28 results on '"Gill, Michael"'
Search Results
2. 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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3. Population structure and genome-wide patterns of variation in Ireland and Britain.
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O'Dushlaine, Colm T., Morris, Derek, Moskvina, Valentina, Kirov, George, Gill, Michael, Corvin, Aiden, Wilson, James F., and Cavalleri, Gianpiero L.
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GENE mapping ,LINKAGE disequilibrium ,GENETIC techniques - Abstract
Located off the northwestern coast of the European mainland, Britain and Ireland were among the last regions of Europe to be colonized by modern humans after the last glacial maximum. Further, the geographical location of Britain, and in particular of Ireland, is such that the impact of historical migration has been minimal. Genetic diversity studies applying the Y chromosome and mitochondrial systems have indicated reduced diversity and an increased population structure across Britain and Ireland relative to the European mainland. Such characteristics would have implications for genetic mapping studies of complex disease. We set out to further our understanding of the genetic architecture of the region from the perspective of (i) population structure, (ii) linkage disequilibrium (LD), (iii) homozygosity and (iv) haplotype diversity (HD). Analysis was conducted on 3654 individuals from Ireland, Britain (with regional sampling in Scotland), Bulgaria, Portugal, Sweden and the Utah HapMap collection. Our results indicate a subtle but clear genetic structure across Britain and Ireland, although levels of structure were reduced in comparison with average cross-European structure. We observed slightly elevated levels of LD and homozygosity in the Irish population compared with neighbouring European populations. We also report on a cline of HD across Europe with greatest levels in southern populations and lowest levels in Ireland and Scotland. These results are consistent with our understanding of the population history of Europe and promote Ireland and Scotland as relatively homogenous resources for genetic mapping of rare variants. [ABSTRACT FROM AUTHOR]
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- 2010
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4. Neurocognition and suicidal behaviour in an Irish population with major psychotic disorders.
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Nangle, Jeanne-Marie, Clarke, Sarah, Morris, Derek W., Schwaiger, Siobhan, McGhee, Kevin A., Kenny, Niamh, Murphy, Kevin, Gill, Michael, Corvin, Aiden, and Donohoe, Gary
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PSYCHOSES , *IRISH people , *SUICIDAL behavior , *SCHIZOPHRENIA , *PSYCHOLOGY , *COGNITION disorders diagnosis , *BRAIN , *COGNITION disorders , *DEMOGRAPHY , *NEUROPSYCHOLOGICAL tests , *CLASSIFICATION of mental disorders , *PUBLIC health surveillance , *SEVERITY of illness index - Abstract
Objectives: Although neurocognitive deficits are seen as core to schizophrenia the association between suicidality and neurocognition has received little attention. Our aim was to examine the relationship between neurocognitive variables and suicidal behaviour in patients with schizophrenia and schizoaffective disorder.Methods: Seventy-eight patients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder were categorised as either having attempted suicide or not having attempted suicide based on clinical interview and chart review. Attempters and non-attempters were compared on an extensive neuropsychological battery examining pre-morbid and current general cognitive functioning, episodic memory, and executive functioning.Results: Suicide attempters tended to out perform non-attempters across all areas of executive functioning, and showed significantly better performances on measures of attention and verbal fluency. After controlling for relevant clinical and demographic variables, the differences between attempters and non-attempters remained significant for measures of attention (F = 4.97, p = 0.03) and verbal fluency (F = 4.28, p = 0.04).Conclusion: This study adds to existing data that suicide attempters with schizophrenia or schizoaffective disorder may have higher cognitive functioning than non-attempters. In particular, the preservation of higher executive function may influence the ability to initiate and plan suicidal behaviour. [ABSTRACT FROM AUTHOR]- Published
- 2006
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5. No evidence for association of the dysbindin gene [DTNBP1] with schizophrenia in an Irish population-based study
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Morris, Derek W., McGhee, Kevin A., Schwaiger, Siobhan, Scully, Paul, Quinn, John, Meagher, David, Waddington, John L., Gill, Michael, and Corvin, Aiden P.
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SCHIZOPHRENIA , *GENES , *CARRIER proteins , *CHROMOSOMES , *GENETIC polymorphisms , *PSYCHOSES , *GENETIC markers , *CASE-control method , *HAPLOTYPES - Abstract
A recent family-based association study identified a putative association between variants in the dystrobrevin binding protein 1 (dysbindin) gene (DTNBP1) and schizophrenia. This study used a sample of 270 Irish pedigrees multiply affected with schizophrenia. We attempted to replicate these findings in an independent Irish sample of 219 schizophrenia cases and 231 controls. No evidence was found to suggest an association between the DTNBP1 gene and schizophrenia in our sample. Possible reasons for these findings are discussed. [Copyright &y& Elsevier]
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- 2003
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6. Assessing Problem Based Learning in Child and Adolescent Psychiatry at the Trinity College Dublin, Ireland.
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Skokauskas, Norbert, Gallagher, Louise, Frodl, Thomas, and Gill, Michael
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LEARNING strategies , *PROBLEM-based learning , *PSYCHIATRY , *UNIVERSITIES & colleges ,STUDY & teaching of medicine - Abstract
The article discusses the assessment of problem based learning (PBL) developed by the School of Medicine of Trinity College Dublin (TCD) in Ireland exclusively to child and adolescent psychiatry (CAP). It notes that such assessment can have a potential impact on how students approach their learning. The authors assert that triple jump assessment could be the most suitable for psychiatry and child and adolescent psychiatry that assesses a student's ability to analyze and resolve a problem.
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- 2012
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7. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.
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Hannon E, Dempster EL, Mansell G, Burrage J, Bass N, Bohlken MM, Corvin A, Curtis CJ, Dempster D, Di Forti M, Dinan TG, Donohoe G, Gaughran F, Gill M, Gillespie A, Gunasinghe C, Hulshoff HE, Hultman CM, Johansson V, Kahn RS, Kaprio J, Kenis G, Kowalec K, MacCabe J, McDonald C, McQuillin A, Morris DW, Murphy KC, Mustard CJ, Nenadic I, O'Donovan MC, Quattrone D, Richards AL, Rutten BP, St Clair D, Therman S, Toulopoulou T, Van Os J, Waddington JL, Sullivan P, Vassos E, Breen G, Collier DA, Murray RM, Schalkwyk LS, and Mill J
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- Adult, Aged, England, Female, Humans, Ireland, Male, Middle Aged, Psychotic Disorders genetics, Schizophrenia, Treatment-Resistant genetics, Scotland, Sweden, Young Adult, DNA Methylation, Epigenome, Psychotic Disorders physiopathology, Schizophrenia, Treatment-Resistant physiopathology
- Abstract
We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia., Competing Interests: EH, ED, GM, JB, NB, MB, AC, CC, DD, TD, GD, MG, AG, CG, HH, CH, VJ, RK, JK, GK, CM, AM, DM, KM, CM, IN, DQ, AR, BR, DS, ST, TT, JV, JW, EV, GB, LS, JM No competing interests declared, MD M Di Forti reports personal fees from Janssen, outside the submitted work. FG Fiona Gaughran has received honoraria from Lundbeck, Otsuka, and Sunovion. She has a family member with professional links to Lilly and GSK, including shares. KK Kaarina Kowalec has consulted with Emerald Lake Safety Ltd. (2017-2018) and has received speaker honoraria from Biogen/Fraser Health Multiple Sclerosis Clinic (2018). Both are unrelated to the work published here. JM James MacCabe has received research funding from H Lundbeck. MO Michael C O'Donovan is supported by a collaborative research grant from Takeda Pharmaceuticals. Takeda played no part in the conception, design, implementation, or interpretation of this study. PS PF Sullivan reports the following potentially competing financial interests. Current: Lundbeck (advisory committee, grant recipient). Past three years: Pfizer (scientific advisory board). DC David A Collier is a full time employee and stockholder of Eli Lilly and Company. RM Robin M Murray reports personal fees from Janssen, Lundbeck, Sunovion, Recordati and Otsuka, (© 2021, Hannon et al.)
- Published
- 2021
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8. Effects of complement gene-set polygenic risk score on brain volume and cortical measures in patients with psychotic disorders and healthy controls.
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Holland JF, Cosgrove D, Whitton L, Harold D, Corvin A, Gill M, Mothersill DO, Morris DW, and Donohoe G
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- Adult, Brain metabolism, Case-Control Studies, Cerebral Cortex metabolism, Complement C4 genetics, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Ireland epidemiology, Male, Prognosis, Psychotic Disorders epidemiology, Psychotic Disorders genetics, Risk Factors, Brain pathology, Cerebral Cortex pathology, Genetic Markers, Immunologic Factors genetics, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Psychotic Disorders pathology
- Abstract
Multiple genome-wide association studies of schizophrenia have reported associations between genetic variants within the MHC region and disease risk, an association that has been partially accounted for by alleles of the complement component 4 (C4) gene. Following on previous findings of association between both C4 and other complement-related variants and memory function, we tested the hypothesis that polygenic scores calculated based on identified schizophrenia risk alleles within the "complement" system would be broadly associated with memory function and associated brain structure. We tested this using a polygenic risk score (PRS) calculated for complement genes, but excluding C4 variants. Higher complement-based PRS scores were observed to be associated with lower memory scores for the sample as a whole (N = 620, F change = 8.25; p = .004). A significant association between higher PRS and lower hippocampal volume was also observed (N = 216, R
2 change = 0.016, p = .015). However, after correcting for further testing of association with the more general indices of cortical thickness, surface area or total brain volume, none of which were associated with complement, the association with hippocampal volume became non-significant. A post-hoc analysis of hippocampal subfields suggested an association between complement PRS and several hippocampal subfields, findings that appeared to be particularly driven by the patient sample. In conclusion, our study yielded suggestive evidence of association between complement-based schizophrenia PRS and variation in memory function and hippocampal volume., (© 2020 Wiley Periodicals LLC.)- Published
- 2020
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9. Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis.
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Rees E, Carrera N, Morgan J, Hambridge K, Escott-Price V, Pocklington AJ, Richards AL, Pardiñas AF, McDonald C, Donohoe G, Morris DW, Kenny E, Kelleher E, Gill M, Corvin A, Kirov G, Walters JTR, Holmans P, Owen MJ, and O'Donovan MC
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- Adult, Cohort Studies, Humans, Ireland, Middle Aged, Netherlands, Risk Factors, United Kingdom, Cytoskeletal Proteins genetics, Nerve Tissue Proteins genetics, Neurons physiology, Receptors, N-Methyl-D-Aspartate genetics, Schizophrenia genetics, Schizophrenia physiopathology, Sequence Analysis, DNA, Voltage-Gated Sodium Channels genetics
- Abstract
Background: Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms., Methods: We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios., Results: While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 × 10
-4 ) and NMDAR (p = 1.7 × 10-5 ) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 × 10-4 )., Conclusions: In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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10. The phenotypic manifestations of rare CNVs in schizophrenia.
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Merikangas AK, Segurado R, Cormican P, Heron EA, Anney RJ, Moore S, Kelleher E, Hargreaves A, Anderson-Schmidt H, Gill M, Gallagher L, and Corvin A
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- Family, Female, Genetic Predisposition to Disease, Humans, Ireland, Logistic Models, Male, Paternal Age, Phenotype, Schizophrenia epidemiology, White People genetics, Brain metabolism, DNA Copy Number Variations, Schizophrenia genetics, Schizophrenia metabolism
- Abstract
There is compelling evidence for the role of copy number variants (CNVs) in schizophrenia susceptibility, and it has been estimated that up to 2-3% of schizophrenia cases may carry rare CNVs. Despite evidence that these events are associated with an increased risk across categorical neurodevelopmental disorders, there is limited understanding of the impact of CNVs on the core features of disorders like schizophrenia. Our objective was to evaluate associations between rare CNVs in differentially brain expressed (BE) genes and the core features and clinical correlates of schizophrenia. The sample included 386 cases of Irish ancestry with a diagnosis of schizophrenia, at least one rare CNV impacting any gene, and a core set of phenotypic measures. Statistically significant associations between deletions in differentially BE genes were found for family history of mental illness (decreased prevalence of all CNVs and deletions, unadjusted and adjusted) and for paternal age (increase in deletions only, unadjusted, among those with later ages at birth of patient). The strong effect of a lack of a family history on BE genes suggests that CNVs may comprise one pathway to schizophrenia, whereas a positive family history could index other genetic mechanisms that increase schizophrenia vulnerability. To our knowledge, this is the first investigation of the association between genome-wide CNVs and risk factors and sub-phenotypic features of schizophrenia beyond cognitive function., (Copyright © 2014 Elsevier B.V. All rights reserved.)
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- 2014
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11. No evidence that runs of homozygosity are associated with schizophrenia in an Irish genome-wide association dataset.
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Heron EA, Cormican P, Donohoe G, O'Neill FA, Kendler KS, Riley BP, Gill M, Corvin AP, and Morris DW
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- Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Ireland, Logistic Models, Haplotypes, Polymorphism, Single Nucleotide, Schizophrenia genetics
- Abstract
Runs of homozygosity (ROH), regions of the genome containing many consecutive homozygous SNPs, may represent two copies of a haplotype inherited from a common ancestor. A rare variant on this haplotype could thus be present in a homozygous and potentially recessive state. To detect rare risk variants for schizophrenia, we performed an ROH analysis in a homogeneous Irish genome wide association study (GWAS) dataset consisting of 1606 cases and 1794 controls. There was no genome-wide excess of ROH in cases compared to controls (p=0.7986). No consensus ROH at individual loci showed association with schizophrenia after genome-wide correction., (Copyright © 2014 Elsevier B.V. All rights reserved.)
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- 2014
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12. Effects of a novel schizophrenia risk variant rs7914558 at CNNM2 on brain structure and attributional style.
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Rose EJ, Hargreaves A, Morris D, Fahey C, Tropea D, Cummings E, Caltagirone C, Bossù P, Chiapponi C, Piras F, Spalletta G, Gill M, Corvin A, and Donohoe G
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- Adolescent, Adult, Aged, Alleles, Analysis of Variance, Case-Control Studies, Cation Transport Proteins, Cyclins genetics, Emotional Intelligence genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Gyrus Cinguli pathology, Humans, Ireland, Italy, Linkage Disequilibrium, Magnetic Resonance Imaging methods, Middle Aged, Neuropsychological Tests statistics & numerical data, Organ Size, Polymorphism, Single Nucleotide physiology, Schizophrenia pathology, Temporal Lobe pathology, Young Adult, Brain pathology, Cyclins physiology, Internal-External Control, Schizophrenia genetics, Schizophrenic Psychology
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Background: A single nucleotide polymorphism (rs7914558) within the cyclin M2 (CNNM2) gene was recently identified as a common risk variant for schizophrenia. The mechanism by which CNNM2 confers risk is unknown., Aims: To determine the impact of the rs7914558 risk 'G' allele [corrected] on measures of neurocognition, social cognition and brain structure., Method: Patients with schizophrenia (n = 400) and healthy controls (n = 160) completed measures of neuropsychological function and social cognition. Structural magnetic resonance imaging data were also acquired from an overlapping sample of Irish healthy controls (n = 159) and an independent sample of Italian patients (n = 82) and healthy controls (n = 39)., Results: No effects of genotype on neuropsychological test performance were observed. However, a dosage effect of the risk allele was found for an index of social cognition (i.e. attributional style), such that risk status was associated with reduced self-serving bias across groups (GG>AG>AA, P<0.05). Using voxel-based morphometry to investigate neuroanatomical regions putatively supporting social cognition, risk carriers had relatively increased grey matter volume in the right temporal pole and right anterior cingulate cortex (Pcorrected<0.05) in the Irish healthy controls sample; neuroanatomical associations between CNNM2 and grey matter volume in anterior cingulate cortex were also observed in the Italian schizophrenia and healthy controls samples., Conclusions: Although the biological role of CNNM2 in schizophrenia remains unknown, these data suggest that this CNNM2 risk variant rs7914558 may have an impact on neural systems relevant to social cognition. How such effects may mediate the relationship between genotype and disease risk remains to be established.
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- 2014
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13. The role of the major histocompatibility complex region in cognition and brain structure: a schizophrenia GWAS follow-up.
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Walters JT, Rujescu D, Franke B, Giegling I, Vásquez AA, Hargreaves A, Russo G, Morris DW, Hoogman M, Da Costa A, Moskvina V, Fernández G, Gill M, Corvin A, O'Donovan MC, Donohoe G, and Owen MJ
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- Adolescent, Adult, Aged, Brain physiopathology, Case-Control Studies, Chromosomes, Human, Pair 6 genetics, Cognition Disorders physiopathology, Cross-Cultural Comparison, Follow-Up Studies, Genetic Loci genetics, Genotype, Germany, Hippocampus pathology, Humans, Ireland, Magnetic Resonance Imaging, Memory, Episodic, Middle Aged, Neurogranin genetics, Neuropsychological Tests, Polymorphism, Single Nucleotide genetics, Schizophrenia physiopathology, Young Adult, Brain pathology, Cognition Disorders genetics, Cognition Disorders pathology, Genome-Wide Association Study, Major Histocompatibility Complex genetics, Schizophrenia genetics, Schizophrenia pathology, Schizophrenic Psychology
- Abstract
OBJECTIVE The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure. METHOD A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide association studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNPs showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample. RESULTS Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume. CONCLUSIONS The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition.
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- 2013
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14. Problem-based learning in child and adolescent psychiatry at Trinity College, Dublin, Ireland.
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Skokauskas N, Doody B, Gallagher L, Lawlor M, Moran T, Fitzgerald M, and Gill M
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- Adult, Career Choice, Consumer Behavior, Cross-Sectional Studies, Female, Humans, Ireland, Male, Students, Medical psychology, Surveys and Questionnaires, Adolescent Psychiatry education, Child Psychiatry education, Education, Medical, Undergraduate methods, Problem-Based Learning methods
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- 2012
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15. Functional assessment of a promoter polymorphism in S100B, a putative risk variant for bipolar disorder.
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Dagdan E, Morris DW, Campbell M, Hill M, Rothermundt M, Kästner F, Hohoff C, von Eiff C, Krakowitzky P, Gill M, McKeon P, and Roche S
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- Base Sequence, Calcium-Binding Proteins genetics, Cell Line, Electrophoretic Mobility Shift Assay, Genes, Reporter, Germany, Glioblastoma, Humans, Ireland, Luciferases genetics, Neuroblastoma, S100 Calcium Binding Protein beta Subunit, Schizophrenia genetics, Sequence Analysis, DNA, Bipolar Disorder genetics, Nerve Growth Factors blood, Nerve Growth Factors genetics, Polymorphism, Single Nucleotide, Promoter Regions, Genetic genetics, S100 Proteins blood, S100 Proteins genetics
- Abstract
Calcium-binding protein S100B has been implicated in the pathology of bipolar affective disorder (BPAD) and schizophrenia (SZ). S100B protein levels are elevated in serum of patients with both disorders compared to controls. We previously reported genetic association of a SNP in the promoter of S100B, rs3788266, with a psychotic form of BPAD. To test for genotypic effects of rs3788266 in vivo, S100B serum protein levels were measured in 350 Irish and German subjects of known S100B genotype. The functional effect of rs3788266 on S100B promoter activity was studied using the luciferase reporter system in U373MG glioblastoma and SH-SY5Y neuroblastoma cell lines. Allelic effects of rs3788266 on protein complex formation at the S100B promoter were investigated by an electrophoretic mobility shift assay. Higher mean serum S100B levels were associated with the risk G allele of rs3788266 in BPAD cases (P = 0.0001), unaffected relatives of BPAD cases (P < 0.0001) and unrelated controls (P < 0.0001). Consistent with the in vivo findings, luciferase gene expression was significantly increased in the presence of the G allele compared to the A allele in SH-SY5Y (P = <0.0001), and in U373MG (P = <0.0008) cell lines. The binding affinity of both SH-SY5Y and U373MG protein complexes for the S100B promoter was significantly stronger in the presence of G allele compared to the A allele promoter fragments. These data support rs3788266 as a functional promoter variant in the S100B gene where the presence of the G allele promotes increased gene expression and is associated with increased serum levels of the protein., (Copyright © 2011 Wiley-Liss, Inc.)
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- 2011
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16. Lack of association between markers in the ITGA3, ITGAV, ITGA6 and ITGB3 and autism in an Irish sample.
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Cochrane LE, Tansey KE, Gill M, Gallagher L, and Anney RJ
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- Female, Genetic Markers genetics, Genetic Predisposition to Disease genetics, Haplotypes genetics, Humans, Ireland, Linkage Disequilibrium genetics, Male, Polymorphism, Single Nucleotide genetics, Autistic Disorder genetics, Integrin alpha3 genetics, Integrin alpha6 genetics, Integrin alphaV genetics, Integrin beta3 genetics
- Abstract
Autism is a neurodevelopmental disorder characterized by impairments in three core areas--language, social interaction and restricted/repetitive behaviours. It is generally accepted that genetics plays a large role in the aetiology of autism, but the exact mechanism is still unknown. We recently published evidence of an association between autism and the ITGA4 gene [Conroy et al., 2008]. Two genomic regions have shown evidence of linkage to autism in multiple studies--2q31-q33 and 17q21-q22. Both of these regions harbour multiple integrin subunit genes. We tested markers in ITGA3, ITGA6, ITGAV and ITGB3 for association with autism in the Irish autism sample. No markers in ITGA3, ITGA6, ITGAV and ITGB3 were found to be associated with autism. Three 3-marker haplotypes in ITGAV, ITGA3 and ITGA6 were found to be nominally associated (0.01 < P < 0.05) and to have unremarkable findings. Our data indicates that in the Irish autism sample the integrin genes tested here do not play an important role in the aetiology of autism.
- Published
- 2010
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17. Psychosis susceptibility gene ZNF804A and cognitive performance in schizophrenia.
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Walters JT, Corvin A, Owen MJ, Williams H, Dragovic M, Quinn EM, Judge R, Smith DJ, Norton N, Giegling I, Hartmann AM, Möller HJ, Muglia P, Moskvina V, Dwyer S, O'Donoghue T, Morar B, Cooper M, Chandler D, Jablensky A, Gill M, Kaladjieva L, Morris DW, O'Donovan MC, Rujescu D, and Donohoe G
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- Adult, Case-Control Studies, Cognition Disorders diagnosis, Female, Gene Frequency, Genetic Variation genetics, Genome-Wide Association Study, Genotype, Germany ethnology, Humans, Ireland ethnology, Male, Memory Disorders diagnosis, Memory Disorders genetics, Neuropsychological Tests, Polymorphism, Single Nucleotide, Psychotic Disorders diagnosis, Psychotic Disorders genetics, Schizophrenia diagnosis, Schizophrenic Psychology, White People genetics, Cognition Disorders genetics, Genetic Predisposition to Disease genetics, Kruppel-Like Transcription Factors genetics, Schizophrenia genetics, Zinc Fingers genetics
- Abstract
Context: The Zinc Finger Protein 804A gene (ZNF804A) has been implicated in schizophrenia susceptibility by several genome-wide association studies. ZNF804A is brain expressed but of unknown function., Objective: To investigate whether the identified risk allele at the disease-associated single nucleotide polymorphism rs1344706 is associated with variation in neuropsychological performance in patients and controls., Design: Comparison of cases and controls grouped according to ZNF804A genotype (AA vs AC vs CC) on selected measures of cognition in 2 independent samples., Setting: Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy participants from the general population were ascertained., Participants: Patients with DSM-IV-diagnosed schizophrenia and healthy participants from independent samples of Irish (297 cases and 165 controls) and German (251 cases and 1472 controls) nationality., Main Outcome Measures: In this 2-stage study, we tested for an association between ZNF804A rs1344706 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attention) in an Irish discovery sample. We then tested significant results in a German replication sample., Results: In the Irish samples, the ZNF804A genotype was associated with differences in episodic and working memory in patients but not in controls. These findings replicated in the same direction in the German samples. Furthermore, in both samples, when patients with a lower IQ were excluded, the association between ZNF804A and schizophrenia strengthened., Conclusions: In a disorder characterized by heterogeneity, a risk variant at ZNF804A seems to delineate a patient subgroup characterized by relatively spared cognitive ability. Further work is required to establish whether this represents a discrete molecular pathogenesis that differs from that of other patient groups and whether this also has consequences for nosologic classification, illness course, or treatment.
- Published
- 2010
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18. Dopaminergic haplotype as a predictor of spatial inattention in children with attention-deficit/hyperactivity disorder.
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Bellgrove MA, Johnson KA, Barry E, Mulligan A, Hawi Z, Gill M, Robertson I, and Chambers CD
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- Adolescent, Attention Deficit Disorder with Hyperactivity diagnosis, Attention Deficit Disorder with Hyperactivity genetics, Attention Deficit Disorder with Hyperactivity physiopathology, Case-Control Studies, Child, Cues, Dopamine physiology, Dopamine Plasma Membrane Transport Proteins genetics, Female, Functional Laterality genetics, Genetic Heterogeneity, Genetic Predisposition to Disease, Genotype, Haplotypes genetics, Humans, Ireland, Male, Models, Genetic, Orientation physiology, Reaction Time genetics, Risk Factors, Attention physiology, Dopamine genetics, Space Perception physiology
- Abstract
Context: A distinct pattern of selective attention deficits in attention-deficit/hyperactivity disorder (ADHD) has been difficult to identify. Heterogeneity may reflect differences in underlying genetics., Objective: To document an objective deficit of selective attention in a large sample of children with and without ADHD using spatial orienting paradigms. By stratifying samples according to the gene dosage of a risk haplotype of the dopamine transporter gene (DAT1), we could determine whether genetic factors predict spatial inattention in ADHD., Design: A case-control design was used., Setting: Children with ADHD were recruited from clinics or support groups in Ireland. Typically developing children were recruited from schools in and around Dublin, Ireland., Participants: One hundred fifteen children were recruited (ADHD = 50, control = 65). Groups were matched for age but differed in estimated intelligence., Intervention: Two versions of a visual spatial orienting task in which attention was directed by valid, neutral, or invalid cues to target locations. Sudden-onset peripheral cues (exogenous) and centrally presented predictive cues (endogenous) were used., Main Outcome Measures: To isolate an attention deficit in ADHD, groups were first compared using analysis of variance on the spatial orienting tasks. Multiple regression was used to assess the main effect of DAT1 haplotype status (heterozygous vs homozygous) and the interaction of diagnosis and genotype on those variables that discriminated children with and without ADHD., Results: Children with ADHD displayed deficits in reorienting attention from invalidly cued spatial locations, particularly for targets in the left visual field. DAT1 haplotype status predicted spatial reorienting deficits for left visual field targets (P = .007) but there was also a significant interaction of diagnosis and genotype (P = .02), which revealed the greatest impairment in children with ADHD homozygous for the DAT1 haplotype., Conclusion: Heterogeneity in selective attention in ADHD can be explained by a replicated genetic risk factor for ADHD, the 10/3 DAT1 haplotype.
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- 2009
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19. Influence of NOS1 on verbal intelligence and working memory in both patients with schizophrenia and healthy control subjects.
- Author
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Donohoe G, Walters J, Morris DW, Quinn EM, Judge R, Norton N, Giegling I, Hartmann AM, Möller HJ, Muglia P, Williams H, Moskvina V, Peel R, O'Donoghue T, Owen MJ, O'Donovan MC, Gill M, Rujescu D, and Corvin A
- Subjects
- Adolescent, Adult, Aged, Attention, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Germany ethnology, Humans, Intelligence genetics, Ireland ethnology, Male, Memory, Middle Aged, Schizophrenic Psychology, Cognition Disorders diagnosis, Cognition Disorders genetics, Ethnicity genetics, Neuropsychological Tests, Nitric Oxide Synthase Type I genetics, Polymorphism, Single Nucleotide genetics, Schizophrenia diagnosis, Schizophrenia genetics
- Abstract
Context: Human and animal studies have implicated the gene NOS1 in both cognition and schizophrenia susceptibility., Objective: To investigate whether a potential schizophrenia risk single-nucleotide polymorphism (rs6490121) identified in a recent genome-wide association study negatively influences cognition in patients with schizophrenia and healthy control subjects., Design: A comparison of both cases and controls grouped according to NOS1 genotype (GG vs AG vs AA) on selected measures of cognition in 2 independent samples. We tested for association between NOS1 rs6490121 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attentional control) in an Irish sample. We then sought to replicate the significant results in a German sample., Setting: Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy volunteers from the general population were ascertained., Participants: Patients with DSM-IV-diagnosed schizophrenia and healthy control subjects from independent samples of Irish (cases, n = 349; controls, n = 230) and German (cases, n = 232; controls, n = 1344) nationality., Results: A main effect of NOS1 genotype on verbal IQ and working memory was observed in the Irish sample where the homozygous carriers of the schizophrenia risk G allele performed poorly compared with the other genotype groups. These findings were replicated in the German sample, again with the GG genotype carriers performing below other genotype groups. Post hoc analysis of additional IQ measures (full-scale and performance IQ) in the German sample revealed that NOS1 GG carriers underperformed on these measures also., Conclusions: NOS1 is associated with clinically significant variation in cognition. Whether this is a mechanism by which schizophrenia risk is increased (eg, via an influence on cognitive reserve) is yet to be confirmed.
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- 2009
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20. Impaired conflict resolution and alerting in children with ADHD: evidence from the Attention Network Task (ANT).
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Johnson KA, Robertson IH, Barry E, Mulligan A, Dáibhis A, Daly M, Watchorn A, Gill M, and Bellgrove MA
- Subjects
- Adolescent, Adolescent Behavior psychology, Attention Deficit Disorder with Hyperactivity epidemiology, Child, Child Behavior psychology, Cognition, Cues, Humans, Ireland epidemiology, Neuropsychological Tests statistics & numerical data, Orientation, Reaction Time, Attention, Attention Deficit Disorder with Hyperactivity psychology, Conflict, Psychological, Task Performance and Analysis
- Abstract
Background: An important theory of attention suggests that there are three separate networks that execute discrete cognitive functions. The 'alerting' network acquires and maintains an alert state, the 'orienting' network selects information from sensory input and the 'conflict' network resolves conflict that arises between potential responses. This theory holds promise for dissociating discrete patterns of cognitive impairment in disorders where attentional deficits may often be subtle, such as in attention deficit hyperactivity disorder (ADHD)., Methods: The Attentional Network Test (ANT), a behavioural assay of the functional integrity of attention networks, was used to examine the performance of 73 children with ADHD and 73 controls., Results: Performance on the ANT clearly differentiated the children with and without ADHD in terms of mean and standard deviation (SD) of reaction time (RT), the number of incorrect responses made and the number of omission errors made. The ADHD group demonstrated deficits in the conflict network in terms of slower RT and a higher number of incorrect responses. The ADHD group showed deficits in the alerting network in terms of the number of omission errors made. There was no demonstration of a deficit in the orienting network in ADHD on this task., Conclusions: The children with ADHD demonstrated deficits in the alerting and conflict attention networks but normal functioning of the orienting network.
- Published
- 2008
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21. An assessment of the Irish population for large-scale genetic mapping studies involving epilepsy and other complex diseases.
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O'Dushlaine CT, Dolan C, Weale ME, Stanton A, Croke DT, Kalviainen R, Eriksson K, Kantanen AM, Gibson RA, Hosford D, Sisodiya SM, Gill M, Corvin AP, Morris DW, Delanty N, and Cavalleri GL
- Subjects
- Gene Frequency, Genetics, Population, Haplotypes, Humans, Ireland, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Chromosome Mapping, Epilepsy genetics, Multifactorial Inheritance genetics
- Abstract
The recent completion of the International HapMap Project has rapidly advanced our understanding of linkage disequilibrium (LD) in the human genome. Today, tagging SNPs (tSNPs) can be quickly and easily selected and consequently HapMap data are regularly applied to both small- and large-scale genetic mapping studies. However, to correctly interpret the application of HapMap-derived tSNPs in a genetic mapping study, an understanding of how well HapMap data represents LD in the study population is critical. The Irish population had not previously been characterised in this way. Here, we do so using a set of 4424 SNPs selected from 279 candidate genes for epilepsy genotyped across 1118 healthy individuals from the Irish, British, Finnish and Australian populations. By considering the Irish population alongside surrounding European populations, our results confirm that the HapMap European-derived population accurately estimates patterning of LD in European descent populations. The Irish population appears notably well matched to the European HapMap population, and is markedly similar to the neighbouring British population. Although we were unable to detect significant substructure within the Irish population (a favourable result for genetic mapping), methods for controlling stratification should always be incorporated. This analysis therefore confirms that the genetic architecture of the Irish population is well suited to the study of complex traits and that tSNPs selected using the HapMap data can be confidently applied to the Irish population.
- Published
- 2008
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22. Protein kinase C-beta 1 gene variants are not associated with autism in the Irish population.
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Yang MS, Cochrane L, Conroy J, Hawi Z, Fitzgerald M, Gallagher L, and Gill M
- Subjects
- Autistic Disorder enzymology, Family, Female, Genotype, Humans, Ireland, Male, Protein Kinase C beta, Autistic Disorder genetics, Genetic Variation, Polymorphism, Single Nucleotide, Protein Kinase C genetics
- Abstract
Some evidences indicate that protein kinase C-beta 1 (PRKCB1) gene may be a predisposition locus of autism. A recent study reported evidence of association between autism and two haplotypes made up of six noncoding single nucleotide polymorphisms in the PRKCB1. To attempt replication of their findings, we examined the same six single nucleotide polymorphisms of PRKCB1 in 171 Irish autism trios. The haploview program was used to calculate D' as a measure of linkage disequilibrium. The transmission disequilibrium test for single nucleotide polymorphism markers and haplotypes was carried out using the TDTPHASE and PDTPHASE from the UNPHASED version 2.404 programs. Transmission disequilibrium test analysis showed no evidence of association for any of the six single nucleotide polymorphisms at the PRKCB1 that we studied, or any of their haplotypes. Our data do not support the finding that the PRKCB1 gene variants contribute risk for the development of autism.
- Published
- 2007
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23. Preferential transmission of paternal alleles at risk genes in attention-deficit/hyperactivity disorder.
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Hawi Z, Segurado R, Conroy J, Sheehan K, Lowe N, Kirley A, Shields D, Fitzgerald M, Gallagher L, and Gill M
- Subjects
- Attention Deficit Disorder with Hyperactivity epidemiology, Chi-Square Distribution, Female, Genetic Markers, Humans, Ireland epidemiology, Linkage Disequilibrium, Male, Nuclear Family, Odds Ratio, Alleles, Attention Deficit Disorder with Hyperactivity genetics, Dopamine Plasma Membrane Transport Proteins genetics, Genetic Predisposition to Disease epidemiology, Receptors, Dopamine D4 genetics, Receptors, Dopamine D5 genetics
- 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 chi 2=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.
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- 2005
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24. Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31.
- Author
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Segurado R, Conroy J, Meally E, Fitzgerald M, Gill M, and Gallagher L
- Subjects
- Adult, Alleles, Child, Chromosome Mapping, Female, Genetic Linkage, Genetic Markers, Genotype, Haplotypes genetics, Humans, Ireland ethnology, Linkage Disequilibrium genetics, Male, Mitochondrial Membrane Transport Proteins, Open Reading Frames genetics, Polymorphism, Single Nucleotide, Reproducibility of Results, Research statistics & numerical data, White People genetics, Autistic Disorder genetics, Calcium-Binding Proteins genetics, Chromosomes, Human, Pair 2 genetics, Membrane Transport Proteins genetics, Mitochondrial Proteins genetics
- Abstract
Objective: Autism is a neurodevelopmental disorder with childhood onset and a known major genetic component. A recent study identified a highly significant association between autism and a two-single-nucleotide-polymorphism haplotype in the SLC25A12 gene, with a homozygote genotype relative risk between 2.4 and 4.8. The authors' goal was to investigate this association with autism in Irish affected child-parent trios because replication in an independent sample is essential in the validation of such potentially important findings., Method: Markers rs2056202 and rs2292813 were genotyped in a total of 158 trios (442 individuals). The Transmission Disequilibrium Test was used to examine these markers for association with autism., Results: In agreement with the recent study, the authors found significant association between autism and the C alleles of both rs2056202 and rs2292813 as well as the two-marker haplotype., Conclusions: These findings provide replication of the association between autism and SLC25A12.
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- 2005
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25. Association analysis of the monoamine oxidase A and B genes with attention deficit hyperactivity disorder (ADHD) in an Irish sample: preferential transmission of the MAO-A 941G allele to affected children.
- Author
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Domschke K, Sheehan K, Lowe N, Kirley A, Mullins C, O'sullivan R, Freitag C, Becker T, Conroy J, Fitzgerald M, Gill M, and Hawi Z
- Subjects
- Adult, Alleles, Attention Deficit Disorder with Hyperactivity enzymology, Child, Dinucleotide Repeats genetics, Female, Genotype, Haplotypes, Humans, Ireland, Linkage Disequilibrium, Male, Minisatellite Repeats genetics, Nuclear Family, Review Literature as Topic, Attention Deficit Disorder with Hyperactivity genetics, Monoamine Oxidase genetics
- Abstract
Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Monoamine oxidases A and B (MAO-A and MAO-B) degrade biogenic amines such as dopamine and serotonin and thereby control the levels of these neurotransmitters in the central nervous system. We examined four polymorphisms in the MAO-A gene (30 bp promoter VNTR, CA microsatellite in intron 2, 941G/T SNP in exon 8, and A/G SNP in intron 12) as well as two markers in the MAO-B gene (CA microsatellite in intron 2 and T/C SNP in intron 13) for association with ADHD in an Irish sample of 179 nuclear families. TDT analysis of the examined MAO-A markers revealed a significant association of the more active MAO-A 941G allele with the disorder (chi2 = 5.1, P = 0.03, OR = 1.7). In addition, haplotype analysis revealed a significantly increased transmission of a haplotype consisting of the shorter allele of the promoter VNTR (allele 1), the 6-repeat allele of the CA microsatellite and the G-allele of the 941G/T SNP (famhap global statistic 34.54, P = 0.01) to ADHD cases. No significant distortion in the number of transmitted alleles was observed between the two examined MAO-B polymorphisms and ADHD. These findings suggest the importance of the 941G/T MAO-A polymorphism in the development of ADHD at least in the Irish population., (Copyright 2005 Wiley-Liss, Inc.)
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- 2005
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26. No association between allelic variants of HOXA1/HOXB1 and autism.
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Gallagher L, Hawi Z, Kearney G, Fitzgerald M, and Gill M
- Subjects
- Alleles, Autistic Disorder pathology, Female, Gene Frequency, Genetic Variation, Genotype, Humans, Ireland, Linkage Disequilibrium, Male, Nuclear Family, Autistic Disorder genetics, Homeodomain Proteins genetics, Transcription Factors genetics
- Abstract
Two recent studies have reported conflicting findings of association of a variant in the HOXA1 gene and autism. To try to resolve the conflict in findings, we conducted an association study in 78 Irish families of the reported DNA variants. We did not find statistically significant association between the variants and autism. Similarly there was no evidence of preferential transmission of variants from parent of either sex to affected offspring. We also report negative findings for HOXB1 variants. We conclude that the HOXA1/B1 are unlikely to be the susceptibility genes for autism in our sample., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2004
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27. Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD.
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Kirley A, Lowe N, Hawi Z, Mullins C, Daly G, Waldman I, McCarron M, O'Donnell D, Fitzgerald M, and Gill M
- Subjects
- Child, Dopamine Plasma Membrane Transport Proteins, Female, Humans, Ireland, Male, Attention Deficit Disorder with Hyperactivity drug therapy, Attention Deficit Disorder with Hyperactivity genetics, Central Nervous System Stimulants pharmacology, Membrane Glycoproteins, Membrane Transport Proteins genetics, Methylphenidate pharmacology, Nerve Tissue Proteins
- Abstract
Several studies have implicated the dopamine transporter gene (DAT1) as conferring susceptibility to attention deficit hyperactivity disorder (ADHD), in particular, a VNTR situated at the 3' end of the gene. In addition, the 10-repeat VNTR allele associated with ADHD has been reported to be associated with an over-active transporter protein (DAT). Thus children possessing this variant might be particularly responsive to methylphenidate, a drug known to act by blocking DAT. We have examined this hypothesis and now report an association between the 10-repeat VNTR DAT1 polymorphism and retrospectively rated methylphenidate response in a sample of 119 Irish children with ADHD (chi(2) = 7.918, df = 1, P = 0.005). Our findings suggest a role for the 10-repeat DAT1 risk allele in medication response and may help to predict positive clinical outcome in ADHD., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2003
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28. No evidence of linkage or association between the norepinephrine transporter (NET) gene polymorphisms and ADHD in the Irish population.
- Author
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McEvoy B, Hawi Z, Fitzgerald M, and Gill M
- Subjects
- Alleles, Attention Deficit Disorder with Hyperactivity ethnology, DNA chemistry, DNA genetics, DNA Mutational Analysis, Female, Gene Frequency, Genetic Linkage, Humans, Ireland epidemiology, Male, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Nuclear Family, Attention Deficit Disorder with Hyperactivity genetics, Minisatellite Repeats genetics, Polymorphism, Genetic genetics, Symporters genetics
- Published
- 2002
- Full Text
- View/download PDF
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