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Articles
by
M. J Owen |
Total Records (
5 ) for
M. J Owen |
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C. M Lewis
,
M. Y Ng
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A. W Butler
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S Cohen Woods
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R Uher
,
K Pirlo
,
M. E Weale
,
A Schosser
,
U. M Paredes
,
M Rivera
,
N Craddock
,
M. J Owen
,
L Jones
,
I Jones
,
A Korszun
,
K. J Aitchison
,
J Shi
,
J. P Quinn
,
A MacKenzie
,
P Vollenweider
,
G Waeber
,
S Heath
,
M Lathrop
,
P Muglia
,
M. R Barnes
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J. C Whittaker
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F Tozzi
,
F Holsboer
,
M Preisig
,
A. E Farmer
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G Breen
,
I. W Craig
and
P. McGuffin
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Objective
Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders.
Method
Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control [DeCC] study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network [DeNT] study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression [GENDEP] study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Génotypage on the Illumina Human610-Quad BeadChip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry.
Results
Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungenotyped markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1.
Conclusions
This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them.
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G Donohoe
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J Walters
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D. W Morris
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E. M Quinn
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R Judge
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N Norton
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I Giegling
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A. M Hartmann
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H. J Moller
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P Muglia
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H Williams
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V Moskvina
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R Peel
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T O'Donoghue
,
M. J Owen
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M. C O'Donovan
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M Gill
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D Rujescu
and
A. Corvin
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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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D Grozeva
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G Kirov
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D Ivanov
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I. R Jones
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L Jones
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E. K Green
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D. M St Clair
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A. H Young
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N Ferrier
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A. E Farmer
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P McGuffin
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P. A Holmans
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M. J Owen
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M. C O'Donovan
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N Craddock
and
for the Wellcome Trust Case Control Consortium
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Context Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date.
Objectives To determine whether large (>100 000 base pairs) and rare (found in <1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia.
Design A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray.
Setting The Wellcome Trust Case Control Consortium.
Participants There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents.
Main Outcome Measures Overall load of CNVs and presence of rare CNVs.
Results The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder.
Conclusions Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder. |
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M. L Hamshere
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E. K Green
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I. R Jones
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L Jones
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V Moskvina
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G Kirov
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D Grozeva
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I Nikolov
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D Vukcevic
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S Caesar
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K Gordon Smith
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C Fraser
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E Russell
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G Breen
,
D St Clair
,
D. A Collier
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A. H Young
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I. N Ferrier
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A Farmer
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P McGuffin
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Holmans Wellcome Trust Case Control Consortium
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M. J Owen
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M. C O'Donovan
and
N. Craddock
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Background
Psychiatric phenotypes are currently defined according to sets of
descriptive criteria. Although many of these phenotypes are heritable, it
would be useful to know whether any of the various diagnostic categories in
current use identify cases that are particularly helpful for
biological–genetic research.
Aims
To use genome-wide genetic association data to explore the relative genetic
utility of seven different descriptive operational diagnostic categories
relevant to bipolar illness within a large UK case–control bipolar
disorder sample.
Method
We analysed our previously published Wellcome Trust Case Control Consortium
(WTCCC) bipolar disorder genome-wide association data-set, comprising 1868
individuals with bipolar disorder and 2938 controls genotyped for 276 122
single nucleotide polymorphisms (SNPs) that met stringent criteria for
genotype quality. For each SNP we performed a test of association (bipolar
disorder group v. control group) and used the number of associated
independent SNPs statistically significant at P<0.00001 as a
metric for the overall genetic signal in the sample. We next compared this
metric with that obtained using each of seven diagnostic subsets of the group
with bipolar disorder: Research Diagnostic Criteria (RDC): bipolar I disorder;
manic disorder; bipolar II disorder; schizoaffective disorder, bipolar type;
DSM–IV: bipolar I disorder; bipolar II disorder; schizoaffective
disorder, bipolar type.
Results
The RDC schizoaffective disorder, bipolar type (v. controls) stood
out from the other diagnostic subsets as having a significant excess of
independent association signals (P<0.003) compared with that
expected in samples of the same size selected randomly from the total bipolar
disorder group data-set. The strongest association in this subset of
participants with bipolar disorder was at rs4818065 (P =
2.42x10–7). Biological systems implicated included
gamma amniobutyric acid (GABA)A receptors. Genes having at least
one associated polymorphism at P<10–4 included
B3GALTS, A2BP1, GABRB1, AUTS2, BSN, PTPRG, GIRK2 and
CDH12.
Conclusions
Our findings show that individuals with broadly defined bipolar
schizoaffective features have either a particularly strong genetic
contribution or that, as a group, are genetically more homogeneous than the
other phenotypes tested. The results point to the importance of using
diagnostic approaches that recognise this group of individuals. Our approach
can be applied to similar data-sets for other psychiatric and non-psychiatric
phenotypes. |
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K Langley
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T Fowler
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T Ford
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A. K Thapar
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M van den Bree
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G Harold
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M. J Owen
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M. C O'Donovan
and
A. Thapar
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Background
Attention-deficit hyperactivity disorder (ADHD) is recognised as a common,
disabling condition. Little information is available regarding the long-term
outcomes for individuals with ADHD in the UK.
Aims
To examine the 5-year outcome for a UK cohort of children with diagnosed,
treated ADHD and identify whether maternal and social factors predict key
outcomes.
Method
One hundred and twenty-six school-aged children (mean age 9.4 years, s.d. =
1.7) diagnosed with ADHD were reassessed 5 years later during adolescence
(mean age 14.5 years, s.d. = 1.7) for ADHD, conduct disorder and other
antisocial behaviours.
Results
Most adolescents (69.8%) continued to meet full criteria for ADHD, were
known to specialist services and exhibited high levels of antisocial
behaviour, criminal activity and substance use problems. Maternal childhood
conduct disorder predicted offspring ADHD continuity; maternal childhood
conduct disorder, lower child IQ and social class predicted offspring conduct
disorder symptoms.
Conclusions
The treatment and monitoring of ADHD need to be intensified as outcomes are
poor especially in offspring of mothers with childhood conduct disorder
symptoms. |
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