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Michael Gill

Publications and source records attributed to Michael Gill.

At least 19 recordsLinked to original sources
PubMed2011

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

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)).

ATP-Binding Cassette Transporters↗
PubMed2007

Protein kinase C-beta 1 gene variants are not associated with autism in the Irish population.

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.

Autistic Disorder↗
PubMed2007

Gene-environment interplay in attention-deficit hyperactivity disorder and the importance of a developmental perspective.

Attention-deficit hyperactivity disorder (ADHD) varies in its clinical presentation and course. Susceptibility gene variants for ADHD and associated antisocial behaviour are being identified with emerging evidence of gene-environment interaction. Genes and environmental factors that influence the origins of disorder are not necessarily the same as those that contribute to its course and outcome.

Adolescent↗
PubMed2006

Response variability in attention deficit hyperactivity disorder: evidence for neuropsychological heterogeneity.

Response time (RT) variability is a common finding in ADHD research. RT variability may reflect frontal cortex function and may be related to deficits in sustained attention. The existence of a sustained attention deficit in ADHD has been debated, largely because of inconsistent evidence of time-on-task effects. A fixed-sequence Sustained Attention to Response Task (SART) was given to 29 control, 39 unimpaired and 24 impaired-ADHD children (impairment defined by the number of commission errors). The response time data were analysed using the Fast Fourier Transform, to define the fast-frequency and slow-frequency contributions to overall response variability. The impaired-ADHD group progressively slowed in RT over the course of the 5.5min task, as reflected in this group's greater slow-frequency variability. The fast-frequency trial-to-trial variability was also significantly greater, but did not differentially worsen over the course of the task. The higher error rates of the impaired-ADHD group did not become differentially greater over the length of the task. The progressive slowing in mean RT over the course of the task may relate to a deficit in arousal in the impaired-ADHD group. The consistently poor performance in fast-frequency variability and error rates may be due to difficulties in sustained attention that fluctuate on a trial-to-trial basis.

Adolescent↗
PubMed2006

No association between TPH2 gene polymorphisms and ADHD in a UK sample.

Tryptophan Hydroxylase 2 (TPH2) is the rate-limiting enzyme in the biosynthesis of serotonin which is exclusively expressed in the brain. Recent molecular studies reported significant association between markers mapped to TPH2 and psychiatric conditions including ADHD. We have examined four single nucleotide polymorphisms (SNPs) two of which (rs1843809, rs1386493) were reported to associate with ADHD in an Irish ADHD sample. Transmission disequilibrium analysis revealed no significant association between any of these markers and ADHD. Dividing by the sex of the transmitting parent has also failed to replicate the previously reported paternal over-transmission of the associated alleles to ADHD probands. A larger sample size will be required to clarify if TPH2 alleles are or are not associated with ADHD.

Adolescent↗
PubMed2006

Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: a preliminary study.

Susceptibility genes for schizophrenia have been hypothesised to mediate liability for the disorder at least partly by influencing cognitive performance. We investigated the association between genotype and cognitive performance for a Dysbindin risk haplotype which is associated with schizophrenia in our sample. Fifty-two patients with schizophrenia or schizoaffective disorder (24 risk haplotypes carriers versus 28 non-risk haplotype carriers) were assessed in areas of cognition showing evidence of familial deficits in schizophrenia. Verbal and spatial memory, working memory, and attentional control was assessed using selected measures from the Weschler memory scale (WMS), Cambridge automated test battery (CANTAB), continuous performance test (CPT), and a simple go/no-go task. Pre-morbid IQ was also assessed using the Weschler Test of Adult Reading (WTAR). Patients carrying the Dysbindin risk haplotype showed significantly lower spatial working memory performance than patients who were non-risk carriers, with genotype explaining 12% of variance in performance. Our study suggests that the increased risk for schizophrenia associated with dysbindin may be partly mediated by its influence on pre-frontal function.

Adolescent↗
PubMed2006

Impaired temporal resolution of visual attention and dopamine beta hydroxylase genotype in attention-deficit/hyperactivity disorder.

BACKGROUND: Dopamine beta hydroxylase (DbetaH) catalyzes the conversion of dopamine to noradrenaline. Attention-deficit/hyperactivity disorder (ADHD) has been associated with the A2 allele of a Taq I polymorphism of the DBH gene. Since catecholamines regulate visual attention, we examined whether participants with ADHD were impaired on a task requiring temporal attention and how DBH genotype influenced temporal attention in ADHD. METHODS: Thirty-seven children and adolescents with ADHD and 52 matched, normal control subjects participated. Participants were presented with two visual stimuli, separated in time by either 50, 100, or 200 milliseconds, and were asked to judge the temporal order of their onset. Genotypes for the Taq 1 polymorphism were available for 33 of the ADHD participants. RESULTS: Attention-deficit/hyperactivity disorder participants were more error prone than control subjects, particularly when stimuli were presented close together in time (i.e., at the 50 milliseconds asynchrony). Moreover, ADHD individuals homozygous for the A2 allele performed more poorly than those without this allele, and this difference was accentuated at the 50 milliseconds asynchrony. CONCLUSIONS: Attention-deficit/hyperactivity disorder participants have an impaired rate of perceptual processing for rapidly presented visual events. Deficits in the temporal resolution of visual attention in ADHD are associated with the A2 allele of the Taq I DBH polymorphism or another variant with which it is in linkage disequilibrium.

Adolescent↗
PubMed2006

Are deficits in executive sub-processes simply reflecting more general cognitive decline in schizophrenia?

BACKGROUND: Schizophrenia is associated with both global and specific cognitive deficits. We sought to investigate whether deficits in executive subcomponents differed in their relationship to global cognitive impairments. METHOD: 95 patients were classified according to pre-morbid and current general cognitive ability as having either (a) intact pre-morbid and current general cognitive ability; (b) intact pre-morbid but deteriorated current ability, and (c) deteriorated both pre-morbid and current cognitive ability. All patients completed measures of verbal and spatial working memory, sustained selective attention, attentional set sifting, and inhibitory control. RESULTS: Deficits on both measures of working memory were associated with general cognitive ability. None of the attentional control deficits observed were associated with general ability. Further, spatial working memory deficits were also associated with more severe negative symptoms. CONCLUSIONS: These results provide further evidence of the discreet nature of attentional deficits in schizophrenia. By contrast, this study suggests that working memory deficits may to some extent index more general cognitive decline. Awareness of such overlap is important for schizophrenia genetics studies where working memory measures has been used to index supposedly discreet aspects of cognitive dysfunction.

Adult↗
PubMed2006

Neurocognition and suicidal behaviour in an Irish population with major psychotic disorders.

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.

Adult↗
PubMed2006

Evaluation of a susceptibility gene for schizophrenia: genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples.

BACKGROUND: Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. METHODS: In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). RESULTS: The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. CONCLUSIONS: Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

Case-Control Studies↗
PubMed2006

Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia.

There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock-out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4. Mutation screening of erbB4 in 14 DSMIV schizophrenics revealed 15 SNPs, none of which were nonsynonymous. Analysis of the allele frequencies of each SNP in pools of 368 DSMIV schizophrenics and 368 controls provided modest evidence for association with two of the SNPs, although individual genotyping in an extended sample of 680 cases did not confirm this. However, we did find evidence for a significant interaction between the NRG1 "Icelandic" schizophrenia risk haplotype and erbB4 (P = 0.019). The NRG1 and erbB4 interacting marker was further genotyped in an independent sample of 290 cases and 634 controls from Dublin. Interaction between NRG1 and erbB4 remained significant in the combined sample of 970 cases and 1,341 controls, OR = 2.98 (CI: 1.16-7.64), P = 0.01, although it only showed a trend in the Dublin sample alone (P = 0.11, two tailed). Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia.

Adult↗
PubMed2006

The cognitive genetics of attention deficit hyperactivity disorder (ADHD): sustained attention as a candidate phenotype.

Here we describe the application of cognitive genetics to the study of attention deficit hyperactivity disorder (ADHD). Cognitive genetics owes much to the pioneering work of cognitive neuropsychologists such as John Marshall, whose careful observations of cognitive dissociations between brain-lesioned patients greatly advanced the theoretical understanding of normal cognitive function. These theories have in turn helped to constrain linkages between candidate genes and cognitive processes and thus help to drive the relatively new field of cognitive genetics in a hypothesis-driven fashion. We examined the relationship between sustained attention deficits in ADHD and genetic variation in a catecholamine-related gene, dopamine beta hydroxylase (DbetaH). DBH encodes the enzyme that converts dopamine to noradrenaline and is crucial to catecholamine regulation. A polymorphism with the DBH gene has been associated with ADHD. In fifty-two children with ADHD, we examined whether variation in the Taq I DBH gene polymorphism was related to sustained attention performance. Participants performed the Sustained Attention to Response Test (SART). Performance on the SART discriminates ADHD from control children, and in imaging work, is associated with right frontoparietal activation. A significant effect of DBH genotype was found on SART performance measures. Children possessing two copies of the ADHD-associated risk allele (A2) had significantly poorer sustained attention than those ADHD children who did not possess this allele or a non-genotyped control group. The DBH gene may contribute to the susceptibility for ADHD, in part because of its varying effects on the development of brain mechanisms mediating sustained attention.

Adolescent↗
PubMed2006

Do antisaccade deficits in schizophrenia provide evidence of a specific inhibitory function?

BACKGROUND: Despite its inhibitory control requirements, antisaccade deficits have been consistently associated with working memory impairments in schizophrenia. We investigated whether variance in antisaccade performance could be better accounted for in terms of a specific inhibitory function. METHOD: We assessed 48 clinically stable out-patients with schizophrenia on an antisaccade task, as well as on measures of spatial and verbal working memory, sustained selective attention, and a simple motoric go/no-go measure of response inhibition. RESULTS: In a stepwise multiple regression analysis, go/no-go task performance accounted for a considerably greater percentage of variance in antisaccade performance (25.3%) than either working memory (8.4%) or sustained selective attention task (9.1%). DISCUSSION: We conclude that antisaccade deficits in schizophrenia appear to be better understood in terms of a specific deficit of inhibitory control than in terms of more general difficulties with context maintenance or goal neglect.

Adult↗
PubMed2005

Preferential transmission of paternal alleles at risk genes in attention-deficit/hyperactivity disorder.

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.

Alleles↗
PubMed2005

Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q.

Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.

Bipolar Disorder↗
PubMed2005

Investigation of the apolipoprotein-L (APOL) gene family and schizophrenia using a novel DNA pooling strategy for public database SNPs.

We performed an extensive genetic association study of the six known apolipoprotein-L (APOL) genes and schizophrenia (SZ) using a novel DNA pooling strategy. The APOL genes are both positional and functional candidate genes for SZ. This gene family maps to chromosome 22q12.3, a region implicated by SZ linkage studies as likely to contain one or more SZ susceptibility genes. A recent gene expression study demonstrated up-regulation of APOL1, 2, and 4 in post-mortem brain samples from SZ patients compared to controls in two independent samples. To test for genetic association with SZ, we analyzed 143 SNPs from dbSNP from across the APOL genes in an Irish sample of 219 cases and 231 controls. Of these 143 SNPs, 51 (36%) were polymorphic in our Irish sample and were genotyped using a novel three-stage DNA pooling strategy. This strategy does not require the identification of a heterozygous individual for DNA pooling association analysis and is therefore very efficient when using public database SNPs. We found no evidence to support the hypothesis that genetic variation at the APOL genes contributes to SZ susceptibility in our sample.

Alleles↗
PubMed2005

DRD4 gene variants and sustained attention in attention deficit hyperactivity disorder (ADHD): effects of associated alleles at the VNTR and -521 SNP.

Associations between attention deficit hyperactivity disorder (ADHD) and genetic variants within the dopamine D4 receptor gene have been much reported. Variants investigated include the 7-repeat allele of a VNTR within the third exon, and two SNPs (-521 and -616) located with the promoter region. We investigated the relationship between the VNTR, -521, and -616 SNPs and sustained attention performance in 54 ADHD probands, relative to a non-genotyped control group. Participants performed the Sustained Attention to Response Task (SART) in which the response to an unpredictably occurring target digit must be inhibited. This task, therefore, challenged sustained attention and included a response inhibition component. Consistent with previous reports, ADHD participants possessing the 7-repeat allele of the VNTR outperformed those children not possessing this allele, both in terms of errors and response variability. In family based analyses, better performance on the SART tended to predict biased transmission of the 7-repeat allele from heterozygous parents. For the -521 SNP, A allele homozygotes showed greater impairment than heterozygotes or those not possessing this allele, both in terms of total errors and response variability. Family based analysis showed that higher total errors on the SART predicted transmission of the A allele from heterozygous parents. There were no effects of the -616 SNP. Our results suggest dissociable effects of the "associated alleles" of DRD4 gene variants on sustained attention: while the 7-repeat allele of the VNTR is associated with relatively better performance, the A allele of the -521 SNP is associated with poorer performance.

Adolescent↗