decreased CSF Aβ(1-42) only with elevated CSF p-tau(181p) . Our findings indicate that Aβ-associated volume loss occurs only in the presence of phospho-tau in humans at risk for dementia.
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4.
  • Desikan, Rahul S, et al. (författare)
  • The role of clusterin in amyloid-β-associated neurodegeneration.
  • 2014
  • Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 71:2, s. 180-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.
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5.
  • Fjell, Anders M, et al. (författare)
  • Brain Atrophy in Healthy Aging Is Related to CSF Levels of A{beta}1-42.
  • 2010
  • Ingår i: Cerebral cortex. - : Oxford University Press (OUP). - 1460-2199 .- 1047-3211. ; 20:9, s. 2069-2079
  • Tidskriftsartikel (refereegranskat)abstract
    • Reduced levels of beta-amyloid(1-42) (Abeta1-42) and increased levels of tau proteins in the cerebrospinal fluid (CSF) are found in Alzheimer's disease (AD), likely reflecting Abeta deposition in plaques and neuronal and axonal damage. It is not known whether these biomarkers are associated with brain atrophy also in healthy aging. We tested the relationship between CSF levels of Abeta1-42 and tau (total tau and tau phosphorylated at threonine 181) proteins and 1-year brain atrophy in 71 cognitively normal elderly individuals. Results showed that under a certain threshold value, levels of Abeta1-42 correlated highly with 1-year change in a wide range of brain areas. The strongest relationships were not found in the regions most vulnerable early in AD. Above the threshold level, Abeta1-42 was not related to brain changes, but significant volume reductions as well as ventricular expansion were still seen. It is concluded that Abeta1-42 correlates with brain atrophy and ventricular expansion in a subgroup of cognitively normal elderly individuals but that reductions independent of CSF levels of Abeta1-42 is common. Further research and follow-up examinations over several years are needed to test whether degenerative pathology will eventually develop in the group of cognitively normal elderly individuals with low levels of Abeta1-42.
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6.
  • Kauppi, Karolina, et al. (författare)
  • Combining Polygenic Hazard Score With Volumetric MRI and Cognitive Measures Improves Prediction of Progression From Mild Cognitive Impairment to Alzheimer's Disease
  • 2018
  • Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 12
  • Tidskriftsartikel (refereegranskat)abstract
    • Improved prediction of progression to Alzheimer's Disease (AD) among older individuals with mild cognitive impairment (MCI) is of high clinical and societal importance. We recently developed a polygenic hazard score (PHS) that predicted age of AD onset above and beyond APOE. Here, we used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to further explore the potential clinical utility of PHS for predicting AD development in older adults with MCI. We examined the predictive value of PHS alone and in combination with baseline structural magnetic resonance imaging (MRI) data on performance on the Mini-Mental State Exam (MMSE). In survival analyses, PHS significantly predicted time to progression from MCI to AD over 120 months (p = 1.07e-5), and PHS was significantly more predictive than APOE alone (p = 0.015). Combining PHS with baseline brain atrophy score and/or MMSE score significantly improved prediction compared to models without PHS (three-factor model p = 4.28e-17). Prediction model accuracies, sensitivities and area under the curve were also improved by including PHS in the model, compared to only using atrophy score and MMSE. Further, using linear mixed-effect modeling, PHS improved the prediction of change in the Clinical Dementia Rating—Sum of Boxes (CDR-SB) score and MMSE over 36 months in patients with MCI at baseline, beyond both APOE and baseline levels of brain atrophy. These results illustrate the potential clinical utility of PHS for assessment of risk for AD progression among individuals with MCI both alone, or in conjunction with clinical measures of prodromal disease including measures of cognitive function and regional brain atrophy.
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7.
  • Kauppi, Karolina, et al. (författare)
  • Revisiting Antipsychotic Drug Actions Through Gene Networks Associated With Schizophrenia
  • 2018
  • Ingår i: American Journal of Psychiatry. - : AMER PSYCHIATRIC PUBLISHING, INC. - 0002-953X .- 1535-7228. ; 175:7, s. 674-682
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Antipsychotic drugs were incidentally discovered in the 1950s, but their mechanisms of action are still not understood. Better understanding of schizophrenia pathogenesis could shed light on actions of current drugs and reveal novel "druggable" pathways for unmet therapeutic needs. Recent genome-wide association studies offer unprecedented opportunities to characterize disease gene networks and uncover drug-disease relationships. Polygenic overlap between schizophrenia risk genes and antipsychotic drug targets has been demonstrated, but specific genes and pathways constituting this overlap are undetermined. Risk genes of polygenic disorders do not operate in isolation but in combination with other genes through protein-protein interactions among gene product.Method: The protein interactome was used to map antipsychotic drug targets (N=88) to networks of schizophrenia risk genes (N=328).Results: Schizophrenia risk genes were significantly localized in the interactome, forming a distinct disease module. Core genes of the module were enriched for genes involved in developmental biology and cognition, which may have a central role in schizophrenia etiology. Antipsychotic drug targets overlapped with the core disease module and comprised multiple pathways beyond dopamine. Some important risk genes like CHRN, PCDH, and HCN families were not connected to existing antipsychotics but may be suitable targets for novel drugs or drug repurposing opportunities to treat other aspects of schizophrenia, such as cognitive or negative symptoms.Conclusions: The network medicine approach provides a platform to collate information of disease genetics and drug-gene interactions to shift focus from development of antipsychotics to multitarget antischizophrenia drugs. This approach is transferable to other diseases.
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8.
  • Lo, Min-Tzu, et al. (författare)
  • Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders
  • 2017
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:1, s. 152-156
  • Tidskriftsartikel (refereegranskat)abstract
    • Personality is influenced by genetic and environmental factors(1) and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci(2,3), significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132-260,861). Of these genome-wide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422-18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit- hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion-introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety).
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9.
  • Lo, Min-Tzu, et al. (författare)
  • Identification of genetic heterogeneity of Alzheimer's disease across age
  • 2019
  • Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 84, s. 243.e1-243.e9
  • Tidskriftsartikel (refereegranskat)abstract
    • The risk of APOE for Alzheimer's disease (AD) is modified by age. Beyond APOE, the polygenic architecture may also be heterogeneous across age. We aim to investigate age-related genetic heterogeneity of AD and identify genomic loci with differential effects across age. Stratified gene-based genome-wide association studies and polygenic variation analyses were performed in the younger (60-79 years, N = 14,895) and older (>= 80 years, N = 6559) age-at-onset groups using Alzheimer's Disease Genetics Consortium data. We showed a moderate genetic correlation (r(g) = 0.64) between the two age groups, supporting genetic heterogeneity. Heritability explained by variants on chromosome 19 (harboring APOE) was significantly larger in younger than in older onset group (p < 0.05). APOE region, BIN1, OR2S2, MS4A4E, and PICALM were identified at the gene-based genome-wide significance (p < 2.73 x 10(-6)) with larger effects at younger age (except MS4A4E). For the novel gene OR2S2, we further performed leave-one-out analyses, which showed consistent effects across subsamples. Our results suggest using genetically more homogeneous individuals may help detect additional susceptible loci. Published by Elsevier Inc.
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