Publications by authors named "Dobril Ivanov"

28 Publications

  • Page 1 of 1

Activating transcription factor 4-dependent lactate dehydrogenase activation as a protective response to amyloid beta toxicity.

Brain Commun 2021 26;3(2):fcab053. Epub 2021 Mar 26.

Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK.

Accumulation of amyloid beta peptides is thought to initiate the pathogenesis of Alzheimer's disease. However, the precise mechanisms mediating their neurotoxicity are unclear. Our microarray analyses show that, in models of amyloid beta 42 toxicity, genes involved in the unfolded protein response and metabolic processes are upregulated in brain. Comparison with the brain transcriptome of early-stage Alzheimer's patients revealed a common transcriptional signature, but with generally opposing directions of gene expression changes between flies and humans. Among these differentially regulated genes, lactate dehydrogenase () was up-regulated by the greatest degree in amyloid beta 42 flies and the human orthologues ( and ) were down-regulated in patients. Functional analyses revealed that either over-expression or inhibition of by RNA interference (RNAi) slightly exacerbated climbing defects in both healthy and amyloid beta 42-induced . This suggests that metabolic responses to lactate dehydrogenase must be finely-tuned, and that its observed upregulation following amyloid beta 42 production could potentially represent a compensatory protection to maintain pathway homeostasis in this model, with further manipulation leading to detrimental effects. The increased expression in amyloid beta 42 flies was regulated partially by unfolded protein response signalling, as RNAi diminished the transcriptional response and enhanced amyloid beta 42-induced climbing phenotypes. Further functional studies are required to determine whether upregulation provides compensatory neuroprotection against amyloid beta 42-induced loss of activating transcription factor 4 activity and endoplasmatic reticulum stress. Our study thus reveals dysregulation of lactate dehydrogenase signalling in models and patients with Alzheimer's disease, which may lead to a detrimental loss of metabolic homeostasis. Importantly, we observed that down-regulation of -dependent endoplasmic reticulum-stress signalling in this context appears to prevent compensation and to exacerbate amyloid beta 42-dependent neuronal toxicity. Our findings, therefore, suggest caution in the use of therapeutic strategies focussed on down-regulation of this pathway for the treatment of Alzheimer's disease, since its natural response to the toxic peptide may induce beneficial neuroprotective effects.
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http://dx.doi.org/10.1093/braincomms/fcab053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093921PMC
March 2021

Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system.

Proc Natl Acad Sci U S A 2021 Feb;118(8)

Institute of Healthy Ageing, University College London, London WC1E 6BT, United Kingdom;

Reduced activity of insulin/insulin-like growth factor signaling (IIS) increases healthy lifespan among diverse animal species. Downstream of IIS, multiple evolutionarily conserved transcription factors (TFs) are required; however, distinct TFs are likely responsible for these effects in different tissues. Here we have asked which TFs can extend healthy lifespan within distinct cell types of the adult nervous system in Starting from published single-cell transcriptomic data, we report that (FKH) is endogenously expressed in neurons, whereas (FOXO) is expressed in glial cells. Accordingly, we find that neuronal FKH and glial FOXO exert independent prolongevity effects. We have further explored the role of neuronal FKH in a model of Alzheimer's disease-associated neuronal dysfunction, where we find that increased neuronal FKH preserves behavioral function and reduces ubiquitinated protein aggregation. Finally, using transcriptomic profiling, we identify , a member of the Atg1 autophagy initiation family, as one FKH-dependent target whose neuronal overexpression is sufficient to extend healthy lifespan. Taken together, our results underscore the importance of cell type-specific mapping of TF activity to preserve healthy function with age.
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http://dx.doi.org/10.1073/pnas.2011491118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923679PMC
February 2021

A novel computational approach for predicting complex phenotypes in Drosophila (starvation-sensitive and sterile) by deriving their gene expression signatures from public data.

PLoS One 2020 26;15(10):e0240824. Epub 2020 Oct 26.

European Molecular Biology Laboratory, The European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridge, United Kingdom.

Many research teams perform numerous genetic, transcriptomic, proteomic and other types of omic experiments to understand molecular, cellular and physiological mechanisms of disease and health. Often (but not always), the results of these experiments are deposited in publicly available repository databases. These data records often include phenotypic characteristics following genetic and environmental perturbations, with the aim of discovering underlying molecular mechanisms leading to the phenotypic responses. A constrained set of phenotypic characteristics is usually recorded and these are mostly hypothesis driven of possible to record within financial or practical constraints. We present a novel proof-of-principal computational approach for combining publicly available gene-expression data from control/mutant animal experiments that exhibit a particular phenotype, and we use this approach to predict unobserved phenotypic characteristics in new experiments (data derived from EBI's ArrayExpress and ExpressionAtlas respectively). We utilised available microarray gene-expression data for two phenotypes (starvation-sensitive and sterile) in Drosophila. The data were combined using a linear-mixed effects model with the inclusion of consecutive principal components to account for variability between experiments in conjunction with Gene Ontology enrichment analysis. We present how available data can be ranked in accordance to a phenotypic likelihood of exhibiting these two phenotypes using random forest. The results from our study show that it is possible to integrate seemingly different gene-expression microarray data and predict a potential phenotypic manifestation with a relatively high degree of confidence (>80% AUC). This provides thus far unexplored opportunities for inferring unknown and unbiased phenotypic characteristics from already performed experiments, in order to identify studies for future analyses. Molecular mechanisms associated with gene and environment perturbations are intrinsically linked and give rise to a variety of phenotypic manifestations. Therefore, unravelling the phenotypic spectrum can help to gain insights into disease mechanisms associated with gene and environmental perturbations. Our approach uses public data that are set to increase in volume, thus providing value for money.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240824PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588067PMC
December 2020

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease.

PLoS One 2019 8;14(7):e0218111. Epub 2019 Jul 8.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218111PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613773PMC
February 2020

Intestinal Fork Head Regulates Nutrient Absorption and Promotes Longevity.

Cell Rep 2017 Oct;21(3):641-653

Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, Gower St, London WC1E 6BT, UK; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany. Electronic address:

Reduced activity of nutrient-sensing signaling networks can extend organismal lifespan, yet the underlying biology remains unclear. We show that the anti-aging effects of rapamycin and reduced intestinal insulin/insulin growth factor (IGF) signaling (IIS) require the Drosophila FoxA transcription factor homolog Fork Head (FKH). Intestinal FKH induction extends lifespan, highlighting a role for the gut. FKH binds to and is phosphorylated by AKT and Target of Rapamycin. Gut-specific FKH upregulation improves gut barrier function in aged flies. Additionally, it increases the expression of nutrient transporters, as does lowered IIS. Evolutionary conservation of this effect of lowered IIS is suggested by the upregulation of related nutrient transporters in insulin receptor substrate 1 knockout mouse intestine. Our study highlights a critical role played by FKH in the gut in mediating anti-aging effects of reduced IIS. Malnutrition caused by poor intestinal absorption is a major problem in the elderly, and a better understanding of the mechanisms involved will have important therapeutic implications for human aging.
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http://dx.doi.org/10.1016/j.celrep.2017.09.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656751PMC
October 2017

Drug repurposing for aging research using model organisms.

Aging Cell 2017 10 16;16(5):1006-1015. Epub 2017 Jun 16.

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), The Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.

Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against aging, despite many genes and pathways shown to be important in the aging process and numerous studies demonstrating that genetic interventions can lead to a healthier aging phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate aging in the invertebrates Caenorhabditis elegans and Drosophila. Our approach combines information on genetic effects on aging, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate aging. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating aging, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human aging.
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http://dx.doi.org/10.1111/acel.12626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595691PMC
October 2017

Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease.

PLoS Genet 2017 Mar 2;13(3):e1006593. Epub 2017 Mar 2.

Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London, United Kingdom.

Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer's disease (AD). Current Nrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimental effects. An understanding of the mechanisms mediating Nrf2 inhibition in neurodegenerative conditions may therefore direct the design of drugs targeted for the prevention of these diseases with minimal side-effects. Our study provides the first in vivo evidence that specific inhibition of Keap1, a negative regulator of Nrf2, can prevent neuronal toxicity in response to the AD-initiating Aβ42 peptide, in correlation with Nrf2 activation. Comparatively, lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented Aβ42 toxicity by mechanisms independent of Nrf2. A new direct inhibitor of the Keap1-Nrf2 binding domain also prevented synaptotoxicity mediated by naturally-derived Aβ oligomers in mouse cortical neurons. Overall, our findings highlight Keap1 specifically as an efficient target for the re-activation of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for the prevention of neurodegeneration in vivo.
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http://dx.doi.org/10.1371/journal.pgen.1006593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333801PMC
March 2017

Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis.

Cell Rep 2016 Apr 7;15(3):638-650. Epub 2016 Apr 7.

Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann Strasse 9-b, 50931 Köln, Germany. Electronic address:

The quest to extend healthspan via pharmacological means is becoming increasingly urgent, both from a health and economic perspective. Here we show that lithium, a drug approved for human use, promotes longevity and healthspan. We demonstrate that lithium extends lifespan in female and male Drosophila, when administered throughout adulthood or only later in life. The life-extending mechanism involves the inhibition of glycogen synthase kinase-3 (GSK-3) and activation of the transcription factor nuclear factor erythroid 2-related factor (NRF-2). Combining genetic loss of the NRF-2 repressor Kelch-like ECH-associated protein 1 (Keap1) with lithium treatment revealed that high levels of NRF-2 activation conferred stress resistance, while low levels additionally promoted longevity. The discovery of GSK-3 as a therapeutic target for aging will likely lead to more effective treatments that can modulate mammalian aging and further improve health in later life.
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http://dx.doi.org/10.1016/j.celrep.2016.03.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850359PMC
April 2016

SurvCurv database and online survival analysis platform update.

Bioinformatics 2015 Dec 6;31(23):3878-80. Epub 2015 Aug 6.

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.

Unlabelled: Understanding the biology of ageing is an important and complex challenge. Survival experiments are one of the primary approaches for measuring changes in ageing. Here, we present a major update to SurvCurv, a database and online resource for survival data in animals. As well as a substantial increase in data and additions to existing graphical and statistical survival analysis features, SurvCurv now includes extended mathematical mortality modelling functions and survival density plots for more advanced representation of groups of survival cohorts.

Availability And Implementation: The database is freely available at https://www.ebi.ac.uk/thornton-srv/databases/SurvCurv/. All data are published under the Creative Commons Attribution License.

Contact: [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btv463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653391PMC
December 2015

Longevity GWAS Using the Drosophila Genetic Reference Panel.

J Gerontol A Biol Sci Med Sci 2015 Dec 28;70(12):1470-8. Epub 2015 Apr 28.

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

We used 197 Drosophila melanogaster Genetic Reference Panel (DGRP) lines to perform a genome-wide association analysis for virgin female lifespan, using ~2M common single nucleotide polymorphisms (SNPs). We found considerable genetic variation in lifespan in the DGRP, with a broad-sense heritability of 0.413. There was little power to detect signals at a genome-wide level in single-SNP and gene-based analyses. Polygenic score analysis revealed that a small proportion of the variation in lifespan (~4.7%) was explicable in terms of additive effects of common SNPs (≥2% minor allele frequency). However, several of the top associated genes are involved in the processes previously shown to impact ageing (eg, carbohydrate-related metabolism, regulation of cell death, proteolysis). Other top-ranked genes are of unknown function and provide promising candidates for experimental examination. Genes in the target of rapamycin pathway (TOR; Chrb, slif, mipp2, dredd, RpS9, dm) contributed to the significant enrichment of this pathway among the top-ranked 100 genes (p = 4.79×10(-06)). Gene Ontology analysis suggested that genes involved in carbohydrate metabolism are important for lifespan; including the InterPro term DUF227, which has been previously associated with lifespan determination. This analysis suggests that our understanding of the genetic basis of natural variation in lifespan from induced mutations is incomplete.
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http://dx.doi.org/10.1093/gerona/glv047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631106PMC
December 2015

Transcriptional feedback in the insulin signalling pathway modulates ageing in both Caenorhabditis elegans and Drosophila melanogaster.

Mol Biosyst 2013 Jul 26;9(7):1756-64. Epub 2013 Apr 26.

EMBL-European Bioinformatics Institute (EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.

Several components have been previously identified, that modulate longevity in several species, including the target of rapamycin (TOR) and the Insulin/IGF-1 (IIS) signalling pathways. In order to infer paths and transcriptional feedback loops that are likely to modulate ageing, we manually built a comprehensive and computationally efficient signalling network model of the IIS and TOR pathways in worms. The core insulin transduction is signalling from the sole insulin receptor daf-2 to ultimately inhibit the translocation of the transcription factor daf-16 into the nucleus. Reduction in this core signalling is thought to increase longevity in several species. In addition to this core insulin signalling, we have also recorded in our worm model the transcription factors skn-1 and hif-1, those are also thought to modulate ageing in a daf-16 independent manner. Several paths that are likely to modulate ageing were inferred via a web-based service NetEffects, by utilising perturbed components (rheb-1, let-363, aak-2, daf-2;daf-16 and InR;foxo in worms and flies respectively) from freely available gene expression microarrays. These included "routes" from TOR pathway to transcription factors daf-16, skn-1, hif-1 and daf-16 independent paths via skn-1/hif-1. Paths that could be tested by experimental hypotheses, with respect to relative contribution to longevity, are also discussed. Direct comparison of the IIS and TOR pathways in both worm and fly suggest a remarkable similarity. While similarities in the paths that could modulate ageing in both organisms were noted, differences are also discussed. This approach can also be extended to other pathways and processes.
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http://dx.doi.org/10.1039/c3mb25485bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693544PMC
July 2013

Implication of a rare deletion at distal 16p11.2 in schizophrenia.

JAMA Psychiatry 2013 Mar;70(3):253-60

Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, New York 11004, USA.

Context: Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication.

Objective: To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples.

Design: Genetic association study of microarray data.

Setting: Samples of DNA were collected at 9 sites from different countries.

Participants: Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parent-offspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12,398 cases and 17,945 controls.

Main Outcome Measures: Statistically increased rate of specific copy number variations in cases vs controls.

Results: One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13,850 cases (0.094%) and 3 of 19,954 controls (0.015%) (odds ratio, 6.25 [95% CI, 1.78-21.93]; P = .001, Fisher exact test).

Conclusions: Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia.
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http://dx.doi.org/10.1001/2013.jamapsychiatry.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750982PMC
March 2013

A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk.

Hum Mol Genet 2013 Feb 11;22(4):816-24. Epub 2012 Nov 11.

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.

We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 × 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not appear to make a significant contribution to the development of AD.
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http://dx.doi.org/10.1093/hmg/dds476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554198PMC
February 2013

Serotonin: from top to bottom.

Biogerontology 2013 Feb 26;14(1):21-45. Epub 2012 Oct 26.

School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, UK.

Serotonin is a monoamine neurotransmitter, which is phylogenetically conserved in a wide range of species from nematodes to humans. In mammals, age-related changes in serotonin systems are known risk factors of age-related diseases, such as diabetes, faecal incontinence and cardiovascular diseases. A decline in serotonin function with aging would be consistent with observations of age-related changes in behaviours, such as sleep, sexual behaviour and mood all of which are linked to serotonergic function. Despite this little is known about serotonin in relation to aging. This review aims to give a comprehensive analysis of the distribution, function and interactions of serotonin in the brain; gastrointestinal tract; skeletal; vascular and immune systems. It also aims to demonstrate how the function of serotonin is linked to aging and disease pathology in these systems. The regulation of serotonin via microRNAs is also discussed, as are possible applications of serotonergic drugs in aging research and age-related diseases. Furthermore, this review demonstrates that serotonin is potentially involved in whole organism aging through its links with multiple organs, the immune system and microRNA regulation. Methods to investigate these links are discussed.
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http://dx.doi.org/10.1007/s10522-012-9406-3DOI Listing
February 2013

The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

J Alzheimers Dis 2012 ;28(2):377-87

MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.

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.
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http://dx.doi.org/10.3233/JAD-2011-110824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118466PMC
May 2012

No evidence that extended tracts of homozygosity are associated with Alzheimer's disease.

Am J Med Genet B Neuropsychiatr Genet 2011 Dec 2;156B(7):764-71. Epub 2011 Aug 2.

MRC Centre for Neuropyschiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, Cardiff University, Heath Park.

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 individual run of homozygosity showed association to Alzheimer's disease.
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http://dx.doi.org/10.1002/ajmg.b.31216DOI Listing
December 2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Nat Genet 2011 May 3;43(5):429-35. Epub 2011 Apr 3.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
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http://dx.doi.org/10.1038/ng.803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084173PMC
May 2011

Comparative analysis of germline and somatic microlesion mutational spectra in 17 human tumor suppressor genes.

Hum Mutat 2011 Jun 22;32(6):620-32. Epub 2011 Mar 22.

Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Mutations associated with tumorigenesis may either arise somatically or can be inherited through the germline. We performed a comparison of somatic, germline, shared (found in both soma and germline) and somatic recurrent mutational spectra for 17 human tumor suppressor genes, which focused upon missense single base-pair substitutions and microdeletions/microinsertions. Somatic and germline mutational spectra were similar in relation to C.G>T.A transitions but differed with respect to the frequency of A.T>G.C, A.T>T.A, and C.G>A.T substitutions. Shared missense mutations were characterized by higher mutability rates, greater physicochemical differences between wild-type and mutant residues, and a tendency to occur in evolutionarily conserved residues and within CpG/CpHpG oligonucleotides. Mononucleotide runs (≥4 bp) were identified as hotspots for shared microdeletions/microinsertions. Both germline and somatic microdeletions/microinsertions were found to be significantly overrepresented within the "indel-hotspot" motif, GTAAGT. Using a naïve Bayes' classifier trained to discriminate between five missense mutation groups, 63% of mutations in our dataset were on average correctly recognized. Applying this classifier to an independent dataset of probable driver mutations, we concluded that ∼50% of these somatic missense mutations possess features consistent with their being either shared or recurrent, suggesting that a disproportionate number of such lesions are likely to be drivers of tumorigenesis.
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http://dx.doi.org/10.1002/humu.21483DOI Listing
June 2011

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.

PLoS One 2010 Nov 15;5(11):e13950. Epub 2010 Nov 15.

Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff, United Kingdom.

Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.

Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.

Principal Findings: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.

Significance: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013950PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981526PMC
November 2010

Genome-wide association study of schizophrenia in a Japanese population.

Biol Psychiatry 2011 Mar 15;69(5):472-8. Epub 2010 Sep 15.

Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.

Background: Genome-wide association studies have detected a small number of weak but strongly supported schizophrenia risk alleles. Moreover, a substantial polygenic component to the disorder consisting of a large number of such alleles has been reported by the International Schizophrenia Consortium.

Method: We report a Japanese genome-wide association study of schizophrenia comprising 575 cases and 564 controls. We attempted to replicate 97 markers, representing a nonredundant panel of markers derived mainly from the top 150 findings, in up to three data sets totaling 1990 cases and 5389 controls. We then attempted to replicate the observation of a polygenic component to the disorder in the Japanese and to determine whether this overlaps that seen in UK populations.

Results: Single-locus analysis did not reveal genome-wide support for any locus in the genome-wide association study sample (best p = 6.2 × 10(-6)) or in the complete data set in which the best supported locus was SULT6B1 (rs11895771: p = 3.7 × 10(-5) in the meta-analysis). Of loci previously supported by genome-wide association studies, we obtained in the Japanese support for NOTCH4 (rs2071287: p(meta) = 5.1 × 10(-5)). Using the approach reported by the International Schizophrenia Consortium, we replicated the observation of a polygenic component to schizophrenia within the Japanese population (p = .005). Our trans Japan-UK analysis of schizophrenia also revealed a significant correlation (best p = 7.0 × 10(-5)) in the polygenic component across populations.

Conclusions: These results indicate a shared polygenic risk of schizophrenia between Japanese and Caucasian samples, although we did not detect unequivocal evidence for a novel susceptibility gene for schizophrenia.
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http://dx.doi.org/10.1016/j.biopsych.2010.07.010DOI Listing
March 2011

Genetic differences between five European populations.

Hum Hered 2010 8;70(2):141-9. Epub 2010 Jul 8.

MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.

Aims: We sought to examine the magnitude of the differences in SNP allele frequencies between five European populations (Scotland, Ireland, Sweden, Bulgaria and Portugal) and to identify the loci with the greatest differences.

Methods: We performed a population-based genome-wide association analysis with Affymetrix 6.0 and 5.0 arrays. We used a 4 degrees of freedom χ(2) test to determine the magnitude of stratification for each SNP. We then examined the genes within the most stratified regions, using a highly conservative cutoff of p < 10(-45).

Results: We found 40,593 SNPs which are genome-wide significantly (p ≤ 10(-8)) stratified between these populations. The largest differences clustered in gene ontology categories for immunity and pigmentation. Some of the top loci span genes that have already been reported as highly stratified: genes for hair color and pigmentation (HERC2, EXOC2, IRF4), the LCT gene, genes involved in NAD metabolism, and in immunity (HLA and the Toll-like receptor genes TLR10, TLR1, TLR6). However, several genes have not previously been reported as stratified within European populations, indicating that they might also have provided selective advantages: several zinc finger genes, two genes involved in glutathione synthesis or function, and most intriguingly, FOXP2, implicated in speech development.

Conclusion: Our analysis demonstrates that many SNPs show genome-wide significant differences within European populations and the magnitude of the differences correlate with the geographical distance. At least some of these differences are due to the selective advantage of polymorphisms within these loci.
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http://dx.doi.org/10.1159/000313854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077089PMC
June 2015

Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia.

Arch Gen Psychiatry 2010 Apr;67(4):318-27

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.

Context: Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date.

Objectives: To determine whether large (>100,000 base pairs) and rare (found in <1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia.

Design: A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray.

Setting: The Wellcome Trust Case Control Consortium.

Participants: There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents.

Main Outcome Measures: Overall load of CNVs and presence of rare CNVs.

Results: The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder.

Conclusions: Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder.
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http://dx.doi.org/10.1001/archgenpsychiatry.2010.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476027PMC
April 2010

Support for the involvement of large copy number variants in the pathogenesis of schizophrenia.

Hum Mol Genet 2009 Apr 29;18(8):1497-503. Epub 2009 Jan 29.

Department of Psychological Medicine, Cardiff University, Heath Park, Cardiff, UK.

We investigated the involvement of rare (<1%) copy number variants (CNVs) in 471 cases of schizophrenia and 2792 controls that had been genotyped using the Affymetrix GeneChip 500K Mapping Array. Large CNVs >1 Mb were 2.26 times more common in cases (P = 0.00027), with the effect coming mostly from deletions (odds ratio, OR = 4.53, P = 0.00013) although duplications were also more common (OR = 1.71, P = 0.04). Two large deletions were found in two cases each, but in no controls: a deletion at 22q11.2 known to be a susceptibility factor for schizophrenia and a deletion on 17p12, at 14.0-15.4 Mb. The latter is known to cause hereditary neuropathy with liability to pressure palsies. The same deletion was found in 6 of 4618 (0.13%) cases and 6 of 36 092 (0.017%) controls in the re-analysed data of two recent large CNV studies of schizophrenia (OR = 7.82, P = 0.001), with the combined significance level for all three studies achieving P = 5 x 10(-5). One large duplication on 16p13.1, which has been previously implicated as a susceptibility factor for autism, was found in three cases and six controls (0.6% versus 0.2%, OR = 2.98, P = 0.13). We also provide the first support for a recently reported association between deletions at 15q11.2 and schizophrenia (P = 0.026). This study confirms the involvement of rare CNVs in the pathogenesis of schizophrenia and contributes to the growing list of specific CNVs that are implicated.
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http://dx.doi.org/10.1093/hmg/ddp043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664144PMC
April 2009

Support for neuregulin 1 as a susceptibility gene for bipolar disorder and schizophrenia.

Biol Psychiatry 2008 Sep 7;64(5):419-27. Epub 2008 May 7.

Department of Psychological Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom.

Background: There is support that Neuregulin 1 (NRG1) plays a role in susceptibility to schizophrenia but limited evidence for its involvement in bipolar disorder. We wished to investigate further the involvement of NRG1 in schizophrenia and bipolar disorder.

Methods: We used hierarchical association analysis in parent-offspring trios, 634 with schizophrenia/schizoaffective disorder (SZ/SA) and 243 with bipolar 1 disorder (BP1). The primary analysis was the markers defining the "core Icelandic haplotype" (HAP(ICE)). We undertook polymorphism discovery, additional genotyping, and also explored phenotypic associations, as a secondary analysis aimed at refining the signal.

Results: The initial global haplotype test yielded significant evidence for association (p = .01) with SZ/SA and BP1 (p = .004), although HAP(ICE) was not overtransmitted. The marker showing strongest evidence for association in the deCODE studies, SNP8NRG221533, was associated with SZ/SA (p(corrected) = .039) and with BP1 (p(corrected) = .039), with BP1 showing association to the opposite allele as SZ/SA. The pattern of transmission at SNP8NRG221533 was significantly different in SZ/SA than in BP1 (p = .0004). Secondary analyses of markers and phenotypes provided no additional evidence for association to SZ/SA. However, a new marker, rs7014762, was associated with an a priori defined "typical" bipolar phenotype characterized by excellent recovery between episodes and no mood incongruent features (p(corrected) = .003).

Conclusions: Our data provide significant levels of support for NRG1 as a susceptibility gene for both major forms of psychosis, and this cannot be interpreted as being due to population stratification. More tentatively, they also might indicate the presence of multiple alleles that influence the psychosis phenotype.
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http://dx.doi.org/10.1016/j.biopsych.2008.03.025DOI Listing
September 2008

A meta-analysis of nonsense mutations causing human genetic disease.

Hum Mutat 2008 Aug;29(8):1037-47

Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Nonsense mutations account for approximately 11% of all described gene lesions causing human inherited disease and approximately 20% of disease-associated single-basepair substitutions affecting gene coding regions. Pathological nonsense mutations resulting in TGA (38.5%), TAG (40.4%), and TAA (21.1%) occur in different proportions to naturally occurring stop codons. Of the 23 different nucleotide substitutions giving rise to nonsense mutations, the most frequent are CGA --> TGA (21%; resulting from methylation-mediated deamination) and CAG --> TAG (19%). The differing nonsense mutation frequencies are largely explicable in terms of variable nucleotide substitution rates such that it is unnecessary to invoke differential translational termination efficiency or differential codon usage. Some genes are characterized by numerous nonsense mutations but relatively few if any missense mutations (e.g., CHM) whereas other genes exhibit many missense mutations but few if any nonsense mutations (e.g., PSEN1). Genes in the latter category have a tendency to encode proteins characterized by multimer formation. Consistent with the operation of a clinical selection bias, genes exhibiting an excess of nonsense mutations are also likely to display an excess of frameshift mutations. Tumor suppressor (TS) genes exhibit a disproportionate number of nonsense mutations while most mutations in oncogenes are missense. A total of 12% of somatic nonsense mutations in TS genes were found to occur recurrently in the hypermutable CpG dinucleotide. In a comparison of somatic and germline mutational spectra for 17 TS genes, approximately 43% of somatic nonsense mutations had counterparts in the germline (rising to 98% for CpG mutations). Finally, the proportion of disease-causing nonsense mutations predicted to elicit nonsense-mediated mRNA decay (NMD) is significantly higher (P=1.56 x 10(-9)) than among nonobserved (potential) nonsense mutations, implying that nonsense mutations that elicit NMD are more likely to come to clinical attention.
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http://dx.doi.org/10.1002/humu.20763DOI Listing
August 2008

Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia.

Proc Natl Acad Sci U S A 2006 Aug 4;103(33):12469-74. Epub 2006 Aug 4.

Department of Psychological Medicine, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.

Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n = approximately 1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10(-7)) and ERBB4 (P = 0.002, corrected P = 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other's expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function.
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http://dx.doi.org/10.1073/pnas.0603029103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1567903PMC
August 2006

No evidence for association between polymorphisms in GRM3 and schizophrenia.

BMC Psychiatry 2005 May 13;5:23. Epub 2005 May 13.

Department of Psychological Medicine, Wales School of Medicine, Henry Wellcome Building, Cardiff University, Heath Park, Cardiff, UK.

Background: Three studies have previously reported data that were interpreted by the authors as supportive of association between schizophrenia and polymorphisms in the gene encoding the metabotropic glutamate receptor GRM3.

Methods: In a bid to examine this hypothesis, we examined seven SNPs spanning GRM3 in a UK case-control sample (schizophrenic cases n = 674, controls n = 716). These included all SNPs previously reported to be associated, alone or in haplotypes, with schizophrenia in European or European American samples.

Results: Our data showed no evidence for association with single markers, or 2, 3, 4 and 5 marker haplotypes, nor did any specific haplotypes show evidence for association according to previously observed patterns.

Conclusion: Examination of our own data and those of other groups leads us to conclude that at present, GRM3 should not be viewed as a gene for which there is replicated evidence for association with schizophrenia.
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http://dx.doi.org/10.1186/1471-244X-5-23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142331PMC
May 2005

Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria.

Biol Psychiatry 2004 May;55(10):971-5

Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, United Kingdom.

Background: The gene encoding the dystrobrevin binding protein (DTNBP1) has been implicated in the pathogenesis of schizophrenia by several association studies. We tried to replicate these findings in a sample of 488 parent-proband trios recruited in Bulgaria. Probands had a diagnosis of schizophrenia (n = 441) or schizoaffective disorder (n = 47).

Methods: We genotyped eight single nucleotide polymorphisms within the gene, four of which had been reported in previous studies, and four identified as informative by our group through direct screening of the gene and genotyping in a sample of cases and control subjects.

Results: A significant excess of transmissions was observed for two of the markers, p1635 and p1757, (p =.0009 and.0013, respectively). Analysis of two-, three-, and four-marker haplotypes produced numerous positive results, with six (4% of the total combinations) at p <.001.

Conclusions: These results provide strong support for DTNBP1 as a susceptibility gene for schizophrenia; however, different haplotypes seem to be associated in different studies.
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http://dx.doi.org/10.1016/j.biopsych.2004.01.025DOI Listing
May 2004