ORCID Profile
0000-0003-0473-4565
Current Organisation
University of Oxford
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Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NN.4228
Publisher: Public Library of Science (PLoS)
Date: 18-08-2015
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: Wiley
Date: 05-01-2009
DOI: 10.1002/AJMG.B.30768
Abstract: A recent scan of single nucleotide polymorphisms (SNPs) in the region 40-107 Mb on chromosome 10q in a large Japanese case-control cohort identified six SNPs in or near the dynamin-binding protein gene (DNMBP) that were associated with late onset Alzheimer's disease (LOAD) in in iduals lacking the APOE epsilon4 allele [Kuwano et al. (2006) Hum Mol Genet 15:2170-2182]. We genotyped these six SNPs in 1,212 unrelated Caucasian patients of UK origin with LOAD and 1,389 ethnically, gender and age matched control subjects. We did not observe a statistically significant association with the risk of LOAD for any of the six SNPs in the s le as a whole. When stratifying the s le by APOE one SNP (intergenic SNP rs11190302) was associated with LOAD in in iduals lacking the epsilon4 allele (genotypic P = 0.027, allelic P = 0.066). However this association was in the opposite direction to that detected in the Japanese population. It remains to be determined whether DNMBP is associated with LOAD.
Publisher: Public Library of Science (PLoS)
Date: 16-06-2015
Publisher: Oxford University Press (OUP)
Date: 22-02-2007
DOI: 10.1093/HMG/DDM031
Abstract: This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of s les from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17 343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery case-control s le from the UK. A tiered strategy was used to follow-up significant variants from the discovery s le in four independent s le sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full s le P = 6.94E - 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOEepsilon4 and epsilon2/3 variants (0.09 < D'<1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P = 0.0010-0.00006 odds ratio (OR) = 1.07-1.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17 343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P = 0.00005, OR = 1.2, false positive rate = 0.87).
Publisher: Public Library of Science (PLoS)
Date: 12-06-2014
Publisher: American Chemical Society (ACS)
Date: 26-08-2016
DOI: 10.1021/ACS.ANALCHEM.6B01481
Abstract: To better understand the molecular mechanisms underpinning physiological variation in human populations, metabolic phenotyping approaches are increasingly being applied to studies involving hundreds and thousands of biofluid s les. Hyphenated ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) has become a fundamental tool for this purpose. However, the seemingly inevitable need to analyze large studies in multiple analytical batches for UPLC-MS analysis poses a challenge to data quality which has been recognized in the field. Herein, we describe in detail a fit-for-purpose UPLC-MS platform, method set, and s le analysis workflow, capable of sustained analysis on an industrial scale and allowing batch-free operation for large studies. Using complementary reversed-phase chromatography (RPC) and hydrophilic interaction liquid chromatography (HILIC) together with high resolution orthogonal acceleration time-of-flight mass spectrometry (oaTOF-MS), exceptional measurement precision is exemplified with independent epidemiological s le sets of approximately 650 and 1000 participant s les. Evaluation of molecular reference targets in repeated injections of pooled quality control (QC) s les distributed throughout each experiment demonstrates a mean retention time relative standard deviation (RSD) of <0.3% across all assays in both studies and a mean peak area RSD of <15% in the raw data. To more globally assess the quality of the profiling data, untargeted feature extraction was performed followed by data filtration according to feature intensity response to QC s le dilution. Analysis of the remaining features within the repeated QC s le measurements demonstrated median peak area RSD values of <20% for the RPC assays and <25% for the HILIC assays. These values represent the quality of the raw data, as no normalization or feature-specific intensity correction was applied. While the data in each experiment was acquired in a single continuous batch, instances of minor time-dependent intensity drift were observed, highlighting the utility of data correction techniques despite reducing the dependency on them for generating high quality data. These results demonstrate that the platform and methodology presented herein is fit-for-use in large scale metabolic phenotyping studies, challenging the assertion that such screening is inherently limited by batch effects. Details of the pipeline used to generate high quality raw data and mitigate the need for batch correction are provided.
Publisher: Springer Science and Business Media LLC
Date: 12-2007
Abstract: Shedding of the Alzheimer amyloid precursor protein (APP) ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC) or through unconventional phorbol-binding proteins such as Munc13-1. We have previously demonstrated that application of phorbol esters or purified PKC potentiates budding of APP-bearing secretory vesicles at the trans -Golgi network (TGN) and toward the plasma membrane where APP becomes a substrate for enzymes responsible for shedding, known collectively as α-secretase(s). However, molecular identification of the presumptive "phospho-state-sensitive modulators of ectodomain shedding" (PMES) responsible for regulated shedding has been challenging. Here, we examined the effects on APP ectodomain shedding of four phorbol-sensitive proteins involved in regulation of vesicular membrane trafficking of APP: Munc13-1, Munc18, NSF, and Eve-1. Overexpression of either phorbol-sensitive wildtype Munc13-1 or phorbol-insensitive Munc13-1 H567K resulted in increased basal APP ectodomain shedding. However, in contrast to the report of Roßner et al (2004), phorbol ester-dependent APP ectodomain shedding from cells overexpressing APP and Munc13-1 wildtype was indistinguishable from that observed following application of phorbol to cells overexpressing APP and Munc13-1 H567K mutant. This pattern of similar effects on basal and stimulated APP shedding was also observed for Munc18 and NSF. Eve-1, an ADAM adaptor protein reported to be essential for PKC-regulated shedding of pro-EGF, was found to play no obvious role in regulated shedding of sAPPα. Our results indicate that, in the HEK293 system, Munc13-1, Munc18, NSF, and EVE-1 fail to meet essential criteria for identity as PMES for APP.
Publisher: Springer Science and Business Media LLC
Date: 26-02-2018
Publisher: Elsevier BV
Date: 11-2011
Publisher: Wiley
Date: 19-12-2014
Publisher: Wiley
Date: 12-06-2012
DOI: 10.1002/AJMG.B.32073
Abstract: The β-amyloid peptide may play a central role in Alzheimer's disease (AD) pathogenesis. We have evaluated variants in seven Aβ-degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, and TF) for association with AD risk in the Genetic and Environmental Risk in Alzheimer's Disease Consortium 1 (GERAD1) cohort, and with three cognitive phenotypes in the Lothian Birth Cohort 1936 (LBC1936), using 128 and 121 SNPs, respectively. In GERAD1, we identified a significant association between a four-SNP intragenic ECE1 haplotype and risk of AD in in iduals that carried at least one APOE ε4 allele (P = 0.00035, odds ratio = 1.61). In LBC1936, we identified a significant association between a different two-SNP ECE1 intragenic haplotype and non-verbal reasoning in in iduals lacking the APOE ε4 allele (P = 0.00036, β = -0.19). Both results showed a trend towards significance after permutation (0.05 < P < 0.10). A follow-up cognitive genetic study evaluated the association of ECE1 SNPs in three additional cohorts of non-demented older people. Meta-analysis of the four cohorts identified the significant association (Z A (rs213045). We observed significantly less expression from the 338A variant in two human neuroblastoma cell lines and speculate that this promoter may be subject to tissue-specific regulation.
Publisher: Elsevier BV
Date: 05-2015
Publisher: Wiley
Date: 29-12-2015
Publisher: Springer Science and Business Media LLC
Date: 21-01-2015
DOI: 10.1038/NATURE14101
Publisher: BMJ
Date: 11-2016
Publisher: Wiley
Date: 28-09-2016
DOI: 10.1016/J.JALZ.2016.08.003
Abstract: The aim of this study was to (1) replicate previous associations between six blood lipids and Alzheimer's disease (AD) (Proitsi et al 2015) and (2) identify novel associations between lipids, clinical AD diagnosis, disease progression and brain atrophy (left/right hippoc us/entorhinal cortex). We performed untargeted lipidomic analysis on 148 AD and 152 elderly control plasma s les and used univariate and multivariate analysis methods. We replicated our previous lipids associations and reported novel associations between lipids molecules and all phenotypes. A combination of 24 molecules classified AD patients with >70% accuracy in a test and a validation data set, and we identified lipid signatures that predicted disease progression (R Blood lipids are promising AD biomarkers that may lead to new treatment strategies.
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.NEUROBIOLAGING.2009.03.005
Abstract: Although there is evidence for distinct behavioural sub-phenotypes in Alzheimer's disease (AD), their inter-relationships and the effect of clinical variables on their expression have been little investigated. We have analysed a s le of 1850 probable AD patients from the UK and Greece with 10 item Neuropsychiatric Inventory (NPI) data. We applied a Multiple Indicators Multiple Causes (MIMIC) approach to investigate the effect of MMSE, disease duration, gender, age and age of onset on the structure of a four-factor model consisting of "psychosis", "moods", "agitation" and "behavioural dyscontrol". Specific clinical variables predicted the expression of in idual factors. When the inter-relationship of factors is modelled, some previously significant associations are lost. For ex le, lower MMSE scores predict psychosis, agitation and behavioural dyscontrol factors, but psychosis and mood predict the agitation factor. Taking these associations into account MMSE scores did not predict agitation. The complexity of the inter-relations between symptoms, factors and clinical variables is efficiently captured by this MIMIC model.
Publisher: Wiley
Date: 2010
DOI: 10.1002/GPS.2294
Abstract: To determine the effects of early life education, mid life employment and later life retirement age on the age of onset (AOO) of Alzheimer's disease (AD). Multiple regression analyses were carried out using data for 1320 probable AD cases, of which 382 were males with employment and retirement age data, using informant based information on education and employment. No relation was found between years of education, best qualification obtained, or employment variables in males and the AOO of AD. A significant effect of later retirement age in delaying the AOO of AD was seen in males. In this study no effect of education or employment was seen, although this may be due to limited variance in the study population. The significant effect of retirement age may have several explanations, the most interesting of which would be the suggestion that active employment later in life allows an in idual to prolong their cognitive assets above the threshold for dementia.
Publisher: Wiley
Date: 09-2006
DOI: 10.1111/J.1532-5415.2006.00854.X
Abstract: To investigate behavioral components of Alzheimer's disease (AD) and to analyze behavioral components in relation to disease severity, apolipoprotein E genotype (APOE), sex, years of education, age at onset, and cognitive impairment. Cross-sectional study. Data were collected from community-dwelling in iduals and those residing in nursing homes. A total of 1,120 in iduals meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria for late-onset probable AD. Behavioral symptoms were assessed using the Neuropsychiatric Inventory. First-order polychoric correlations, controlling for disease severity, between the 12 symptom domain scores were estimated, and the resulting matrix underwent principal components analysis. Four interpretable components were identified: behavioral dyscontrol (euphoria, disinhibition, aberrant motor behavior, and sleep and appetite disturbances), psychosis (delusions and hallucinations), mood (depression, anxiety, and apathy), and agitation (aggression and irritability). Scores on the four components were associated with severity of cognitive impairment. Higher behavioral dysfunction, agitation, and mood component scores were associated with lower age at onset. Behavioral dysfunction and mood component scores were associated with sex. None of the components were associated with age at assessment, years of education, or number of APOE epsilon4 alleles. Four behavioral components were identified that were comparable with those observed previously. Future analysis of these components will strengthen understanding of the underlying pathology of behavioral symptoms and AD.
Publisher: Wiley
Date: 2007
DOI: 10.1002/AJMG.B.30456
Abstract: The neuropathology of Alzheimer's disease (AD) is characterized by intracellular neurofibrillary tangles and the extracellular deposition of beta-amyloid (Abeta) in senile plaques. Abeta has been shown to mediate neurodegenerative and inflammatory changes associated with amyloid plaques, although the pathological mechanism of Abeta remains largely unknown. Recent evidence suggests that the FISH adapter protein binds to, and potentially regulates, ADAM12 (a disintegrin and metalloprotease 12) to mediate a neurotoxic effect of Abeta. The ADAM12 gene lies on chromosome 10q26.3, and the gene encoding FISH, SH3MD1, lies within a region of linkage to late-onset AD (LOAD) on 10q25.1. This study investigates whether there is a relationship between variation in ADAM12 and SH3MD1 and susceptibility to LOAD in a s le of 1,051 AD cases and 1,269 matched controls. We observe significant interactions between variants in the two genes that may influence susceptibility to LOAD. The most significant statistical interaction is between rs3740473, a synonymous single nucleotide polymorphism (SNP) in SH3MD1 and rs11244787, an intronic SNP in ADAM12 (effect size = 2.1 for interaction term, P = 0.006).
Publisher: Oxford University Press (OUP)
Date: 06-12-2007
DOI: 10.1093/HMG/DDM348
Abstract: Late-onset Alzheimer's disease (LOAD) and Parkinson's disease (PD) are the most common neurodegenerative disorders and in both diseases susceptibility is known to be influenced by genes. We set out to identify novel susceptibility genes for LOAD by performing a large scale, multi-tiered association study testing 4692 single nucleotide polymorphism (SNPs). We identified a SNP within a putative transcription factor binding site in the NEDD9 gene (neural precursor cell expressed, developmentally down-regulated), that shows good evidence of association with disease risk in four out of five LOAD s les [N = 3521, P = 5.38x10(-6), odds ratio (OR) = 1.38 (1.20-1.59)] and in addition, we observed a similar pattern of association in two PD s le sets [N = 1464, P = 0.0145, OR =1.31 (1.05-1.62)]. In exploring a potential mechanism for the association, we observed that expression of NEDD9 and APOE show a strong inverse correlation in the hippoc us of Alzheimer's cases. These data implicate NEDD9 as a novel susceptibility gene for LOAD and possibly PD.
Publisher: Oxford University Press (OUP)
Date: 17-07-2006
DOI: 10.1093/HMG/DDL178
Abstract: Genetic factors play an important role in the etiology of late-onset Alzheimer's disease (LOAD). We tested gene-centric single nucleotide polymorphisms (SNPs) on chromosome 9 and identified two SNPs in the death-associated protein kinase, DAPK1, that show significant association with LOAD. SNP rs4878104 was significantly associated with LOAD in our discovery case-control s le set (WU) and replicated in each of two initial validation case-control s le sets (P<0.05, UK1, SD). The risk-allele frequency of this SNP showed a similar direction in three other case-control s le sets. A meta-analysis of the six s le sets combined, totaling 2012 cases and 2336 controls, showed an allelic P-value of 0.0016 and an odds ratio (OR) of 0.87 (95%CI: 0.79-0.95). Minor allele homozygotes had a consistently lower risk than major allele homozygotes in the discovery and initial two replication s le sets, which remained significant in the meta-analysis of all six s le sets (OR=0.7, 95%CI: 0.58-0.85), whereas the risk for heterozygous subjects was not significantly different from that of major allele homozygotes. A second SNP, rs4877365, which is in high linkage disequilibrium with rs4878104 (r2=0.64), was also significantly associated with LOAD (meta P=0.0017 in the initial three s le sets). Furthermore, DAPK1 transcripts show differential allelic gene expression, and both rs4878104 and rs4877365 were significantly associated with DAPK1 allele-specific expression (P=0.015 to <0.0001). These data suggest that genetic variation in DAPK1 modulates susceptibility to LOAD.
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/NN.4398
Publisher: Springer Science and Business Media LLC
Date: 18-10-2011
DOI: 10.1038/MP.2011.125
Publisher: Elsevier BV
Date: 02-2014
Publisher: Massachusetts Medical Society
Date: 10-01-2013
Publisher: Elsevier BV
Date: 03-2004
Publisher: Oxford University Press (OUP)
Date: 11-11-2012
DOI: 10.1093/HMG/DDS476
Publisher: Wiley
Date: 10-2008
DOI: 10.1002/ANA.21476
Abstract: We examined the epistatic effect between haplotypes of glycogen synthase kinase-3beta (GSK3B) gene and microtubule-associated protein Tau (MAPT) gene in Alzheimer's disease (AD). A genetic association study of three AD cohorts was made. Linear regression analyses were used to examine effects of MAPT polymorphisms on gene expression and alternative splicing. beta-Catenin levels and signaling were determined using Western blot and luciferase reporter assays in cells transfected with a combination of GSK3B and MAPT complementary DNA. Consistent interaction between GSK3B and MAPT genes in three late-onset AD cohorts was observed, with the GSK3B haplotype (T-T) significantly increasing the risk for AD in in iduals with at least one H2 haplotype (odds ratio, 1.68-2.33 p = 0.005-0.036). The GSK3B haplotype was significantly protective in the Chinese cohort (odds ratio, 0.33 p = 0.016), after adjusting for the effect of age and sex. There are significant differences in in vivo transcriptional efficiency between the two MAPT haplotypes (H1 and H2) as determined by measurement of cerebellar transcripts (p < 0.001). Overexpression of either MAPT or GSK3B resulted in decreased beta-catenin levels compared with a control vector (p < 0.001). Conversely, cotransfection of both of these molecules increased beta-catenin signaling. Our genetic and biochemical analyses have identified a novel interaction between Tau and GSK-3beta in late-onset AD causative factors. Our data are consistent with an epistatic model of interaction where discordant levels of GSK3B and MAPT gene expression can lead to altered beta-catenin levels and pathogenicity.
Publisher: Wiley
Date: 30-03-2016
DOI: 10.1002/ANA.24621
Publisher: Wiley
Date: 05-01-2005
DOI: 10.1002/AJMG.B.30068
Abstract: Consistent deficits in the cholinergic system are evident in the brains of Alzheimer's Disease (AD) patients, including reductions in the activities of acetylcholine, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT), increased butyrylcholinesterase (BChE) activity, and a selective loss of nicotinic acetylcholine receptors (nAChRs). Accordingly, we have analyzed polymorphisms in the genes encoding AChE, ChAT, BChE, and several of the subunit genes from neuronal nAChRs, for genetic associations with late-onset AD. A significant association for disease was detected for a non-coding polymorphism in ChAT (allele chi(1) (2) = 12.84, P = 0.0003 genotype chi(2) (2) = 11.89, P = 0.0026). Although replication analysis did not confirm the significance of this finding when the replication s les were considered alone (allele chi(1) (2) = 1.02, P = 0.32 genotype chi(2) (2) = 1.101, P = 0.58) the trends were in the correct direction and a significant association remained when the two s le sets were pooled (allele chi(1) (2) = 12.37, P = 0.0004 genotype chi(2) (2) = 11.61, P = 0.003). Previous studies have reported significant disease associations for both the K-variant of BChE and the coding ChAT rs3810950 polymorphism with AD. Replication analyses of these two loci failed to detect any significant association for disease in our case-control s les.
Publisher: Wiley
Date: 30-09-2014
Publisher: Springer Science and Business Media LLC
Date: 17-03-2015
DOI: 10.1038/MP.2015.23
Publisher: Wiley
Date: 2007
DOI: 10.1002/AJMG.B.30509
Abstract: Late-onset Alzheimer's disease (LOAD) is a common neurodegenerative disorder, with a complex etiology. APOE is the only confirmed susceptibility gene for LOAD. Others remain yet to be found. Evidence from linkage studies suggests that a gene (or genes) conferring susceptibility for LOAD resides on chromosome 10. We studied 23 positional/functional candidate genes from our linkage region on chromosome 10 (APBB1IP, ALOX5, AD037, SLC18A3, DKK1, ZWINT, ANK3, UBE2D1, CDC2, SIRT1, JDP1, NET7, SUPV3L1, NEN3, SAR1, SGPL1, SEC24C, CAMK2G, PP3CB, SNCG, CH25H, PLCE1, ANXV111) in the MRC genetic resource for LOAD. These candidates were screened for sequence polymorphisms in a s le of 14 LOAD subjects and detected polymorphisms tested for association with LOAD in a three-stage design involving two stages of genotyping pooled DNA s les followed by a third stage in which markers showing evidence for association in the first stages were subjected to in idual genotyping. One hundred and twenty polymorphisms were identified and tested in stage 1 (4 case + 4 control pools totaling 366 case and 366 control in iduals). Single nucleotide polymorphisms (SNPs) showing evidence of association with LOAD were then studied in stage 2 (8 case + 4 control pools totaling 1,001 case and 1,001 control in iduals). Five SNPs, in four genes, showed evidence for association (P < 0.1) at stage 2 and were in idually genotyped in the complete dataset, comprising 1,160 LOAD cases and 1,389 normal controls. Two SNPs in SGPL1 demonstrated marginal evidence of association, with uncorrected P values of 0.042 and 0.056, suggesting that variation in SGPL1 may confer susceptibility to LOAD.
Publisher: Springer Science and Business Media LLC
Date: 2004
DOI: 10.1385/NMM:5:2:133
Publisher: Elsevier BV
Date: 08-2012
Publisher: Oxford University Press (OUP)
Date: 03-05-2012
DOI: 10.1093/HMG/DDS161
Publisher: Springer Science and Business Media LLC
Date: 18-01-2017
DOI: 10.1038/NCOMMS13624
Abstract: The hippoc al formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippoc al volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippoc al structure here we perform a genome-wide association study (GWAS) of 33,536 in iduals and discover six independent loci significantly associated with hippoc al 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 hippoc al 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 hippoc al 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 hippoc al volume and risk for neuropsychiatric illness.
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.NEULET.2009.05.051
Abstract: Psychotic symptoms are common in in iduals with Alzheimer's disease (AD), and define a phenotype associated with more rapid cognitive and functional decline. Evidence suggests that psychotic symptoms may be influenced by genetic factors, and recent studies in schizophrenia, bipolar affective disorder (BPAD) and Alzheimer's disease with psychosis (AD+P) suggest that psychosis susceptibility or modifier genes may act across diseases. We hypothesised that oligodendrocyte lineage transcription factor 2 (OLIG2), a regulator of white matter development and a candidate gene for schizophrenia, may also be associated with psychotic symptoms in AD. We genotyped 11 SNPs in OLIG2 previously tested for association with schizophrenia [L. Georgieva, V. Moskvina, T. Peirce, N. Norton, N.J. Bray, L. Jones, P. Holmans, S. Macgregor, S. Zammit, J. Wilkinson, H. Williams, I. Nikolov, N. Williams, D. Ivanov, K.L. Davis, V. Haroutunian, J.D. Buxbaum, N. Craddock, G. Kirov, M.J. Owen, M.C. O'Donovan, Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia, Proc. Natl. Acad. Sci. U.S.A. 103 (33) (2006) 12469-12474] and tested these for association with AD and AD+P. Significant evidence for association of psychotic symptoms within cases was identified for two SNPs, rs762237 (allelic P=0.002, OR=1.42, corrected P=0.019) and rs2834072 (allelic P=0.004, OR=1.41, corrected P=0.05).
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.NEUROBIOLAGING.2014.07.023
Abstract: Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 in iduals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 in iduals 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988 95% confidence interval, 0.972-1.004 p = 0.144 and odds ratio = 0.993 95% confidence interval, 0.983-1.003 p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.
Publisher: S. Karger AG
Date: 2001
DOI: 10.1159/000051267
Abstract: A reduced risk of Alzheimer’s disease (AD) associated with the apolipoprotein E (APOE) & #917 allele is reported in populations of African origin. In order to clarify possible reasons for this, we examined the association between APOE genotype and early cognitive impairment in a community-based African Caribbean UK population aged 55–75 years. APOE genotype was available for 202 participants, 57 (28%) of whom were classified as having relative cognitive impairment on a battery of neuropsychological tests. Cognitive impairment was negatively associated with & #917 and positively but more weakly associated with & #917 . Effects of both alleles increased markedly after age 70. The effect of & #917 was increased in combination with hypertension, diabetes or lower educational attainment, but these factors did not influence & #917 effects. Cholesterol and triglyceride levels partially explained effects of & #917 , but did not account for those of & #917 . A reduced association between & #917 and later AD in populations of African origin is unlikely to be explained by reduced cognitive effects or by differential mortality. However, it may be accounted for by vascular comorbidity. The different patterns of association between & #917 and & #917 alleles suggest different pathways of effect.
Publisher: Wiley
Date: 28-12-2007
DOI: 10.1002/AJMG.B.30670
Abstract: Late-onset Alzheimer's disease (LOAD) is a genetically complex neurodegenerative disorder. Currently, only the epsilon4 allele of the Apolipoprotein E gene has been identified unequivocally as a genetic susceptibility factor for LOAD. Others remain to be found. In 2002 we observed genome-wide significant evidence of linkage to a region on chromosome 10q11.23-q21.3 [Myers et al. (2002) Am J Med Genet 114:235-244]. Our objective in this study was to test every gene within the maximum LOD-1 linkage region, for association with LOAD. We obtained results for 528 SNPs from 67 genes, with an average density of 1 SNP every 10 kb within the genes. We demonstrated nominally significant association with LOAD for 4 SNPs: rs1881747 near DKK1 (P = 0.011, OR = 1.24), rs2279420 in ANK3 (P = 0.022, OR = 0.79), rs2306402 in CTNNA3 (P = 0.024, OR = 1.18), and rs5030882 in CXXC6 (P = 0.046, OR = 1.29) in 1,160 cases and 1,389 controls. These results would not survive correction for multiple testing but warrant attempts at confirmation in independent s les.
Publisher: Elsevier BV
Date: 04-2016
Publisher: Springer Science and Business Media LLC
Date: 03-07-2202
DOI: 10.1038/NG.803
Publisher: Springer Science and Business Media LLC
Date: 27-10-2013
DOI: 10.1038/NG.2802
Publisher: Cold Spring Harbor Laboratory
Date: 10-06-2021
DOI: 10.1101/2021.06.07.21258457
Abstract: The levels of many blood proteins are associated with Alzheimer’s disease or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins causally associated with the disease. Here, genome-wide and epigenome-wide studies (n in iduals ≤1,064) were performed on plasma levels of 281 Alzheimer’s disease-associated proteins, identified by a systematic review of the literature. We quantified the contributions of genetic and epigenetic variation towards inter-in idual variability in plasma protein levels. Sixty-one independent genetic and 32 epigenetic loci were associated with expression levels of 49 proteins eight and 24 of these respective findings are previously unreported. Novel findings included an association between plasma TREM2 levels and a polymorphism and CpG site within the MS4A4A locus. Through Mendelian randomisation analyses, causal associations were observed between higher plasma TBCA and TREM2 levels and lower Alzheimer’s disease risk. Our data inform the regulation of biomarker levels and their relationships with Alzheimer’s disease.
Publisher: Springer Science and Business Media LLC
Date: 13-06-2012
DOI: 10.1038/EJHG.2012.98
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.NEUROBIOLAGING.2010.06.011
Abstract: Genetic association studies investigating the association between genes of serotonergic and dopaminergic systems and behavioral and psychological symptoms in dementia (BPSD) are contradictory. We have utilized 1008 probable Alzheimer's disease (AD) patients from the UK and used the 12-item Neuropsychiatric Inventory. We applied a multiple indicators-multiple causes (MIMIC) approach to investigate the effect of 11 polymorphisms on the 4 behavioral subphenotypes "psychosis", "moods", "agitation", and "behavioural dyscontrol". Significant associations were observed between the serotonin transporter gene (SERT) polymorphism STin2 and "psychosis" the dopamine transporter gene (DAT) 3' variable number tandem repeats (VNTR) and "agitation" and the dopamine receptor 4 (DRD4) VNTR and "moods" factors. Direct associations were identified between the dopamine receptor 3 (DRD3) BalI polymorphism and depression the dopamine receptor 1 (DRD1) and dopamine transporter gene 3' VNTR polymorphisms and aberrant motor behavior the DRD4 VNTR and sleep disturbances and the SERT gene VNTR 5HTTLPR and apathy items. Significant interactions observed between polymorphisms suggested epistatic effects and interactions between polymorphisms and medications highlighted potential treatment response. This multiple indicators multiple causes (MIMIC) model efficiently captured the complexity of the interrelations between genetic variation, behavioral symptoms, and clinical variables.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2009
DOI: 10.1038/NG.440
Publisher: Oxford University Press (OUP)
Date: 28-11-2012
DOI: 10.1093/HMG/DDS491
Publisher: Springer Science and Business Media LLC
Date: 05-11-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-03-2012
Publisher: Public Library of Science (PLoS)
Date: 15-11-2010
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.NEUROBIOLAGING.2011.12.036
Abstract: Alzheimer's disease (AD) and age-related macular degeneration (AMD) are both neurodegenerative disorders which share common pathological and biochemical features of the complement pathway. The aim of this study was to investigate whether there is an association between well replicated AMD genetic risk factors and AD. A large cohort of AD (n = 3898) patients and controls were genotyped for single nucleotide polymorphisms (SNPs) in the complement factor H (CFH), the Age-related maculopathy susceptibility protein 2 (ARMS2) the complement component 2 (C2), the complement factor B (CFB), and the complement component 3 (C3) genes. While significant but modest associations were identified between the complement factor H, the age-related maculopathy susceptibility protein 2, and the complement component 3 single nucleotide polymorphisms and AD, these were different in direction or genetic model to that observed in AMD. In addition the multilocus genetic model that predicts around a half of the sibling risk for AMD does not predict risk for AD. Our study provides further support to the hypothesis that while activation of the alternative complement pathway is central to AMD pathogenesis, it is less involved in AD.
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.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2015
DOI: 10.1038/TP.2014.127
Abstract: There is an urgent need for the identification of Alzheimer’s disease (AD) biomarkers. Studies have now suggested the promising use of associations with blood metabolites as functional intermediate phenotypes in biomedical and pharmaceutical research. The aim of this study was to use lipidomics to identify a battery of plasma metabolite molecules that could predict AD patients from controls. We performed a comprehensive untargeted lipidomic analysis, using ultra-performance liquid chromatography/mass spectrometry on plasma s les from 35 AD patients, 40 elderly controls and 48 in iduals with mild cognitive impairment (MCI) and used multivariate analysis methods to identify metabolites associated with AD status. A combination of 10 metabolites could discriminate AD patients from controls with 79.2% accuracy (81.8% sensitivity, 76.9% specificity and an area under curve of 0.792) in a novel test set. Six of the metabolites were identified as long chain cholesteryl esters (ChEs) and were reduced in AD (ChE 32:0, odds ratio (OR)=0.237, 95% confidence interval (CI)=0.10–0.48, P =4.19E−04 ChE 34:0, OR=0.152, 95% CI=0.05–0.37, P =2.90E−04 ChE 34:6, OR=0.126, 95% CI=0.03–0.35, P =5.40E−04 ChE 32:4, OR=0.056, 95% CI=0.01–0.24, P =6.56E−04 and ChE 33:6, OR=0.205, 95% CI=0.06–0.50, P =2.21E−03, per (log2) metabolite unit). The levels of these metabolites followed the trend control MCI AD. We, additionally, found no association between cholesterol, the precursor of ChE and AD. This study identified new ChE molecules, involved in cholesterol metabolism, implicated in AD, which may help identify new therapeutic targets although, these findings need to be replicated in larger well-phenotyped cohorts.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Simon Lovestone.