ORCID Profile
0000-0002-8217-2396
Current Organisation
University of Nottingham
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Publisher: Springer Science and Business Media LLC
Date: 11-12-2013
DOI: 10.1038/NATURE12825
Publisher: Springer Science and Business Media LLC
Date: 17-03-2015
DOI: 10.1038/MP.2015.23
Publisher: Springer Science and Business Media LLC
Date: 2009
Publisher: Wiley
Date: 02-08-2011
DOI: 10.1002/AJMG.B.31216
Abstract: We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no in idual run of homozygosity showed association to Alzheimer's disease.
Publisher: Public Library of Science (PLoS)
Date: 16-06-2015
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.NEUROBIOLAGING.2012.08.010
Abstract: Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial "hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimer's disease and 6294 control subjects of the Epistasis Project, ided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35-2.36 p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the ε4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27 95% CI, 1.60-3.20 p < 0.00001), but not in those younger than 75 years (SF, 1.06 95% CI, 0.59-1.91 p = 0.84). The association with Alzheimer's disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0 p ≥ 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the ε4 allele of apolipoprotein E genotype, and geographic region.
Publisher: Public Library of Science (PLoS)
Date: 19-01-2010
Publisher: Elsevier BV
Date: 02-2016
Publisher: Elsevier BV
Date: 08-2012
Publisher: Springer Science and Business Media LLC
Date: 08-11-2011
DOI: 10.1007/S00702-011-0732-4
Abstract: Altered glucose metabolism has been described in Alzheimer's disease (AD). We re-investigated the interaction of the insulin (INS) and the peroxisome proliferator-activated receptor alpha (PPARA) genes in AD risk in the Epistasis Project, including 1,757 AD cases and 6,294 controls. Allele frequencies of both SNPs (PPARA L162V, INS intron 0 A/T) differed between Northern Europeans and Northern Spanish. The PPARA 162LL genotype increased AD risk in Northern Europeans (p = 0.04), but not in Northern Spanish (p = 0.2). There was no association of the INS intron 0 TT genotype with AD. We observed an interaction on AD risk between PPARA 162LL and INS intron 0 TT genotypes in Northern Europeans (Synergy factor 2.5, p = 0.016), but not in Northern Spanish. We suggest that dysregulation of glucose metabolism contributes to the development of AD and might be due in part to genetic variations in INS and PPARA and their interaction especially in Northern Europeans.
Publisher: Public Library of Science (PLoS)
Date: 12-06-2014
Publisher: Public Library of Science (PLoS)
Date: 22-06-2011
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.NEUROBIOLAGING.2008.02.013
Abstract: Mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes are known to cause familial early-onset Alzheimer's disease (AD), which account for around 5% of AD cases. Genetic associations for the remaining "sporadic" cases, other than the risks associated with the apolipoprotein (APOE) epsilon4 allele are currently not fully established. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in PSEN1 are associated with a modified risk for sporadic AD or a modified disease phenotype. Eight tag SNPs were identified using linkage disequilibrium (LD) data from the International HapMap project providing coverage of the entire PSEN1 gene. These SNPs were investigated for AD susceptibility in a case-control haplotype association study (N=714) and for genotype-specific effects on cognitive performance in AD patients (N=169) using non-linear mixed effects modelling. Replication of a mild associated-risk of an intronic PSEN1 polymorphism with AD was achieved (P=0.03). No other single SNPs or haplotypes were associated with AD risk. However, 3 SNPs were associated with an altered rate of cognitive decline underlining their role as genetic modifiers of disease.
Publisher: Wiley
Date: 19-12-2014
Publisher: Springer Science and Business Media LLC
Date: 11-11-2010
Publisher: Elsevier BV
Date: 05-2015
Publisher: Public Library of Science (PLoS)
Date: 23-08-2005
Publisher: IMR Press
Date: 2007
DOI: 10.2741/2275
Abstract: Recent advances in proteomic, transcriptomic and genomic technologies have revealed much about the ACT protein and gene. In this review, we summarize our current understanding of the structure and potential physiological roles of the ACT protein, catalogue the regulatory elements that have been implicated in expression of the ACT gene, describe its tissue-specific expression and list the single nucleotide polymorphisms (SNPs) within the gene that track ACT variability. The ACT gene has been implicated in a number of complex human disorders and its potential involvement as a risk factor for Alzheimer's disease has been the subject of intensive research. However, due to previous limitations in methodologies and inadequate s le numbers the data has been conflicting with many studies failing to be replicated. In this regard, we highlight some potential approaches, which may prove to be beneficial in future studies.
Publisher: The Endocrine Society
Date: 13-03-2008
DOI: 10.1210/EN.2007-1633
Abstract: Prokineticin 1 (PROK1) is a recently described protein with a wide range of functions including tissue-specific angiogenesis, modulation of inflammatory responses, and regulation of hematopoiesis. The objective of this study was to investigate the role of PROK1 and prokineticin receptor 1 (PROKR1) in human endometrium during early pregnancy. PROK1 and PROKR1 expression is significantly elevated in first-trimester decidua, compared with nonpregnant endometrium. Expression of PROK1 and PROKR1 was localized in glandular epithelial and various cellular compartments within the stroma. To investigate the signaling pathways and target genes activated by PROK1, we generated an endometrial epithelial cell line stably expressing PROKR1 (Ishikawa PROKR1 cells). PROK1-PROKR1 interaction induced inositol phosphate mobilization and sequential phosphorylation of c-Src, epidermal growth factor receptor, and ERK 1/2. Gene microarray analysis on RNA extracted from Ishikawa PROKR1 cells treated with 40 nm PROK1 for 8 h revealed 49 genes to be differentially regulated. A number of these genes, including cyclooxygenase (COX)-2, leukemia inhibitory factor, IL-6, IL-8, and IL-11 are regulated in the endometrium during implantation and early pregnancy. We subsequently investigated the effect of PROK1 on expression of COX-2 in Ishikawa PROKR1 cells and first-trimester decidua. COX-2 mRNA and protein expression, and prostaglandin synthesis, were elevated in response to treatment with PROK1. Moreover, expression of COX-2 by PROK1 was dependent on activation of the Gq-phospholipase C-β-cSrc-epidermal growth factor receptor-MAPK/ERK kinase pathway. These data demonstrate that PROK1 and PROKR1 expression is elevated in human decidua during early pregnancy and that PROK1-PROKR1 interaction regulates expression of a host of implantation-related genes.
Publisher: Springer Science and Business Media LLC
Date: 03-07-2202
DOI: 10.1038/NG.803
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.NEUROBIOLAGING.2010.07.018
Abstract: Iron overload may contribute to the risk of Alzheimer's disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.75 (95% confidence interval, 1.1-2.8, p = 0.02) in Northern Europeans. The synergy factor was 3.1 (1.4-6.9 0.007) in subjects with the APOEε4 allele. We found another interaction, between HFE 63HH and TF -2AA, markedly modified by age. Both interactions were found mainly or only in Northern Europeans. The interaction between HFE 282Y and TF C2 has now been replicated twice, in altogether 2313 cases of AD and 7065 controls, and has also been associated with increased iron load. We therefore suggest that iron overload may be a causative factor in the development of AD. Treatment for iron overload might thus be protective in some cases.
Publisher: Springer Science and Business Media LLC
Date: 27-10-2013
DOI: 10.1038/NG.2802
Publisher: Elsevier BV
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 05-06-2013
Publisher: Springer Science and Business Media LLC
Date: 15-02-2021
Publisher: Springer Science and Business Media LLC
Date: 18-10-2011
DOI: 10.1038/MP.2011.125
Publisher: Springer Science and Business Media LLC
Date: 17-07-2017
DOI: 10.1038/NG.3916
Publisher: Springer Science and Business Media LLC
Date: 22-08-2001
Abstract: Alpha1-antichymotrypsin (ACT: new identification SERPINA3) is a member of the serine proteinase inhibitor (serpin) gene family and biochemically has been shown to be a constituent of the senile plaques of Alzheimer's disease. We describe a polymorphism (G-->T) in the promoter region of the ACT gene with the T allele being associated with a 22% increase in the mean plasma ACT concentrations. By reporter gene studies, the T allele is consistently associated with higher mean basal expression in both the human liver cell-line Hep G2 (32%) and in a human glial cell-line T98G (30%). Following 6-h stimulation with the cytokine oncostatin-M, there was a 30-fold increase in Hep G2 and a four-fold increase in T98G cells. The T allele in the promoter region is also in almost complete linkage disequilibrium with the T allele in the signal peptide region of the ACT gene with a standardised disequilibrium coefficient (D') of 0.97 P<0.001. This is the first description of a polymorphism in the ACT gene promoter directly associated with altered gene expression.
Publisher: Massachusetts Medical Society
Date: 10-01-2013
Publisher: Springer Science and Business Media LLC
Date: 06-09-2009
DOI: 10.1038/NG.440
Publisher: American Medical Association (AMA)
Date: 08-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-02-2010
Publisher: Oxford University Press (OUP)
Date: 27-06-2014
DOI: 10.1093/HMG/DDU334
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-03-2012
Publisher: Oxford University Press (OUP)
Date: 11-11-2012
DOI: 10.1093/HMG/DDS476
Publisher: Springer Science and Business Media LLC
Date: 29-05-2013
DOI: 10.1038/NG0613-712A
Publisher: Public Library of Science (PLoS)
Date: 15-11-2010
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-06-2018
Abstract: Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric and neurologic disorders share relatively little common genetic risk. However, different and independent pathways can result in similar clinical manifestations (e.g., psychosis, which occurs in both schizophrenia and Alzheimer's disease). Schizophrenia correlated with many psychiatric disorders, whereas the immunopathological affliction Crohn's disease did not, and posttraumatic stress syndrome was also largely independent of underlying traits. Essentially, the earlier the onset of a disorder, the more inheritable it appeared to be. Science , this issue p. eaap8757
Publisher: Wiley
Date: 30-03-2016
DOI: 10.1002/ANA.24621
Publisher: Springer Science and Business Media LLC
Date: 28-07-2011
Abstract: A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33 . Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A , independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B . In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B , and CD33 ) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 dosage. We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for EPHA1 (rs11767557 OR = 0.87, p = 5 × 10 -4 ) and CD33 (rs3865444 OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two ARID5B variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the CD2AP variant (rs9349407, p = 0.56). Our data overwhelmingly support the association of EPHA1 and CD33 variants with LOAD risk: addition of our data to the results previously reported (total n 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10 -15 ( EPHA1 ) and 1.8 × 10 -13 ( CD33 ).
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.NEUROBIOLAGING.2013.10.084
Abstract: Alzheimer's disease (AD) is the most common and complex neurodegenerative disease in the elderly in iduals. Recently, genome-wide association studies (GWAS) have been used to investigate AD pathogenesis. These GWAS have yielded important new insights into the genetic mechanisms of AD. However, these newly identified AD susceptibility loci exert only very small risk effects and cannot fully explain the underlying AD genetic risk. We hypothesize that combining the findings from different AD GWAS may have greater power than genetic analysis alone. To identify new AD risk factors, we integrated findings from 3 previous large-scale AD GWAS (n = 14,138) using a gene-based meta-analysis and subsequently conducted a pathway analysis using the kyoto encyclopedia of genes and genomes and gene ontology databases. Interestingly, we not only confirmed previous findings, but also highlighted, for the first time, the involvement of cardiovascular disease-related pathways in AD. Our results provided the clues as to the link between these diseases using pathway analysis methods. We believe that these findings will be very useful for future genetic studies of AD.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Kevin Morgan.