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ABSTRACT: CONTEXT Affective disorders are common in women, with many episodes having an onset in pregnancy or during the postpartum period. OBJECTIVE To investigate the occurrence and timing of perinatal mood episodes in women with bipolar I disorder, bipolar II disorder, and recurrent major depression (RMD). SETTING AND PATIENTS Women were recruited in our ongoing research on the genetic and nongenetic determinants of major affective disorders. Participants were interviewed and case notes were reviewed. Best-estimate diagnoses were made according to DSM-IV criteria. The 1785 parous women identified included 1212 women with bipolar disorder (980 with type I and 232 with type II) and 573 with RMD. Data were available on 3017 live births. MAIN OUTCOME MEASURES We report the lifetime occurrence of perinatal mood episodes, the rates of perinatal episodes per pregnancy/postpartum period, and the timing of the onset of episodes in relation to delivery. RESULTS More than two-thirds of all diagnostic groups reported at least 1 lifetime episode of illness during pregnancy or the postpartum period. Women with bipolar I disorder reported an approximately 50% risk of a perinatal major affective episode per pregnancy/postpartum period. Risks were lower in women with RMD or bipolar II disorder, at approximately 40% per pregnancy/postpartum period. Mood episodes were significantly more common in the postpartum period in bipolar I disorder and RMD. Most perinatal episodes occurred within the first postpartum month, with mania or psychosis having an earlier onset than depression. CONCLUSIONS Although episodes of postpartum mood disorder are more common in bipolar I disorder and manic and psychotic presentations occur earlier in the postpartum period, perinatal episodes are highly prevalent across the mood disorder spectrum.
Archives of general psychiatry 12/2012; · 12.26 Impact Factor
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Lam C Tsoi,
Sarah L Spain,
Jo Knight,
Eva Ellinghaus,
Philip E Stuart,
Francesca Capon,
Jun Ding,
Yanming Li,
Trilokraj Tejasvi,
Johann E Gudjonsson, [......],
Matthew Waller,
Paul Weston,
Sara Widaa,
Pamela Whittaker,
Rajan P Nair,
Andre Franke,
Jonathan N W N Barker,
Goncalo R Abecasis,
James T Elder,
Richard C Trembath
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ABSTRACT: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
Nature Genetics 11/2012; · 35.53 Impact Factor
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Robert Potter,
Becky Mars,
Olga Eyre,
Sophie Legge,
Tamsin Ford,
Ruth Sellers, Nicholas Craddock,
Frances Rice,
Stephan Collishaw,
Anita Thapar,
Ajay K Thapar
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ABSTRACT: Emerging evidence suggests that early intervention and prevention programmes for mental health problems in the offspring of parents with depression are important. Such programmes are difficult to implement if children with psychiatric disorder are not identified and are not accessing services, even if their parents are known to primary care.
To investigate service use in children of parents who have recurrent depression, and factors that influence such contact.
A total of 333 families were recruited, mainly through primary health care, in which at least one parent had received treatment for recurrent depression and had a child aged 9-17 years.
Psychiatric assessments of parents and children were completed using research diagnostic interviews. The service-use interview recorded current (in the 3 months prior to interview) and lifetime contact with health, educational, and social services due to concerns about the child's emotions or behaviour.
Only 37% of children who met criteria for psychiatric disorder were in contact with any service at the time of interview. A third, who were suicidal or self-harming and had a psychiatric disorder at that time, were not in contact with any service. Lack of parental worry predicted lower service use, with higher rates in children with comorbidity and suicidality.
Most children with a psychiatric disorder in this high-risk sample were not in contact with services. Improving ease of access to services, increasing parental and professional awareness that mental health problems can cluster in families, and improving links between adult and child services may help early detection and intervention strategies for the offspring of parents with depression.
British Journal of General Practice 07/2012; 62(600):e487-93. · 1.83 Impact Factor
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ABSTRACT: Parents with depression are thought to be unreliable reporters of children's depression symptoms, but findings are contradictory and primarily focus on discrepancies between parent and child reports rather than on the predictive validity of informants. Using a sample of parents with recurrent depression, our analyses utilised data from a prospective high-risk longitudinal study (the Early Prediction of Adolescent Depression study) to investigate whether baseline parental reports of child depression symptoms predicted new onset mood disorder (NOMD) in children.
The sample included 287 parents with a history of recurrent depression and their adolescent offspring (aged 9-17 at baseline). Families were assessed at three time points. The Child and Adolescent Psychiatric assessment (parent and child versions) was used to assess the number of child depression symptoms (computed separately by informant at baseline) and NOMD at follow-up. All DSM-IV diagnoses were confirmed by two child psychiatrists.
Parent reports of child depression symptoms at baseline significantly predicted NOMD in children. Secondary analyses stratifying the sample according to child age showed that, for younger children, parent reports were significantly better at predicting NOMD compared to child reports. For children aged 12 or older, there were no significant differences between parent and child reports in predicting NOMD. The pattern of association remained the same once we controlled for baseline levels of parental depression.
Not all parents were currently experiencing an episode of depression at the baseline assessments; the sample consisted predominantly of mothers, thus findings may not be applicable to fathers or families without a history of parental depression.
In this high risk sample, child and parent ratings of depression predict new onset child mood disorder to a similar degree. Clinicians and researchers should give due consideration to parent ratings of their children's depression symptoms, regardless of whether the parent suffers with depression.
Journal of affective disorders 05/2012; 141(2-3):233-6. · 3.76 Impact Factor
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ABSTRACT: Additional information about risk genes or risk pathways for diseases can be extracted from genome-wide association studies through analyses of groups of markers. The most commonly employed approaches involve combining individual marker data by adding the test statistics, or summing the logarithms of their P-values, and then using permutation testing to derive empirical P-values that allow for the statistical dependence of single-marker tests arising from linkage disequilibrium (LD). In the present study, we use simulated data to show that these approaches fail to reflect the structure of the sampling error, and the effect of this is to give undue weight to correlated markers. We show that the results obtained are internally inconsistent in the presence of strong LD, and are externally inconsistent with the results derived from multi-locus analysis. We also show that the results obtained from regression and multivariate Hotelling T(2) (H-T2) testing, but not those obtained from permutations, are consistent with the theoretically expected distributions, and that the H-T2 test has greater power to detect gene-wide associations in real datasets. Finally, we show that while the results from permutation testing can be made to approximate those from regression and multivariate Hotelling T(2) testing through aggressive LD pruning of markers, this comes at the cost of loss of information. We conclude that when conducting multi-locus analyses of sets of single-nucleotide polymorphisms, regression or multivariate Hotelling T(2) testing, which give equivalent results, are preferable to the other more commonly applied approaches.
European journal of human genetics: EJHG 02/2012; 20(8):890-6. · 3.56 Impact Factor
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ABSTRACT: Parental depression is associated with an increased risk of psychiatric disorder in offspring, although outcomes vary. At present relatively little is known about how differences in episode timing, severity, and course of recurrent depression relate to risk in children. The aim of this study was to consider the offspring of parents with recurrent depression and examine whether a recent episode of parental depression indexes risk for offspring psychopathology over and above these other parental depression features.
Three hundred and thirty seven recurrently depressed parents and their offspring (aged 9-17) were interviewed as part of an ongoing study, the 'Early Prediction of Adolescent Depression Study'. The Child and Adolescent Psychiatric Assessment was used to assess two child outcomes; presence of a DSM-IV psychiatric disorder and number of DSM-IV child-rated depression symptoms.
Children whose parents had experienced a recent episode of depression reported significantly more depression symptoms, and odds of child psychiatric disorder were doubled relative to children whose parents had not experienced a recent episode of depression. Past severity of parental depression was also significantly associated with child depression symptoms.
Statistical analyses preclude causal conclusions pertaining to parental depression influences on offspring psychopathology; several features of parental depression were recalled retrospectively.
This study suggests that particular features of parental depression, specifically past depression severity and presence of a recent episode, may be important indicators of risk for child psychiatric disorder and depressive symptoms.
Journal of affective disorders 09/2011; 136(1-2):44-53. · 3.76 Impact Factor
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Marian L Hamshere,
Peter A Holmans,
Geraldine M McCarthy,
Lisa A Jones,
Kieran C Murphy,
Robert D Sanders,
Marion Y Gray,
Stanley Zammit,
Nigel M Williams,
Nadine Norton,
Hywel J Williams,
Peter McGuffin,
Michael C O'Donovan, Nicholas Craddock,
Michael J Owen,
Alastair G Cardno
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ABSTRACT: Genetic factors are likely to influence clinical variation in schizophrenia, but it is unclear which variables are most suitable as phenotypes and which molecular genetic loci are involved. We evaluated clinical variable phenotypes and applied suitable phenotypes in genome-wide covariate linkage analysis. We ascertained 170 affected relative pairs (168 sibling-pairs and two avuncular pairs) with DSM-IV schizophrenia or schizoaffective disorder from the United Kingdom. We defined psychotic symptom dimensions, age at onset (AAO), and illness course using the OPCRIT checklist. We evaluated phenotypes using within sibling-pair correlations and applied suitable phenotypes in multipoint covariate linkage analysis based on 372 microsatellite markers at ∼10 cM intervals. The statistical significance of linkage results was assessed by simulation. The positive and disorganized symptom dimensions, AAO, and illness course qualified as suitable phenotypes. There were no genome-wide significant linkage results. There was suggestive evidence of linkage for the positive dimension on chromosomes 2q32, 10q26, and 20q12; the disorganized dimension on 8p21 and 17q21; and illness course on 2q33 and 22q11. The linkage peak for disorganization on 17q21 remained suggestive after correction for multiple testing. To our knowledge, this is the first study to integrate phenotype evaluation and genome-wide covariate linkage analysis for symptom dimensions and illness history variables in sibling-pairs with schizophrenia. The significant within-pair correlations strengthen the evidence that some clinical variables within schizophrenia are suitable phenotypes for molecular genetic investigations. At present there are no genome-wide significant linkage results for these phenotypes, but a number of suggestive findings warrant further investigation.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2011; 156B(8):929-40. · 3.70 Impact Factor
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Stephan Ripke,
Alan R Sanders,
Kenneth S Kendler,
Douglas F Levinson,
Pamela Sklar,
Peter A Holmans,
Dan-Yu Lin,
Jubao Duan,
Roel A Ophoff,
Ole A Andreassen, [......],
Durk Wiersma,
Dieter B Wildenauer,
Hywel J Williams,
Nigel M Williams,
Brandon Wormley,
Stan Zammit,
Patrick F Sullivan,
Michael C O'Donovan,
Mark J Daly,
Pablo V Gejman
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ABSTRACT: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).
Nature Genetics 09/2011; 43(10):969-76. · 35.53 Impact Factor
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The Australo-Anglo-American Spondyloarthritis Consortium (TASC,
the Wellcome Trust Case Control Consortium,
David M Evans,
Chris C A Spencer,
Jennifer J Pointon,
Zhan Su,
David Harvey,
Grazyna Kochan,
Udo Oppermann,
Alexander Dilthey, [......],
Matthew Waller,
Paul Weston,
Pamela Whittaker,
Sara Widaa,
Nicholas W Wood,
Gilean McVean,
John D Reveille,
B Paul Wordsworth,
Matthew A Brown,
Peter Donnelly
Nature Genetics 07/2011; 43(8):761-767. · 35.53 Impact Factor
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ABSTRACT: The neurodevelopmental hypothesis of schizophrenia provided a valuable framework that allowed a condition that usually presents with frank disorder in adolescence or early adulthood to be understood at least in part as a consequence of events occurring early in development. However, the implications of the neurodevelopmental hypothesis for nosological conceptions of the disorder can only now be fully appreciated. Recent research indicates genetic overlap between schizophrenia and syndromes in which psychopathology is manifest in childhood and that are often grouped together as 'neurodevelopmental disorders' such as autism-spectrum disorders, intellectual disability and attention-deficit hyperactivity disorder. These findings challenge the aetiological basis of current diagnostic categories and, together with evidence for frequent comorbidity, suggest that we should view the functional psychoses as members of a group of related and overlapping syndromes that result in part from a combination of genetic and environmental effects on brain development and that are associated with specific and general impairments of cognitive function. This has important implications for future research and for the configuration of psychiatric services.
The British journal of psychiatry: the journal of mental science 03/2011; 198(3):173-5. · 6.62 Impact Factor
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Kaixin Zhou,
Celine Bellenguez,
Chris C A Spencer,
Amanda J Bennett,
Ruth L Coleman,
Roger Tavendale,
Simon A Hawley,
Louise A Donnelly,
Chris Schofield,
Christopher J Groves, [......],
Helen Colhoun,
Andrew D Morris,
Calum Sutherland,
D Grahame Hardie,
Leena Peltonen,
Mark I McCarthy,
Rury R Holman,
Colin N A Palmer,
Peter Donnelly,
Ewan R Pearson
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ABSTRACT: Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.
Nature Genetics 02/2011; 43(2):117-20. · 35.53 Impact Factor
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Chris C A Spencer,
Vincent Plagnol,
Amy Strange,
Michelle Gardner,
Coro Paisan-Ruiz,
Gavin Band,
Roger A Barker,
Celine Bellenguez,
Kailash Bhatia,
Hannah Blackburn, [......],
Simon Potter,
Anna Rautanen,
Stephen J Sawcer,
Zhan Su,
Richard C Trembath,
Ananth C Viswanathan,
Nigel W Williams,
Huw R Morris,
Peter Donnelly,
Nicholas W Wood
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ABSTRACT: We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P< 10(-4)). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P< 10(-10)) and found evidence for an additional independent association in 4q22/SNCA. A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease.
Human Molecular Genetics 01/2011; 20(2):345-53. · 7.64 Impact Factor
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David M Evans,
Chris C A Spencer,
Jennifer J Pointon,
Zhan Su,
David Harvey,
Grazyna Kochan,
Udo Oppermann,
Udo Opperman,
Alexander Dilthey,
Matti Pirinen, [......],
Matthew Waller,
Paul Weston,
Pamela Whittaker,
Sara Widaa,
Nicholas W Wood,
Gilean McVean,
John D Reveille,
B Paul Wordsworth,
Matthew A Brown,
Peter Donnelly
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ABSTRACT: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
Nature Genetics 01/2011; 43(8):761-7. · 35.53 Impact Factor
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Hywel J Williams, Nicholas Craddock,
Giancarlo Russo,
Marian L Hamshere,
Valentina Moskvina,
Sarah Dwyer,
Rhodri L Smith,
Elaine Green,
Detelina Grozeva,
Peter Holmans,
Michael J Owen,
Michael C O'Donovan
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ABSTRACT: Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger binding protein 804A (ZNF804A), as showing trans-disorder effects, and the same is true for one of the best supported bipolar loci, calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) which has also been associated with schizophrenia. We have undertaken a cross-phenotype study based upon the remaining variants that show genome-wide evidence for association in large schizophrenia and BD meta-analyses. These comprise in schizophrenia, SNPs in or in the vicinity of transcription factor 4 (TCF4), neurogranin (NRGN) and an extended region covering the MHC locus on chromosome 6. For BD, the strongly supported variants are in the vicinity of ankyrin 3, node of Ranvier (ANK3) and polybromo-1 (PBRM1). Using data sets entirely independent of their original discoveries, we observed strong evidence that the PBRM1 locus is also associated with schizophrenia (P = 0.00015) and nominally significant evidence (P < 0.05) that the NRGN and the extended MHC region are associated with BD. Moreover, considering this highly restricted set of loci as a group, the evidence for trans-disorder effects is compelling (P = 4.7 × 10(-5)). Including earlier reported data for trans-disorder effects for ZNF804A and CACNA1C, six out of eight of the most robustly associated loci for either disorder show trans-disorder effects.
Human Molecular Genetics 10/2010; 20(2):387-91. · 7.64 Impact Factor
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Cathryn M Lewis,
Mandy Y Ng,
Amy W Butler,
Sarah Cohen-Woods,
Rudolf Uher,
Katrina Pirlo,
Michael E Weale,
Alexandra Schosser,
Ursula M Paredes,
Margarita Rivera, [......],
Pierandrea Muglia,
Michael R Barnes,
John C Whittaker,
Federica Tozzi,
Florian Holsboer,
Martin Preisig,
Anne E Farmer,
Gerome Breen,
Ian W Craig,
Peter McGuffin
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ABSTRACT: 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.
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.
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.
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.
American Journal of Psychiatry 08/2010; 167(8):949-57. · 12.54 Impact Factor
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Jeffrey C Barrett,
James C Lee,
Charles W Lees,
Natalie J Prescott,
Carl A Anderson,
Anne Phillips,
Emma Wesley,
Kirstie Parnell,
Hu Zhang,
Hazel Drummond, [......],
Paul Weston,
Sara Widaa,
Pamela Whittaker,
Antony P Attwood,
Jonathan Stephens,
Jennifer Sambrook,
Willem H Ouwehand,
Wendy L McArdle,
Susan M Ring,
David P Strachan
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[hide abstract]
ABSTRACT: Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17)), 16q22 (CDH1 and CDH3; P = 2.8 x 10(-8)) and 7q31 (LAMB1; P = 3.0 x 10(-8)). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.
Nature Genetics 11/2009; 41(12):1330-4. · 35.53 Impact Factor
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Michael C O'Donovan, Nicholas Craddock,
Nadine Norton,
Hywel Williams,
Timothy Peirce,
Valentina Moskvina,
Ivan Nikolov,
Marian Hamshere,
Liam Carroll,
Lyudmila Georgieva, [......],
Jeremy M Silverman,
William F Byerley,
C Robert Cloninger,
Sven Cichon,
Markus M N|[ouml]|then,
Michael Gill,
Aiden Corvin,
Dan Rujescu,
George Kirov,
Michael J Owen
[show abstract]
[hide abstract]
ABSTRACT: We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with
Nature Genetics 07/2008; 40(9):1053-1055. · 35.53 Impact Factor
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Michael C O'Donovan, Nicholas Craddock,
Nadine Norton,
Hywel Williams,
Timothy Peirce,
Valentina Moskvina,
Ivan Nikolov,
Marian Hamshere,
Liam Carroll,
Lyudmila Georgieva, [......],
George Kirov,
Michael J Owen,
Nancy G Buccola,
Bryan J Mowry,
Robert Freedman,
Farooq Amin,
Donald W Black,
Jeremy M Silverman,
William F Byerley,
C Robert Cloninger
[show abstract]
[hide abstract]
ABSTRACT: We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)).
Nature Genetics 07/2008; 40(9):1053-5. · 35.53 Impact Factor
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Nigel M Williams,
Beate Glaser,
Nadine Norton,
Hywel Williams,
Timothy Pierce,
Valentina Moskvina,
Stephen Monks,
Jurgen Del Favero,
Dirk Goossens,
Dan Rujescu,
Ina Giegling,
George Kirov, Nicholas Craddock,
Kieran C Murphy,
Michael C O'Donovan,
Michael J Owen
[show abstract]
[hide abstract]
ABSTRACT: Evidence that a gene or genes on chromosome 22 is involved in susceptibility to schizophrenia comes from two sources: the increased incidence of schizophrenia in individuals with 22q11 deletion syndrome (22q11DS) and genetic linkage studies. In mice, hemizygous deletion of either Tbx1 or Gnb1l can cause deficits in pre-pulse inhibition, a sensory motor gating defect which is associated with schizophrenia. We tested the hypothesis that variation at this locus confers risk of schizophrenia and related disorders in a series of case-control association studies. First, we found evidence for a male-specific genotypic association (P = 0.00017) TBX1/GNB1L in 662 schizophrenia cases and 1416 controls from the UK. Moreover, we replicated this finding in two independent case-control samples (additional 746 cases and 1330 controls) (meta analysis P = 1.8 x 10(-5)) and also observed significant evidence for genotypic association in an independent sample of 480 schizophrenia parent-proband trios from Bulgaria with markers at this locus, which was again strongest in the male probands (P = 0.004). Genotyping the most significant SNPs in a sample of 83 subjects with 22q11DS with and without psychosis again revealed a significant allelic association with psychosis in males with 22q11DS (P = 0.01). Finally, using allele specific expression analysis, we have shown that the markers associated with psychosis are also correlated with alterations in GNB1L expression, raising the hypothesis that the risk to develop psychosis at this locus could be mediated in a dose sensitive manner via gene expression. However, other explanations are possible, and further analyses will be required to clarify the correct functional mechanism.
Human Molecular Genetics 03/2008; 17(4):555-66. · 7.64 Impact Factor
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Michael C. Donovan, Nicholas Craddock,
Nadine Norton,
Hywel Williams,
Timothy Peirce,
Valentina Moskvina,
Ivan Nikolov,
Marian Hamshere,
Liam Carroll,
Lyudmila Georgieva, [......],
Pablo V Gejman,
Molecular Genetics of Schizophrenia,
Sven Cichon,
Markus M. No¨then,
Michael Gill,
Aiden Corvin,
Dan Rujescu,
George Kirov,
Michael J Owen,
Bryan Mowry
[show abstract]
[hide abstract]
ABSTRACT: We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10-5 in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 10-4), and the overall pattern of replication was unlikely to occur by chance (P = 9 10-8). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 10-7) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 10-9).
