Your search for: 'author:("Morgan, Kevin")' has returned 8 results. (0.022s) Save search

Authors: Turton, James C. | Bullock, James | Medway, Christopher | Shi, Hui | Brown, Kristelle | Belbin, Olivia | Kalsheker, Noor | Carrasquillo, Minerva M. | Dickson, Dennis W. | Graff-Radford, Neill R. | Petersen, Ronald C. | Younkin, Steven G. | Morgan, Kevin

Article Type: Research Article

Abstract: The missing heritability exhibited by late-onset Alzheimer's disease is unexplained and has been partly attributed to epistatic interaction. Methods available to explore this are often based on logistic regression and allow for determination of deviation from an expected outcome as a result of statistical epistasis. Three such methodologies including Synergy Factor and the PLINK modules, –epistasis and –fast-epistasis, were applied to study an epistatic interaction between interleukin-6 and interleukin-10. The models analyzed consisted of two synergistic interactions (SF ≈ 4.2 and 1.6) and two antagonistic interactions (SF ≈ 0.9 and 0.6). As with any statistical test, power to detect association …is paramount; and most studies will be underpowered for the task. However, the availability of large sample sizes through genome-wide association studies make it feasible to examine approaches for determining epistatic interactions. This study documents the sample sizes needed to achieve a statistically significant outcome from each of the methods examined and discusses the limitations/advantages of the chosen approaches. Show more

Keywords: Complex disorders, epistasis, LOAD, modeling, PLINK, synergy factor

DOI: 10.3233/JAD-2011-110197

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 635-644, 2011

Authors: Vafadar-Isfahani, Baharak | Ball, Graham | Coveney, Clare | Lemetre, Christophe | Boocock, David | Minthon, Lennart | Hansson, Oskar | Miles, Amanda Kathleen | Janciauskiene, Sabina M | Warden, Donald | Smith, A. David | Wilcock, Gordon | Kalsheker, Noor | Rees, Robert | Matharoo-Ball, Balwir | Morgan, Kevin

Article Type: Research Article

Abstract: We have used proteomic fingerprinting to investigate diagnosis of Alzheimer's disease (AD). Samples of lumbar cerebrospinal fluid (CSF) from clinically-diagnosed AD cases (n = 33), age-matched controls (n = 20), and mild cognitive impairment (MCI) patients (n = 10) were used to obtain proteomic profiles, followed by bioinformatic analysis that generated a set of potential biomarkers in CSF samples that could discriminate AD cases from controls. The identity of the biomarker ions was determined using mass spectroscopy. The panel of seven peptide biomarker ions was able to discriminate AD patients from controls with a median accuracy of 95% (sensitivity 85%, …specificity 97%). When this model was applied to an independent blind dataset from MCI patients, the intensity of signals was intermediate between the control and AD patients implying that these markers could potentially predict patients with early neurodegenerative disease. The panel were identified, in order of predictive ability, as SPARC-like 1 protein, fibrinogen alpha chain precursor, amyloid-β, apolipoprotein E precursor, serum albumin precursor, keratin type I cytoskeletal 9, and tetranectin. The 7 ion ANN model was further validated using an independent cohort of samples, where the model was able to classify AD cases from controls with median accuracy of 84.5% (sensitivity 93.3%, specificity 75.7%). Validation by immunoassay was performed on the top three identified markers using the discovery samples and an independent sample cohort which was from postmortem confirmed AD patients (n = 17). Show more

Keywords: Alzheimer's disease, biomarker, MALDI-MS, SPARCL1

DOI: 10.3233/JAD-2011-111505

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 625-636, 2012

Authors: Brookes, Keeley J. | McConnell, George | Williams, Kirsty | Chaudhury, Sultan | Madhan, Gaganjit | Patel, Tulsi | Turley, Christopher | Guetta-Baranes, Tamar | Bras, Jose | Guerreiro, Rita | Hardy, John | Francis, Paul T. | Morgan, Kevin

Article Type: Short Communication

Abstract: The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer’s disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOE ɛ 4 allele was identified (p = 3.99×10–12 ). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert et al. …GWAS meta-analysis was observed. Show more

Keywords: Alzheimer’s disease, association, Brains for Dementia Research, genome-wide association study, single nucleotide polymorphisms

DOI: 10.3233/JAD-180191

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 355-362, 2018

Authors: Boden, Kirsty A. | Barber, Imelda S. | Clement, Naomi | Patel, Tulsi | Guetta-Baranes, Tamar | Brookes, Keeley J. | Chappell, Sally | Craigon, Jim | Chapman, Natalie H. | ARUK Consortium | Morgan, Kevin | Seymour, Graham B. | Bottley, Andrew

Article Type: Research Article

Abstract: A number of genetic loci associate with early onset Alzheimer’s disease (EOAD); however, the drivers of this disease remains enigmatic. Genome wide association and in vivo modeling have shown that loss-of-function, e.g., ABCA7, reduced levels of SIRT1 and MEFF2C, or increased levels of PTK2β confer risk or link to the pathogenies. It is known that DNA methylation can profoundly affect gene expression and can impact on the composition of the proteome; therefore, the aim of this study is to assess if genes associated with sporadic EOAD (sEOAD) are differentially methylated. Epi-profiles of DNA extracted from blood and cortex were compared …using a pyrosequencing platform. We identified significant group-wide hypomethylation in AD blood when compared to controls for 7 CpGs located within the 3’UTR of RIN3 (CpG1 p  = 0.019, CpG2 p  = 0.018, CpG3 p  = 0.012, CpG4 p  = 0.009, CpG5 p  = 0.002, CpG6 p  = 0.018, and CpG7 p  = 0.013, respectively; AD/Control n  = 22/26; Male/Female n  = 27/21). Observed effects were not gender specific. No group wide significant differences were found in the promoter methylation of PTK2 β, ABCA7 , SIRT1 , or MEF2C, genes known to associate with late onset AD. A rare and significant difference in methylation was observed for one CpG located upstream of the MEF2C promoter in one AD individual only (22% reduction in methylation, p  = 2.0E-10; Control n  = 26, AD n  = 25, Male/Female n  = 29/22). It is plausible aberrant methylation may mark sEOAD in blood and may manifest in some individuals as rare epi-variants for genes linked to sEOAD. Show more

Keywords: Alzheimer’s disease, epigenetics, methylation, sporadic early onset

DOI: 10.3233/ADR-170015

Citation: Journal of Alzheimer's Disease Reports, vol. 1, no. 1, pp. 97-108, 2017

Authors: Belbin, Olivia | Morgan, Kevin | Medway, Chris | Warden, Donald | Cortina-Borja, Mario | van Duijn, Cornelia M. | Adams, Hieab H.H. | Frank-Garcia, Ana | Brookes, Keeley | Sánchez-Juan, Pascual | Alvarez, Victoria | Heun, Reinhard | Kölsch, Heike | Coto, Eliecer | Kehoe, Patrick G. | Rodriguez-Rodriguez, Eloy | Bullido, Maria J | Ikram, M. Arfan | Smith, A. David | Lehmann, Donald J.

Article Type: Research Article

Abstract: Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer’s disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF , DBH , and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern …Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1–1.2, p  = 0.005–0.3), an effect size that was consistent in the Northern European (OR = 1.1–1.2, p  = 0.002–0.8) but not the smaller Spanish (OR = 0.8–1.6, p  = 0.4–1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3–1.5 p  = 0.002–0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2–1.3, p  = 0.007–0.00008) than men (OR = 0.9–1.0, p  = 0.3–0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p  = 0.04) the synergistic interaction (SF = 2.2, p  = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p  = 0.04) than men (SF = 2.0, p  = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, dopamine beta-hydroxylase, epistasis, genetics, neurotrophins, Sortilin

DOI: 10.3233/JAD-181116

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1535-1547, 2019

Authors: Carrasquillo, Minerva M. | Belbin, Olivia | Hunter, Talisha A. | Ma, Li | Bisceglio, Gina D. | Zou, Fanggeng | Crook, Julia E. | Pankratz, V. Shane | Sando, Sigrid B. | Aasly, Jan O. | Barcikowska, Maria | Wszolek, Zbigniew K. | Dickson, Dennis W. | Graff-Radford, Neill R. | Petersen, Ronald C. | Morgan, Kevin | for the Alzheimer's Research Trust Consortium (ART) | Younkin, Steven G.

Article Type: Research Article

Abstract: The most recent late-onset Alzheimer's disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p = 1.6 × 10−11 ) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p = 6.5 × 10−9 ). We have genotyped these variants in a large (3,287 LOAD, 4,396 controls), independent dataset comprising eleven case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and also tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 status. Meta-analysis results showed no evidence of series heterogeneity and logistic regression analysis successfully …replicated the association of BIN1 (rs744373) with LOAD with an odds ratio (OR = 1.17, p = 1.1 × 10−4 ) comparable to that previously reported (OR = 1.15). The variant near EXOC3L2 (rs597668) showed only suggestive association with LOAD (p = 0.09) after correcting for the presence of the APOE ε4 allele. Addition of our follow-up data to the results previously reported increased the strength of evidence for association with BIN1 (11,825 LOAD, 32,570 controls, rs744373 Fisher combined p = 3.8 × 10−20 ). We also tested for epistatic interaction between these variants and APOE ε4 as well as with the previously replicated LOAD GWAS genes (CLU: rs11136000, CR1: rs3818361, and PICALM: rs3851179). No significant interactions between these genes were detected. In summary, we provide additional evidence for the variant near BIN1 (rs744373) as a LOAD risk modifier, but our results indicate that the effect of EXOC3L2 independent of APOE ε4 should be studied further. Show more

Keywords: Alzheimer's disease, case-control studies, heterogeneity, late onset, meta-analysis

DOI: 10.3233/JAD-2011-101932

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 751-758, 2011

Authors: Belbin, Olivia | Brown, Kristelle | Shi, Hui | Medway, Christopher | Abraham, Richard | Passmore, Peter | Mann, David | Smith, A. David | Holmes, Clive | McGuinness, Bernadette | Craig, David | Warden, Donald | Heun, Reinhard | Kölsch, Heike | Love, Seth | Kalsheker, Noor | Williams, Julie | Owen, Michael J. | Carrasquillo, Minerva | Younkin, Steven | Morgan, Kevin | Kehoe, Patrick G.

Article Type: Research Article

Abstract: A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-β (Aβ) peptide. Thus, altered Aβ degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aβ-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association …with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies. Show more

Keywords: Alzheimer's disease, angiotensin-1 converting enzyme, haplotype, heterogeneity, late onset, meta-analysis

DOI: 10.3233/JAD-2011-101914

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 587-597, 2011

Authors: Gerrish, Amy | Russo, Giancarlo | Richards, Alexander | Moskvina, Valentina | Ivanov, Dobril | Harold, Denise | Sims, Rebecca | Abraham, Richard | Hollingworth, Paul | Chapman, Jade | Hamshere, Marian | Pahwa, Jaspreet Singh | Dowzell, Kimberley | Williams, Amy | Jones, Nicola | Thomas, Charlene | Stretton, Alexandra | Morgan, Angharad R. | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K. | Brayne, Carol | Rubinsztein, David C. | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Morgan, Kevin | Brown, Kristelle S. | Passmore, Peter A. | Craig, David | McGuinness, Bernadette | Todd, Stephen | Johnston, Janet A. | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Hardy, John | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Kölsch, Heike | Heun, Reinhard | Schürmann, Britta | Bussche, Hendrik van den | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Rujescu, Dan | Goate, Alison M. | Kauwe, John S. K | Cruchaga, Carlos | Nowotny, Petra | Morris, John C. | Mayo, Kevin | Livingston, Gill | Bass, Nicholas J. | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Davies, Gail | Harris, Sarah E. | Starr, John M. | Deary, Ian J. | Al-Chalabi, Ammar | Shaw, Christopher E. | Tsolaki, Magda | Singleton, Andrew B. | Guerreiro, Rita | Mühleisen, Thomas W. | Nöthen, Markus M. | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H-Erich | Carrasquillo, Minerva M | Pankratz, V Shane | Younkin, Steven G. | Jones, Lesley | Holmans, Peter A | O'Donovan, Michael C. | Owen, Michael J. | Williams, Julie

Article Type: Research Article

Abstract: Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent …genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, genetics, human, MAPT protein, PSEN1 protein, PSEN2 protein

DOI: 10.3233/JAD-2011-110824

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 377-387, 2012