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Biomedical subjects

Michael Gill

Publications and source records attributed to Michael Gill.

At least 37 records · Page 2Linked to original sources
PubMed2005

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.

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.

Adult↗
PubMed2005

The methionine allele of the COMT polymorphism impairs prefrontal cognition in children and adolescents with ADHD.

ADHD is a highly heritable psychiatric disorder of childhood. A functional polymorphism (Val158Met) of the catechol-O-methyltransferase (COMT) gene has attracted interest as a candidate gene for ADHD. The high-activity valine variant of this polymorphism degrades prefrontal dopamine three to four times more quickly than the low-activity methionine variant and could therefore contribute to the proposed hypodopaminergic state in ADHD. Here we tested for association of this polymorphism with ADHD and examined its influence on prefrontal cognition in ADHD. We have previously reported no association of the Val158Met COMT gene polymorphism in 94 Irish ADHD families (Hawi et al. (2000) Am J Med Genet 96:282-284). Here we re-examined this finding with an extended sample of 179 ADHD cases using a family control design. We also examined the performance of children and adolescents with ADHD (n = 61) on a standardised test of sustained attention. Analysis confirmed the absence of an association between the Val158Met COMT gene polymorphism and the clinical phenotype of ADHD. COMT genotype, however, affected prefrontal cognition in ADHD: ADHD children who were homozygous for the valine variant had significantly better sustained attention than those ADHD children possessing at least one copy of the methionine variant. Children possessing the methionine variant performed significantly below age-related norms on tests of sustained attention. Contrary to expectations, the methionine variant of the Val158Met COMT gene polymorphism impaired prefrontally-mediated cognition in ADHD. This effect may be understood by positing a hyper-functioning of prefrontal dopaminergic systems. Against this background, the slower clearance of dopamine associated with the methionine variant of the COMT gene polymorphism may be disadvantageous to cognition in ADHD.

Adolescent↗
PubMed2005

Genomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13.

CONTEXT: Traditionally, the search for genes involved in predisposition to major psychoses has proceeded with separate studies of schizophrenia and bipolar disorder. However, twin data suggest that, in addition to genes with specificity for these phenotypes, there exist genes that simultaneously influence susceptibility to schizophrenia, bipolar disorder, and schizoaffective disorder. OBJECTIVE: To undertake, to our knowledge, the first systematic search for such loci. DESIGN: Genomewide linkage scan. SETTING: Affected individuals were ascertained in the United Kingdom and Ireland from general psychiatric inpatient and outpatient services. PARTICIPANTS: The families were selected for linkage studies of either schizophrenia or bipolar disorder. Pedigrees were selected for the current analysis where there was at least 1 member with DSM-IV schizoaffective disorder, bipolar type. Within these pedigrees, individuals were coded as affected if they had been diagnosed with DSM-IV schizophrenia, schizoaffective disorder of bipolar type, or bipolar I disorder. A total of 24 pedigrees contributed 35 affected sibling pairs to the sample. METHOD: A 10-centimorgan genome scan using microsatellite markers was analyzed using MAPMAKER/SIBS software. RESULTS: A genomewide significant signal (LOD = 3.54) was observed at chromosome 1q42 (near D1S2800), and suggestive LOD scores were observed at chromosomes 22q11 (LOD = 1.96) and 19p13 (LOD = 1.85). No linkage was observed in these regions in our original schizophrenia or bipolar scans in individuals from the United Kingdom. CONCLUSIONS: Our linkage findings strongly support the existence of loci that influence susceptibility across the functional psychosis spectrum. The DISC1 gene lies within 2.5 megabases of our peak marker on chromosome 1q42 and has been previously implicated in schizophrenia, bipolar disorder, and, recently, schizoaffective disorder. Follow-up of this region should use samples enriched for cases of schizoaffective disorder. Our findings have similar implications for the search for genetic variation on chromosome 22q11 that influences susceptibility to psychosis.

Bipolar Disorder↗
PubMed2005

Dissecting the attention deficit hyperactivity disorder (ADHD) phenotype: sustained attention, response variability and spatial attentional asymmetries in relation to dopamine transporter (DAT1) genotype.

ADHD is a childhood-onset behavioural disorder with a heterogeneous profile of neuropsychological impairment. Neuropsychological heterogeneity may, in part, reflect underlying genetic differences. Here we examined sustained attention, response variability and spatial attentional asymmetries in a sample of children and adolescents with ADHD (n=22) in relation to dopamine transporter genotype (DAT1) and also controls (n=20). Participants performed the sustained attention to response task (SART) (testing sustained attention and response variability) and the greyscales task (a perceptual measure of attentional bias). The latter has previously been shown to yield a robust leftward attentional asymmetry in healthy subjects. The 10-repeat allele of the DAT1 gene has been associated with ADHD in a number of studies and appears to have biological significance. The ADHD group was sub-divided into those individuals with two copies of the "high-risk" 10-repeat allele (high-risk DAT1) versus those with one or no copies of this allele (low-risk DAT1). The high-risk DAT1 ADHD group displayed greater response variability on the SART than either the low-risk DAT1 group or healthy controls, whereas the latter two groups did not differ. Further, the high-risk DAT1 group showed an attenuated spatial asymmetry, relative to the low-risk DAT1 ADHD group, who showed the typical leftward attentional asymmetry. Our results suggest that the 10-repeat DAT1 allele may mediate neuropsychological impairment in ADHD. The application of molecular genetics may help to define neuropsychological impaired subgroups of ADHD.

Adolescent↗
PubMed2005

Association between dopamine transporter (DAT1) genotype, left-sided inattention, and an enhanced response to methylphenidate in attention-deficit hyperactivity disorder.

A polymorphism of the dopamine transporter gene (DAT1, 10-repeat) is associated with attention-deficit hyperactivity disorder (ADHD) and has been linked to an enhanced response to methylphenidate (MPH). One aspect of the attention deficit in ADHD includes a subtle inattention to left space, resembling that seen after right cerebral hemisphere damage. Since left-sided inattention in ADHD may resolve when treated with MPH, we asked whether left-sided inattention in ADHD was related to DAT1 genotype and the therapeutic efficacy of MPH. A total of 43 ADHD children and their parents were genotyped for the DAT1 3' variable number of tandem repeats polymorphism. The children performed the Landmark Test, a well-validated measure yielding a spatial attentional asymmetry index (leftward to rightward attentional bias). Parents rated their child's response to MPH retrospectively using a three-point scale (no, mediocre or very good response). Additionally, parents used a symptom checklist to rate behavior while on and off medication. A within-family control design determined whether asymmetry indices predicted biased transmission of 10-repeat parental DAT1 alleles and/or response to MPH. It was found that left-sided inattention predicted transmission of the 10-repeat allele from parents to probands and was associated with the severity of ADHD symptomatology. Children rated as achieving a very good response to MPH displayed left-sided inattention, while those rated as achieving a poorer response did not. Our results suggest a subgroup of children with ADHD for whom the 10-repeat DAT1 allele is associated with left-sided inattention. MPH may be most efficacious in this group because it ameliorates a DAT1-mediated hypodopaminergic state.

Adolescent↗
PubMed2005

Variability in time reproduction: difference in ADHD combined and inattentive subtypes.

OBJECTIVE: To examine the relationship between time reproduction, performance variability, and sustained attention deficits in children with attention-deficit/hyperactivity disorder (ADHD) combined (ADHD-C) and inattentive (ADHD-I) subtypes, relative to matched controls. METHOD: Participants (age range 7.1-14.1 years) performed a time reproduction task. A subset of the ADHD group was also tested on the Sustained Attention to Response Test. Absolute discrepancy, accuracy coefficient, and intraindividual variability scores on the time reproduction task were compared across the three groups (ADHD-C: N = 20; ADHD-I: N = 19; controls: N = 44) and correlated with the Sustained Attention to Response Test. RESULTS: First, significantly better performance was observed in matched controls than in children with ADHD on the time reproduction task. Second, there was a significant difference between the two ADHD subtypes in the variability of the size of errors made at high time intervals (36-60 seconds). Third, intraindividual performance variability in the direction (over- versus underestimations) of time reproductions correlated with sustained attention performance. CONCLUSIONS: Children with ADHD varied more in the size and direction of their time reproduction errors than control children. Those with ADHD-C demonstrated more intraindividual variability than did those with ADHD-I in the size of their errors. The data provide support for a relationship between sustained attention and time reproduction. This relationship has previously been inferred from common right-lateralized neural circuitry that is thought to subserve these processes.

Adolescent↗
PubMed2005

Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31.

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.

Adult↗
PubMed2004

Multiple marker analysis at the promoter region of the DRD4 gene and ADHD: evidence of linkage and association with the SNP -616.

Abnormalities of dopamine neurotransmission have been hypothesized to play an important role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Support for this has come from numerous association studies on candidate genes including the dopamine D4 receptor gene (DRD4). One of the most replicated associations between ADHD and the dopaminergic system is the 7-repeat allele of the VNTR polymorphism of this gene. A lack of association between this marker and ADHD has also been reported in several investigations. In the absence of a firm link between the number of the VNTR repeats and the function of the gene, we sought to investigate several additional markers at the 5'-end of the gene with potential influence on the expression of the DRD4. We observed a significant over transmission of single nucleotide polymorphism (SNP) (chi(2) = 7.45, P = 0.008, OR = 1.63). In addition, an excess transmission of the A allele of the -521 SNP was observed, although it did not attain statistical significance (chi(2) = 2.14, P = 0.17, OR = 1.25). Linkage disequilibrium (LD) analysis demonstrated a weak level of D' between any of the tested markers implying that this may be a region of high recombination. It also raises the possibility that the new association with ADHD may be independent of the 7-repeat allele. Further analyses, preferably in samples demonstrating association with the VNTR, or in other ethnic groups, are required to confirm these observations.

Adult↗
PubMed2004

Phenotype studies of the DRD4 gene polymorphisms in ADHD: association with oppositional defiant disorder and positive family history.

The objective of this study was to investigate association of DRD4 polymorphisms with ADHD subtypes for which there is evidence for increased heritability. The genetic variants tested were the 120 bp insertion/deletion, the -616, -521, -376, and the 48 bp DRD4 VNTR. The primary analyses were of association with oppositional defiant disorder (ODD), conduct disorder (CD), and diagnostic subtypes. Secondary analyses of clinical subtype were exploratory in nature and included analysis of association of DRD4 polymorphisms with family history of ADHD. We observed significant association between DRD4 7-repeat allele transmission and ADHD children with comorbid ODD (chi(2) = 6.74, df = 1, P = 0.01, OR = 2.45) The DRD4 7-repeat allele was also significantly associated with family history positive ADHD (chi(2) = 10.12, df = 1, P = 0.0021, OR = 3.57). We observed no significant distortion in the transmission of any of the tested DRD4 variants with inattentive or hyperactive-impulsive subtypes or symptom dimensions. In conclusion, our findings of increased DRD4 7-repeat allele transmission in ODD extend those reported by Holmes et al. To our knowledge, this is the first study to report association of the DRD4 7-repeat allele with ADHD children who have a positive family history of ADHD. Overall, the results from this study support the investigation of clinical subtypes in molecular genetic studies of ADHD.

Adult↗
PubMed2004

Confirming RGS4 as a susceptibility gene for schizophrenia.

A recent study identified a putative association between variants in the regulator of G-protein signalling 4 (RGS4) and schizophrenia, Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. RGS4 is both a positional and functional candidate gene for schizophrenia. Chowdari and colleagues identified association at this locus in a number of distinct and ethnically diverse samples, although the pattern of association was not the same in all the samples. Our study attempted to replicate this association in an independent Irish sample of schizophrenia cases and controls. We succeeded in detecting evidence of association at the RGS4 locus. The signal comes from a four-marker haplotype that is in significant excess in our case sample. The same haplotype is in excess in the Caucasian schizophrenia sample used by Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. This study provides further support for the contribution of RGS4 to schizophrenia susceptibility.

Disease Susceptibility↗
PubMed2004

Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)(n) repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

No association between allelic variants of HOXA1/HOXB1 and autism.

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.

Alleles↗
PubMed2004

Familiality of symptom dimensions in depression.

BACKGROUND: Depression is a clinically heterogeneous disorder thought to result from multiple genes interacting with environmental and developmental components. A dimensional rather than a categorical approach to depressive phenotype definition may be more useful for identification of susceptibility genes. OBJECTIVES: To perform an exploratory factor analysis on a range of depressive and anxiety symptoms in a large, well-defined sample of depressed siblings, as well as a confirmatory factor analysis in a separate large group of unrelated depressed subjects, and to analyze correlations of identified symptom dimensions between depressed siblings. DESIGN: Subjects (N = 1034), including 475 sibling pairs, with a history of at least 2 depressive episodes were recruited from the Depression Network Study, a large-scale multicenter collection of families affected by recurrent unipolar depression. Subjects were interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to the DSM-IV and the International Classification of Diseases, 10th Revision, using a computerized scoring program (CATEGO5). Factor analysis was carried out on 26 depression symptom items, including 4 anxiety screening items. Confirmatory factor analysis was performed on an independent sample of 485 depressed individuals. RESULTS: Four interpretable factors were identified: (1) mood symptoms and psychomotor retardation; (2) anxiety; (3) psychomotor agitation, guilt, and suicidality; and (4) appetite gain and hypersomnia. For each symptom group, a quantitative scale was constructed, and correlations between siblings were calculated. There was a moderate degree of sibling homotypia for some depressive symptoms, and factors 1, 2, and 3 showed significant positive familial correlation (0.145 [P =.001], 0.335 [P<.001], and 0.362 [P<.001], respectively). CONCLUSIONS: This is the first study of large, well-defined samples of depressed subjects in whom symptom dimensions have been derived and then confirmed using independent material. The significant correlations between siblings for 3 of the dimensions suggest substantial familial, perhaps genetic, etiologies.

Adult↗
PubMed2003

Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD.

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.

Attention Deficit Disorder with Hyperactivity↗
PubMed2003

Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.

Bipolar Disorder↗
PubMed2003

No evidence for association of the dysbindin gene [DTNBP1] with schizophrenia in an Irish population-based study.

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.

Adult↗
PubMed2003

Brief report: A case of autism associated with del(2)(q32.1q32.2) or (q32.2q32.3).

Autism is a neurodevelopmental disorder presenting in the first 3 years of life. Deficits occur in the three core areas of communication, social interaction, and behavior. The causes of autism are unknown, but clinical genetic studies show strong evidence in favor of a genetic etiology. Molecular genetic studies report some association with candidate genes, and candidate regions have emerged from several genome-wide linkage studies. Here we report a clinical case of autism with a deletion on chromosome 2 in a young male with high-functioning autism. The deletion seems to correspond with regions emerging from linkage studies. We propose this as a possible candidate region in the search for autism genes.

Adolescent↗