7 results on '"Gill, Michael"'
Search Results
2. Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease.
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Baker, Emily, Sims, Rebecca, Leonenko, Ganna, Frizzati, Aura, Harwood, Janet C., Grozeva, Detelina, null, null, Morgan, Kevin, Passmore, Peter, Holmes, Clive, Powell, John, Brayne, Carol, Gill, Michael, Mead, Simon, Bossù, Paola, Spalletta, Gianfranco, Goate, Alison M., Cruchaga, Carlos, Maier, Wolfgang, and Heun, Reinhard
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ALZHEIMER'S disease ,SINGLE nucleotide polymorphisms ,GENES ,CIRCADIAN rhythms ,MOLECULAR genetics ,CHOLESTEROL metabolism - Abstract
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. [ABSTRACT FROM AUTHOR]- Published
- 2019
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3. DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli.
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Frodl, Thomas, Szyf, Moshe, Carballedo, Angela, Ly, Victoria, Dymov, Sergiy, Vaisheva, Farida, Morris, Derek, Fahey, Ciara, Meaney, James, Gill, Michael, and Booij, Linda
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BRAIN physiology ,DNA ,ANALYSIS of covariance ,CHI-squared test ,MENTAL depression ,EMOTIONS ,GENES ,REGRESSION analysis ,RESEARCH funding ,SEROTONIN ,STATISTICS ,DATA analysis ,CASE-control method ,DATA analysis software ,DESCRIPTIVE statistics ,PHYSIOLOGY - Abstract
Background: The aim of the present study was to investigate the association of fMRI blood oxygen--level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD). Methods: We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyro-sequencing. Results: Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation. Limitations: It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn. Conclusion: Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery. [ABSTRACT FROM AUTHOR]
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- 2015
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4. Epistasis between neurochemical gene polymorphisms and risk for ADHD.
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Segurado, Ricardo, Bellgrove, Mark A., Manconi, Francesca, Gill, Michael, and Hawi, Ziarah
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GENES ,NEUROCHEMISTRY ,GENETICS ,ATTENTION-deficit hyperactivity disorder ,MEDICAL research - Abstract
A number of genes with function related to synaptic neurochemistry have been genetically associated with attention deficit/hyperactivity disorder. However, susceptibility to the development of common psychiatric disorders by single variants acting alone, can so far only explain a small proportion of the heritability of the phenotype. It has been postulated that the unexplained 'dark heritability' may at least in part be due to epistatic effects, which may account for the small observed marginal associations, and the difficulties with replication of positive findings. We undertook a comprehensive exploration of pair-wise interactions between genetic variants in 24 candidate genic regions involved in monoaminergic catabolism, anabolism, release, re-uptake and signal transmission in a sample of 177 parent-affected child trios using a case-only design and a case-pseudocontrol design using conditional logistic regression. Marker-pairs thresholded on interaction odds ratio (OR) and P-value are presented. We detected a number of interaction ORs >4.0, including an interesting correlation between markers in the ADRA1B and DBH genes in affected individuals, and several further interesting but smaller effects. These effects are no larger than you would expect by chance under the assumption of independence of all pair-wise relations; however, independence is unlikely. Furthermore, the size of these effects is of interest and attempts to replicate these results in other samples are anticipated. [ABSTRACT FROM AUTHOR]
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- 2011
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5. The SNP ratio test: pathway analysis of genome-wide association datasets.
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O'Dushlaine, Colm, Kenny, Elaine, Heron, Elizabeth A., Segurado, Ricardo, Gill, Michael, Morris, Derek W., and Corvin, Aiden
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GENOMES ,GENES ,PARKINSON'S disease ,DATABASES ,GENOMICS - Abstract
Summary: We present a tool that assesses the enrichment of significant associations from genome-wide association studies (GWAS) in a pathway context. The SNP ratio test (SRT) compares the proportion of significant to all SNPs within genes that are part of a pathway and computes an empirical P-value based on comparisons to ratios in datasets where the assignment of case/control status has been randomized. We applied the SRT to a Parkinson's disease GWAS dataset, using the KEGG database, revealing significance for Parkinson's disease and related pathways. [ABSTRACT FROM PUBLISHER]
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- 2009
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6. Preferential Transmission of Paternal Alleles at Risk Genes in Attention- Deficit/Hyperactivity Disorder.
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Hawi, Ziarih, Segurado, Ricardo, Conroy, Judith, Sheehan, Karen, Lowe, Naomi, Kirley, Aiveen, Shields, Denis, Fitzgerald, Michael, Gallagher, Louise, and Gill, Michael
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ATTENTION-deficit hyperactivity disorder , *DOPAMINERGIC mechanisms , *NEURAL transmission , *BEHAVIOR disorders in children , *GENES , *HEREDITY - Abstract
Family, twin, and adoption studies have demonstrated a significant genetic contribution to the etiology of attention-deficit/hyperactivity disorder (ADHD). Pharmacological, neuroimaging, and animal-model findings suggest imbalances in monoaminergic (dopaminergic, serotonergic, and noradrenergic) neurotransmission in ADHD. We have examined monoaminergic candidate genes for possible genetic association with ADHD in the Irish population, focusing particularly on genes of the dopaminergic and serotonergic systems. We have observed that several of these genes are associated with ADHD, including DAT1, DBH, DRD4, DRD5, and 5HT1B. Here, we present what appears to be a systematic overtransmission of paternal alleles at candidate genes associated with ADHD. For the nine genes included in the analysis, the overall odds ratio for paternal transmission was 2, compared with 1.3 for maternal transmission (paternal vs. maternal χ2 = 9.6; P = .0019). Transmission to females, from either parent, was significantly stronger than to males. Possible reasons for this preferential transmission include imprinting and ascertainment bias, although results of further analyses show that the latter is unlikely. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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7. Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia
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Eleni Giannoulatou, Nancy Buccola, Tune Pers, Sarah TOSATO, Christos Pantelis, James Walters, Hon-Cheong So, Igor Nenadić, Joseph Buxbaum, Lili Milani, Miloš Milovančević, Naomi Wray, Joanne Knight, Nicholas Wood, Srihari Gopal, Silviu-Alin Bacanu, Colin Palmer, Inez Myin-Germeys, Francis Anthony O'Neill, Matthew A Brown, Sang Hong Lee, Robert Plomin, Peter Visscher, Tracey Petryshen, Preben Bo Mortensen, Thomas Folkmann Hansen, Esben Agerbo, Digby Quested, Jianjun Liu, Engilbert Sigurdsson, Sara Marsal, Céline Bellenguez, Robert Freedman, Panos Deloukas, Ditte Demontis, Donald Black, David Collier, Fritz Zimprich, Clement C Zai, Nakao IWATA, Elvira Bramon, Masashi Ikeda, Andrew McIntosh, Bryan Mowry, Patrik Magnusson, Janis Klovins, Srdjan Djurovic, Jim Van Os, Ulrich Schall, Jan Lubinski, Milica Pejovic Milovancevic, Kang Sim, Rodney Scott, Anders Børglum, Jennifer Moran, Denise Harold, Sergi Papiol, Bradley Webb, Elisabeth Stögmann, Davidson, Michael, Germeys, Inez, Harold, Denise, Connolly, Siobhan, Riley, Brien P, Kendler, Kenneth S, McCarthy, Shane E, McCombie, William R, Richards, Alex, Owen, Michael J, O'Donovan, Michael C, Walters, James, Donohoe, Gary, Gill, Michael, Corvin, Aiden, Morris, Derek W, Lee, SH, Schizophrenia Working Group of the Psychiatric Genomics Consortuim, Wellcome Trust Case Control Consortium, National Institutes of Health, Science Foundation Ireland, Wellcome Trust, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, and Adult Psychiatry
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Male ,Genome-wide association study ,WHOLE-GENOME ASSOCIATION ,Identity by descent ,0302 clinical medicine ,Risk Factors ,Databases, Genetic ,2.1 Biological and endogenous factors ,GWAS ,Exome ,Copy-number variation ,Aetiology ,Genetics (clinical) ,Exome sequencing ,Genetics & Heredity ,Psychiatry ,Schizophrenia Working Group of the Psychiatric Genomics Consortium ,0303 health sciences ,Chromosome Mapping ,Middle Aged ,Serious Mental Illness ,3. Good health ,Psychiatry and Mental health ,Mental Health ,DISEASES ,Female ,BURDEN ,Sequence Analysis ,Life Sciences & Biomedicine ,Adult ,GENES ,DNA Copy Number Variations ,Genotype ,DISORDERS ,Clinical Sciences ,Single-nucleotide polymorphism ,Computational biology ,Biology ,IBD mapping ,Article ,Databases ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Genetic ,Clinical Research ,Exome Sequencing ,rare variants ,Genetics ,Humans ,Genetic Predisposition to Disease ,AUTISM ,Genome‐wide association studies (GWASs) ,030304 developmental biology ,Genetic association ,Science & Technology ,risk variants ,Prevention ,Wellcome Trust Case Control Consortium 2 ,Human Genome ,Haplotype ,Neurosciences ,DNA ,Sequence Analysis, DNA ,Brain Disorders ,Haplotypes ,DE-NOVO MUTATIONS ,Case-Control Studies ,API ,Schizophrenia ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Genome‐wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re‐analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity‐by‐descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow‐up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes. National Institutes of Health, Grant/Award Numbers: R01‐MH041953, R01‐MH083094; Science Foundation Ireland, Grant/Award Numbers: 08/IN.1/B1916, 12/IP/1359, 12/IP/1670; Wellcome Trust, Grant/Award Number: 085475/B/08/Z peer-reviewed
- Published
- 2019
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