Biomedical subjects

Michael Owen

Publications and source records attributed to Michael Owen.

16 recordsLinked to original sources

PubMed2006

DAPK1 variants are associated with Alzheimer's disease and allele-specific expression.

Genetic factors play an important role in the etiology of late-onset Alzheimer's disease (LOAD). We tested gene-centric single nucleotide polymorphisms (SNPs) on chromosome 9 and identified two SNPs in the death-associated protein kinase, DAPK1, that show significant association with LOAD. SNP rs4878104 was significantly associated with LOAD in our discovery case-control sample set (WU) and replicated in each of two initial validation case-control sample sets (P<0.05, UK1, SD). The risk-allele frequency of this SNP showed a similar direction in three other case-control sample sets. A meta-analysis of the six sample sets combined, totaling 2012 cases and 2336 controls, showed an allelic P-value of 0.0016 and an odds ratio (OR) of 0.87 (95%CI: 0.79-0.95). Minor allele homozygotes had a consistently lower risk than major allele homozygotes in the discovery and initial two replication sample sets, which remained significant in the meta-analysis of all six sample sets (OR=0.7, 95%CI: 0.58-0.85), whereas the risk for heterozygous subjects was not significantly different from that of major allele homozygotes. A second SNP, rs4877365, which is in high linkage disequilibrium with rs4878104 (r2=0.64), was also significantly associated with LOAD (meta P=0.0017 in the initial three sample sets). Furthermore, DAPK1 transcripts show differential allelic gene expression, and both rs4878104 and rs4877365 were significantly associated with DAPK1 allele-specific expression (P=0.015 to <0.0001). These data suggest that genetic variation in DAPK1 modulates susceptibility to LOAD.

Alleles↗

PubMed2006

Processing facial emotions in adults with velo-cardio-facial syndrome: functional magnetic resonance imaging.

We studied the functional neuroanatomy of social behaviour in velo-cardio-facial syndrome (VCFS) using a facial emotional processing task and functional magnetic resonance imaging in adults with this syndrome and controls matched for age and IQ. The VCFS group had less activation in the right insula and frontal brain regions and more activation in occipital regions. Genetically determined abnormalities in pathways including those involved in emotional processing may underlie deficits in social cognition in people with VCFS.

Adult↗

PubMed2005

A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.

Alleles↗

PubMed2005

Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease.

We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the NIMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE epsilon4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.

Age of Onset↗

PubMed2005

Catechol O-methyltransferase gene variant and birth weight predict early-onset antisocial behavior in children with attention-deficit/hyperactivity disorder.

CONTEXT: Early-onset antisocial behavior accompanied by attention-deficit/hyperactivity disorder is a clinically severe variant of antisocial behavior that is associated with a particularly poor outcome. Identifying early predictors is thus important. Genetic and prenatal environmental risk factors and prefrontal cortical function are thought to contribute. Recent evidence suggests that prefrontal cortical function is influenced by a valine/methionine variant in the catechol O-methyltransferase (COMT) gene. OBJECTIVE: To test the a priori hypothesis that this genetic variant predicts early-onset antisocial behavior in a high-risk sample and further examine the effects of birth weight, an environmentally influenced index of prenatal adversity previously linked to childhood disruptive behaviors and genotype x birth weight interaction. DESIGN, SETTING, AND PARTICIPANTS: A family-based genetic study was undertaken between 1997 and 2003. Participants were prospectively recruited from child and adolescent psychiatry and child health clinics in the United Kingdom and included 240 clinic children who met diagnostic criteria for attention-deficit/hyperactivity disorder or hyperkinetic disorder. Participants underwent comprehensive standardized assessments including measures of antisocial behavior and IQ. Main Outcome Measure DSM-IV symptoms of childhood-onset conduct disorder rated by trained interviewers using a standard diagnostic interview. RESULTS: The results show main effects of the COMT gene variant (P = .002), birth weight (P = .002), and a significant gene x environment (COMT x birth weight) interaction (P = .006). CONCLUSIONS: Early-onset antisocial behavior in a high-risk clinical group is predicted by a specific COMT gene variant previously linked with prefrontal cortical function and birth weight, and those possessing the val/val genotype are more susceptible to the adverse effects of prenatal risk as indexed by lower birth weight.

Adolescent↗

PubMed2005

Streamlined analysis of pooled genotype data in SNP-based association studies.

Several groups have developed methods for estimating allele frequencies in DNA pools as a fast and cheap way for detecting allelic association between genetic markers and disease. To obtain accurate estimates of allele frequencies, a correction factor k for the degree to which measurement of allele-specific products is biased is generally applied. Factor k is usually obtained as the ratio of the two allele-specific signals in samples from heterozygous individuals, a step that can significantly impair throughput and increase cost. We have systematically investigated the properties of k through the use of empirical and simulated data. We show that for the dye terminator primer extension genotyping method we have applied, the correction factor k is substantially influenced by the dye terminators incorporated, but also by the terminal 3' base of the extension primer. We also show that the variation in k is large enough to result in unacceptable error rates if association studies are conducted without regard to k. We show that the impact of ignoring k can be neutralized by applying a correction factor k(max) that can be easily derived, but this at the potential cost of an increase in type I error. Finally, based upon observed distributions for k we derive a method allowing the estimation of the probability pooled data reflects significant differences in the allele frequencies between the subjects comprising the pools. By controlling the error rates in the absence of knowledge of the appropriate SNP-specific correction factors, each approach enhances the performance of DNA pooling, while considerably streamlining the method by reducing time and cost.

Alleles↗

PubMed2005

Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease.

Alzheimer disease (AD) is a complex neurodegenerative disorder predisposed by multiple genetic factors. Mutations in amyloid beta precursor protein (APP) are known to be associated with autosomal dominant, early onset familial AD and possibly also late onset AD (LOAD). A number of genes encoding proteins capable of binding to APP have been identified, but their contribution to AD pathobiology remains unclear. Conceivably, mutations in these genes may play a role in affecting AD susceptibility, which appears to be substantiated by some genetic studies. Here we report results of the first genetic association study with APBB2, an APP binding protein (also known as FE65L), and LOAD, in three independently collected case-control series totaling approximately 2,000 samples. Two SNPs were significantly associated with LOAD in two sample series and in meta-analyses of all three sample sets (for rs13133980: odds ratio [OR](hom)=1.36 [95% CI: 1.05-1.75], OR(het)=1.32 [95% CI: 1.04-1.67], minor allele frequency=43%, P=0.041; and for hCV1558625: OR(hom)=1.37 [95% CI: 1.06-1.77], OR(het)=1.02 [95% CI: 0.82-1.26], minor allele frequency=48%, P=0.026). One of these SNPs, located in a region conserved between the human and mouse genome, showed a significant interaction with age of disease onset. For this marker, the association with LOAD was most pronounced in subjects with disease onset before 75 years of age (OR(hom)=2.43 [95% CI: 1.61-3.67]; OR(het)=2.15 [95% CI: 1.46-3.17]; P=0.00006) in the combined sample set. Our data raise the possibility that genetic variations in APBB2 may affect LOAD susceptibility.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family.

Although several genes have been implicated in the development of the early-onset autosomal dominant form of Alzheimer's disease (AD), the genetics of late-onset AD (LOAD) is complex. Loci on several chromosomes have been linked to the disease, but so far only the apolipoprotein E gene has been consistently shown to be a risk factor. We have performed a large-scale single-nucleotide polymorphism (SNP)-based association study, across the region of linkage on chromosome 12, in multiple case-control series totaling 1,089 LOAD patients and 1,196 control subjects and report association with SNPs in the glyceraldehyde-3-phosphate dehydrogenase (GAPD) gene. Subsequent analysis of GAPD paralogs on other chromosomes demonstrated association with two other paralogs. A significant association between LOAD and a compound genotype of the three GAPD genes was observed in all three sample sets. Individually, these SNPs make differential contributions to disease risk in each of the casecontrol series, suggesting that variants in functionally similar genes may account for series-to-series heterogeneity of disease risk. Our observations raise the possibility that GAPD genes are AD risk factors, a hypothesis that is consistent with the role of GAPD in neuronal apoptosis.

Age of Onset↗

PubMed2004

Cognitive deficits associated with schizophrenia in velo-cardio-facial syndrome.

Velo-cardio-facial syndrome (VCFS) is a genetic disorder associated with 22q11 deletion, a characteristic clinical phenotype, behavourial problems, specific cognitive deficits and a high rate of psychosis (particularly schizophrenia). The study of VCFS provides a unique opportunity to identify susceptibility genes for schizophrenia and its associated cognitive deficits. To date, there have been no studies investigating the impact of schizophrenia on cognitive function in adults with VCFS. Therefore we studied the neuropsychological profile of 28 adults with VCFS; 13 with schizophrenia (mean age (+/-S.D.) 34 years +/-11, IQ 71+/-11) and 15 without a history of psychosis (mean age 33 years +/-11, IQ 75+/-11). The VCFS group with schizophrenia compared to the VCFS group without schizophrenia performed significantly (P<0.05) worse on tests of: (1) spatial working memory and strategy formation; (2) the similarities sub-test of the Weschler Adult Intelligence Scale (WAIS); (3) visual recognition; (4) and attention. These deficits may reflect differences in the development and function of frontal brain regions, and this might increase the risk of developing schizophrenia in VCFS. Future studies will need to address how haploinsufficiency of genes on chromosome 22q11 might affect cognition and its relation to the development of psychosis.

Adult↗

PubMed2004

Association of ABCA1 with late-onset Alzheimer's disease is not observed in a case-control study.

Genetic association of ABCA1 or the ATP-binding cassette A1 transporter with late-onset Alzheimer's disease (LOAD) has recently been proposed for a haplotype comprised of three single nucleotide polymorphisms (SNPs). We have genotyped these and other ABCA1 SNPs in a LOAD case-control series of 796 individuals (419 cases versus 377 controls) collected at Washington University. While our sample series is larger and thus presumably has greater power than any of the series used to implicate ABCA1, we were unable to replicate the published association, using either single markers or multiple marker haplotypes. Further, we did not observe significant and replicated association of other ABCA1 SNPs we examined with the disease, thus these ABCA1 variants do not appear to influence the risk of LOAD in this study.

ATP Binding Cassette Transporter 1↗

PubMed2004

Brain anatomy in adults with velocardiofacial syndrome with and without schizophrenia: preliminary results of a structural magnetic resonance imaging study.

CONTEXT: Velocardiofacial syndrome is associated with interstitial deletions of chromosome 22q11, mild to borderline learning disability, characteristic dysmorphology, and a high prevalence of schizophrenia. The biological basis for this increased risk for schizophrenia is unknown, but people with velocardiofacial syndrome may have genetically determined differences in brain anatomy that predispose to the development of schizophrenia. OBJECTIVE: To determine whether there are differences in brain structure between subjects with velocardiofacial syndrome with and without schizophrenia. DESIGN: A cross-sectional quantitative structural magnetic resonance imaging study in 39 adult subjects. SETTING: Referrals were made through medical genetics clinics and psychiatric services throughout the United Kingdom. PARTICIPANTS: Thirteen subjects with velocardiofacial syndrome and schizophrenia, 12 with velocardiofacial syndrome without history of a psychosis, and 14 healthy controls volunteered to participate after screening for eligibility. MAIN OUTCOME MEASURES: Total and regional brain volumes were analyzed by means of manual tracing, and gray- and white-matter densities were obtained by computerized voxel-based methods. RESULTS: People with velocardiofacial syndrome and schizophrenia, compared with both controls and nonschizophrenic patients with velocardiofacial syndrome, had a significant (P<.05) reduction in volume of whole-brain (white + gray) matter and whole-brain white matter, and an increase in total and sulcal cerebrospinal fluid volume. Both velocardiofacial syndrome groups had a reduced cerebellar volume compared with controls. CONCLUSIONS: Within velocardiofacial syndrome, schizophrenia is associated with generalized differences in brain anatomy, but white matter may be particularly implicated. Studies with larger samples are needed to replicate our findings.

Adult↗

PubMed2004

Association of the dopamine D4 receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD.

OBJECTIVE: Association between attention deficit hyperactivity disorder (ADHD) and the 7-repeat allele of a variant (a 48 bp variable number of tandem repeats) in the dopamine D4 receptor gene (DRD4) has been widely documented. A meta-analysis of 21 studies revealed evidence of significant association. In this article the authors examine whether the DRD4 7-repeat allele is associated with performance on a variety of neuropsychological tasks in children with ADHD. METHOD: The presence or absence of the 7-repeat allele was determined in 133 drug-naive children 6 to 13 years of age who fulfilled diagnostic criteria for ADHD. These children were then assessed on several neuropsychological tests known to be associated with attention, impulse control, and response inhibition (the Continuous Performance Test, Matching Familiar Figures Test, Go/No Go Task, and Stop Task). Activity levels were assessed with an actigraph. Children with and without at least one 7-repeat allele were compared with each other and with children in a previous population-based study. RESULTS: Children who had the 7-repeat allele had significantly more incorrect responses on the Matching Familiar Figures Test (16.1 versus 14.3) than children who did not have the allele. Children with the allele also had shorter mean reaction times for incorrect responses on the Matching Familiar Figures Test (846.1 versus 1103.7 msec) and on the Stop Task (116.6 versus 134.1 msec) than children without the allele. Children with the allele also displayed higher activity levels. The children with and without the allele did not differ significantly in number of ADHD symptoms when the symptoms were split into the areas of inattention and hyperactivity/impulsivity. Both groups of children with ADHD were more neuropsychologically impaired than the nonpatient comparison group. CONCLUSIONS: In children with ADHD, possession of the DRD4 7-repeat allele appears to be associated with an inaccurate, impulsive response style on neuropsychological tasks that is not explained by ADHD symptom severity.

Adolescent↗

PubMed2004

Duration and effect of single-dose atropine: paralysis of accommodation in penalization treatment of functional amblyopia.

BACKGROUND AND PURPOSE: Atropine dilates the pupil and paralyzes the ciliary muscle accommodation, blurring vision, and therefore is an effective penalization of the sound eye in the treatment of functional amblyopia of the other eye. The degree of blur induced is a function of the amount of the patient's uncorrected hyperopia and the distance from the eye of the viewed material or object. Another factor determining effectiveness of atropine penalization is the duration of the effect of the atropine. It is the purpose of this study to investigate these factors. METHODS: Six normal children underwent complete eye exam with cycloplegic refraction several days before deliberate instillation of atropine 1% in the sound, or right eye. Distance and near acuity was then tested after 30 minutes, and on subsequent days. Additional data points were derived by placing known minus lenses in front of the tested eye. In addition, we also studied one successfully treated amblyopic patient when he terminated chronic daily atropine in his normal, sound eye. RESULTS: Atropine initially produced a linear reduction in logMAR acuity (blur) at distance of about 0.2 logMAR lines per diopters of uncorrected hyperopia. The magnitude of the blur was greater for near, but the effect of increased hyperopia was slightly greater for distance measurements. This blurring of acuity lasted just less than 48 hours for normal subjects, and just over 48 hours following prompt cessation of chronic daily atropine in that one subject. Regression formulae were derived relating uncorrected hyperopia and time interval following atropine cessation on distance and near acuity in children of amblyopic age range. CONCLUSION: The degree of penalization is highly dependent on the uncorrected hyperopic refractive error. A significant penalization effect is present only for one day or so. Daily atropine is therefore indicated for penalization. To better tailor penalization therapy to target sound eye acuity blur, these formulae and graphs can be used, specifically, in addition, to determine the amount of deliberate spectacle hyperopic undercorrection to maximize the penalization effect.

Accommodation, Ocular↗

PubMed2002

Association of DRD4 in children with ADHD and comorbid conduct problems.

Recent family and twin study findings suggest that ADHD when comorbid with conduct problems may represent a particularly familial and heritable form of ADHD. Although several independent groups have shown association between the DRD4 7 repeat allele and ADHD, others have failed to replicate this finding. Previous TDT analyses of UK and Eire samples had also been negative. We set out to further examine the role of DRD4 but selecting a subgroup of children with ADHD and comorbid conduct problems. Families were recruited from Manchester, Ireland, Birmingham and London clinics. From these, 67 children who fulfilled diagnostic criteria for ADHD and who displayed conduct disorder symptoms were selected. TDT analysis, which had previously yielded negative results for the total sample, showed evidence of association between DRD4 and "ADHD with conduct problems" (7 repeat allele-24 transmissions, 13 non-transmissions; one-tailed P=0.05). These results provide further support for the role of DRD4 in ADHD. Furthermore, these results when considered together with family and twin study findings, suggest that those children with ADHD and comorbid conduct problems may be particularly informative for molecular genetic studies of ADHD. Further work is needed to examine these phenotype issues.

Adolescent↗

PubMed2002

DNA Pooling: a tool for large-scale association studies.

DNA pooling is a practical way to reduce the cost of large-scale association studies to identify susceptibility loci for common diseases. Pooling allows allele frequencies in groups of individuals to be measured using far fewer PCR reactions and genotyping assays than are used when genotyping individuals. Here, we discuss recent developments in quantitative genotyping assays and in the design and analysis of pooling studies. Sophisticated pooling designs are being developed that can take account of hidden population stratification, confounders and inter-loci interactions, and that allow the analysis of haplotypes.

Animals↗

PubMed2002

Dentin matrix protein 1, a target molecule for Cbfa1 in bone, is a unique bone marker gene.

Dentin matrix protein 1 (Dmp1), a phosphoprotein highly linked to dentin formation, has also been reported to be expressed in the skeleton. However, the role of Dmp1 in skeletal tissues remains unclear. To clarify the role of Dmp1 in bone formation, we characterized the expression profile of Dmp1 in bone and cartilage and examined whether Dmp1 expression was regulated by core-binding factor a1 (Cbfa1). Studies of fetal rat calvarial (FRC) cell cultures showed that the expression of Dmp1 was associated closely with "bone nodule" formation and mineralization in vitro. In situ hybridization studies were performed to examine the spatial and temporal expression patterns of Dmp1 during development in mouse embryos from 12.5 day postcoitus (dpc) to 8 weeks postnatal; these studies showed that Dmp1 first appeared in hypertrophic cartilage cells, followed by osteoblasts, and later was expressed strongly in osteocytes. The expression profiles of Cbfa1 and Dmp1 overlapped in both cartilage and bone during development, with Cbfa1 preceding Dmp1. Examination of Dmp1 expression in Cbfa1-/- mice revealed that Dmp1 was absent in the developing bones of Cbfa1-null mice, whereas there was essentially no change in Dmp1 expression in the arrested tooth bud. Transient transfection studies showed forced expression of Dmp1 under the control of Cbfa1 and gel shift data indicated the presence of a functional osteocalcin-specific element (OSE)-2 response element in the Dmp1 proximal promoter region. However, in vitro promoter studies suggested that regulation of Dmp1 by Cbfa1 was not mediated by direct binding of Cbfa1 to this site and may be through indirect mechanisms. These studies highlight Dmp1 as a unique marker gene for osteoblastic differentiation. The close association of Dmp1 and Cbfa1 in the developing skeleton suggests that Dmp1 may play an important role in bone formation.

Animals↗