Christine Fraser

Publications (14)221.73 Total impact

• Source

  Available from: Stephanie H Witt

  Article: Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.

  Pamela Sklar, Stephan Ripke, Laura J Scott, Ole A Andreassen, Sven Cichon, Nick Craddock, Howard J Edenberg, John I Nurnberger, Marcella Rietschel, Douglas Blackwood, [......], Grant W Montgomery, Mark Lathrop, Högni Oskarsson, Michael Bauer, Adam Wright, Philip B Mitchell, Martin Hautzinger, Andreas Reif, John R Kelsoe, Shaun M Purcell
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  ABSTRACT: We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.
  Nature Genetics 09/2011; 43(10):977-83. · 35.53 Impact Factor
• Article: Variation at the GABAA receptor gene, Rho 1 (GABRR1) associated with susceptibility to bipolar schizoaffective disorder.

  Elaine K Green, Detelina Grozeva, Valentina Moskvina, Marian L Hamshere, Ian R Jones, Lisa Jones, Liz Forty, Sian Caesar, Katherine Gordon-Smith, Christine Fraser, Ellie Russell, David St Clair, Allan H Young, Nicol Ferrier, Anne Farmer, Peter McGuffin, Peter A Holmans, Michael J Owen, Michael C O'Donovan, Nick Craddock
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  ABSTRACT: We have previously reported evidence that variation at GABA(A) receptor genes is associated with susceptibility to bipolar disorder with schizophrenia-like psychotic features (Research Diagnostic Criteria (RDC) schizoaffective disorder, bipolar type) with gene-wide significance at GABRB1, GABRA4, GABRB3, GABRA5, and GABRR3. Here we provide suggestive evidence implicating a sixth member of the gene family, GABRR1 (gene-wide P = 0.0058; experiment-wide corrected significance P = 0.052).
  American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2010; 153B(7):1347-9. · 3.70 Impact Factor
• Article: Reducing the Hypomania Checklist (HCL-32) to a 16-item version.

  Liz Forty, Mark Kelly, Lisa Jones, Ian Jones, Emma Barnes, Sian Caesar, Christine Fraser, Katherine Gordon-Smith, Emily Griffiths, Nick Craddock, Daniel J Smith
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  ABSTRACT: The under-recognition of hypomanic symptoms by both clinicians and patients is a major clinical problem which contributes to misdiagnosis and diagnostic delay in patients with bipolar disorder. The recent development of validated screening instruments for hypomania, such as the Hypomania Checklist (HCL-32), may help to improve the detection of bipolar disorder. In this study, we assess whether it is possible to reduce the number of items on the HCL-32 without any loss in the screening tool's ability to reliably differentiate between bipolar disorder (BD) and major depressive disorder (MDD). Using our large samples of patients with DSM-IV defined bipolar I disorder (BD-I) (n=230) and recurrent MDD (n=322), we performed item correlations in order to identify potentially redundant items in the HCL-32. We then tested the performance of a shortened 16-item HCL questionnaire within a separate sample of patients with BD (including BD-I, BD-II and BD-NOS) (n=59) and MDD (n=76). The structure of the 16-item HCL demonstrated two main factors similar to those identified for the HCL-32 (an 'active-elated' factor and a 'risk-taking/irritable' factor). A score of 8 or more on a shortened 16-item version of the HCL had excellent ability to distinguish between BD and MDD. The sensitivity (83%) and specificity (71%) of the 16-item version were very similar to those for the full 32-item HCL. The HCL-16 was derived after subjects had completed the full HCL-32. It will be important to test the validity of a 'stand-alone' 16-item HCL questionnaire. A shortened 16-item HCL (the HCL-16) is potentially a useful screening tool for hypomania within busy clinical settings.
  Journal of affective disorders 08/2010; 124(3):351-6. · 3.76 Impact Factor
• Article: Affective temperaments across the bipolar-unipolar spectrum: examination of the TEMPS-A in 927 patients and controls.

  Arianna Di Florio, Marian Hamshere, Liz Forty, Elaine K Green, Detelina Grozeva, Ian Jones, Sian Caesar, Christine Fraser, Katherine Gordon-Smith, Lisa Jones, Nick Craddock, Daniel J Smith
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  ABSTRACT: There is currently a great deal of interest in the use of affective temperaments as possible intermediate phenotypes for bipolar disorder. However, much of the literature in this area is conflicting. Our aims were to test the hypothesis of a gradient in affective temperament scores, as measured by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A), from bipolar disorder type I (BP-I), through bipolar disorder type II (BP-II), recurrent major depressive disorder (MDD-R), and a control group (CG) in the largest sample to date of 927 subjects. Non parametric tests were used to compare TEMPS-A scores between diagnostic groups and multinomial logistic regression was used to test the association between TEMPS-A scores and diagnosis while controlling for current mood state, age and gender. Although the BP-II group scored higher than the BP-I and MDD-R groups on several TEMPS-A subscales, these differences were not significant when confounding variables were controlled for. The dysthymic subscale differentiated between affected and controls and the anxious subscale differentiated the MDD-R group from controls. The cross-sectional design did not allow us to evaluate potential longitudinal changes of temperament scores, which were assessed only with a self-report questionnaire. We failed to find evidence of a gradient in affective temperament scores. Both unipolar and bipolar patients reported high dysthymic scores relative to controls, perhaps supporting a unitary view of depression across the bipolar-unipolar spectrum. Taking account of potential confounders will be important in future studies which seek to use affective temperaments as intermediate phenotypes in genetic research.
  Journal of affective disorders 10/2009; 123(1-3):42-51. · 3.76 Impact Factor
• Article: Clinical characteristics of unipolar disorder and bipolar disorder according to the lifetime presence of recurrent panic attacks.

  Liz Forty, Daniel Smith, Lisa Jones, Ian Jones, Sian Caesar, Carly Cooper, Christine Fraser, Katherine Gordon-Smith, Sally Hyde, Anne Farmer, Peter McGuffin, Nick Craddock
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  ABSTRACT: The frequent comorbidity of panic and affective disorders has been described in previous studies. However, it is not clear how panic disorder comorbidity in unipolar disorder and bipolar disorder is related to illness course. We compared lifetime clinical characteristics of illness and items of symptomatology in samples of individuals with bipolar I disorder (n = 290) and unipolar disorder (n = 335) according to the lifetime presence of recurrent panic attacks. We found significant differences in clinical course of illness characteristics that were shared across the unipolar and bipolar samples according to the lifetime presence of panic attacks. We also found a number of differences according to the presence of panic attacks that may be specific to the diagnostic group. Distinguishing patients who have mood disorder diagnoses, especially bipolar I disorder, according to the lifetime presence of panic attacks may not only be of use in clinical practice, but may also be informative for aetiological research, such as molecular genetic studies.
  Bipolar Disorders 06/2009; 11(3):307-15. · 5.29 Impact Factor
• Article: Polarity at illness onset in bipolar I disorder and clinical course of illness.

  Liz Forty, Lisa Jones, Ian Jones, Daniel J Smith, Sian Caesar, Christine Fraser, Katherine Gordon-Smith, Sally Hyde, Nick Craddock
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  ABSTRACT: Studies have suggested that episode polarity at illness onset in bipolar disorder may be predictive of some aspects of lifetime clinical characteristics. We here examine this possibility in a large, well-characterized sample of patients with bipolar I disorder. We assessed polarity at onset in patients with bipolar I disorder (N = 553) recruited as part of our ongoing studies of affective disorders. Lifetime clinical characteristics of illness were compared in patients who had a depressive episode at first illness onset (n = 343) and patients who had a manic episode at first illness onset (n = 210). Several lifetime clinical features differed between patients according to the polarity of their onset episode of illness. A logistic regression analysis showed that the lifetime clinical features significantly associated with a depressive episode at illness onset in our sample were: an earlier age at illness onset; a predominantly depressive polarity during the lifetime; more frequent and more severe depressive episodes; and less prominent lifetime psychotic features. Knowledge of pole of onset may help the clinician in providing prognostic information and management advice to an individual with bipolar disorder.
  Bipolar Disorders 03/2009; 11(1):82-8. · 5.29 Impact Factor
• Article: Age-at-onset in bipolar-I disorder: mixture analysis of 1369 cases identifies three distinct clinical sub-groups.

  Marian L Hamshere, Katherine Gordon-Smith, Liz Forty, Lisa Jones, Sian Caesar, Christine Fraser, Sally Hyde, John Tredget, George Kirov, Ian Jones, Nick Craddock, Daniel J Smith
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  ABSTRACT: To assess whether bipolar disorder type I segregates into three clinically distinct sub-groups defined by age-at-onset. Clinical data were available on 1369 individuals with DSM-IV bipolar I disorder. Mixture analysis was performed on the age-at-onset (AAO) data to determine whether they were composed of more than one normal distribution. Individuals were allocated to groups according to the results of the mixture analysis. Categorical logistic regression was then used to investigate relationships between AAO and nine clinical characteristics. The distribution of AAOs in our sample comprised a mixture of three normal distributions with means of 18.7 (SD=3.7), 28.3 (SD=5.5) and 43.3 (SD=9.1) years, with relative proportions of 0.47, 0.39 and 0.14 respectively. Individuals were allocated into three groups dependent on their AAO: < or = 22; 25-37; and > or = 40 years, producing a sample of 1225 individuals (144 with borderline values were excluded). Eight out of the nine clinical characteristics showed evidence for a statistical association with AAO group. Systematic and non-systematic recruitment of participants. Some data relied on retrospective recall. Our results provide further robust evidence to suggest that the AAO distribution of individuals affected with bipolar disorder is composed of three normal distributions. Substantial clinical heterogeneity between the three AAO groups may reflect genetic heterogeneity within bipolar I disorder. Future genetic studies should consider AAO grouping as potential sub-phenotypes.
  Journal of affective disorders 01/2009; 116(1-2):23-9. · 3.76 Impact Factor
• Article: Authors' reply.

  Liz Forty, Daniel Smith, Lisa Jones, Ian Jones, Sian Caesar, Carly Cooper, Christine Fraser, Katherine Gordon-Smith, Sally Hyde, Anne Farmer, Peter McGuffin, Nick Craddock
  The British journal of psychiatry: the journal of mental science 12/2008; 193(5):427. · 6.62 Impact Factor
• Article: Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.

  Manuel A R Ferreira, Michael C O'Donovan, Yan A Meng, Ian R Jones, Douglas M Ruderfer, Lisa Jones, Jinbo Fan, George Kirov, Roy H Perlis, Elaine K Green, [......], Peter McGuffin, Mark J Daly, Aiden P Corvin, Peter A Holmans, Douglas H Blackwood, Hugh M Gurling, Michael J Owen, Shaun M Purcell, Pamela Sklar, Nick Craddock
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  ABSTRACT: To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.
  Nature Genetics 09/2008; 40(9):1056-8. · 35.53 Impact Factor
• Article: Identifying hypomanic features in major depressive disorder using the hypomania checklist (HCL-32).

  Liz Forty, Daniel Smith, Lisa Jones, Ian Jones, Sian Caesar, Christine Fraser, Katherine Gordon-Smith, Nick Craddock
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  ABSTRACT: Recent studies have challenged the traditional unipolar/bipolar divide with increasing support for a more dimensional view of affective disorders. We here examine the occurrence of hypomanic symptoms in individuals with a history of major depression selected to exclude indicators of underlying bipolarity. The presence of hypomanic symptoms was assessed by the Hypomania Checklist (HCL-32) self-report questionnaire in a sample of almost 600 patients meeting DSM-IV criteria for Bipolar I disorder (BPI N=260) or Major Recurrent Depressive disorder (MDDR N=322). Subjects were recruited and assessed using consistent, robust methodology. We found that a score of 20 or more on the HCL-32 yielded the best combination of sensitivity (68%) and specificity (83%) to distinguish between BPI and MDDR. Within our highly selected and well defined MDDR sample (for which exclusion criteria included personal or family histories of bipolar or psychotic illness), 17% of MDDR subjects scored over the threshold of 20 on the HCL-32. The HCL-32 identified a substantial number of patients meeting DSM-IV criteria for recurrent major depression (even when selected to exclude personal and family histories of bipolar illness) who reported bipolar symptoms at a level similar to that reported by patients meeting diagnostic criteria for bipolar disorder. This demonstrates the limitations of using DSM-IV criteria to distinguish those with and without bipolar features of illness.
  Journal of affective disorders 09/2008; 114(1-3):68-73. · 3.76 Impact Factor
• Article: Clinical differences between bipolar and unipolar depression.

  Liz Forty, Daniel Smith, Lisa Jones, Ian Jones, Sian Caesar, Carly Cooper, Christine Fraser, Katherine Gordon-Smith, Sally Hyde, Anne Farmer, Peter McGuffin, Nick Craddock
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  ABSTRACT: It is commonly -- but wrongly -- assumed that there are no important differences between the clinical presentations of major depressive disorder and bipolar depression. Here we compare clinical course variables and depressive symptom profiles in a large sample of individuals with major depressive disorder (n=593) and bipolar disorder (n=443). Clinical characteristics associated with a bipolar course included the presence of psychosis, diurnal mood variation and hypersomnia during depressive episodes, and a greater number of shorter depressive episodes. Such features should alert a clinician to a possible bipolar course. This is important because optimal management is not the same for bipolar and unipolar depression.
  The British Journal of Psychiatry 06/2008; 192(5):388-9. · 6.62 Impact Factor
• Article: Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.

  Paul R Burton, David G Clayton, Lon R Cardon, Nick Craddock, Panos Deloukas, Audrey Duncanson, Dominic P Kwiatkowski, Mark I McCarthy, Willem H Ouwehand, Nilesh J Samani, [......], Anne-Marie Sims, Alison Dowling, Jacqueline Taylor, Tracy Doan, John C Davis, Laurie Savage, Michael M Ward, Thomas L Learch, Michael H Weisman, Mathew Brown
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  ABSTRACT: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.
  Nature Genetics 12/2007; 39(11):1329-37. · 35.53 Impact Factor
• Article: Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

  Sergey Nejentsev, Joanna M. M. Howson, Neil M. Walker, Jeffrey Szeszko, Sarah F. Field, Helen E. Stevens, Pamela Reynolds, Matthew Hardy, Erna King, Jennifer Masters, [......], Niall J. Cardin, Teresa Ferreira, Joanne Pereira-Gale, Ingeleif B. Hallgrimsd|[oacute]|ttir, Bryan N. Howie, Zhan Su, Yik Ying Teo, Damjan Vukcevic, David Bentley, Alistair Compston
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  ABSTRACT: The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes
  Nature 11/2007; 450(7171):887-892. · 36.28 Impact Factor
• Article: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

  Paul R. Burton, David G. Clayton, Lon R. Cardon, Nick Craddock, Panos Deloukas, Audrey Duncanson, Dominic P. Kwiatkowski, Mark I. McCarthy, Willem H. Ouwehand, Nilesh J. Samani, [......], Niall J. Cardin, Teresa Ferreira, Joanne Pereira-Gale, Ingileif B. Hallgrimsd|[oacute]|ttir, Bryan N. Howie, Zhan Su, Yik Ying Teo, Damjan Vukcevic, David Bentley, Alistair Compston
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  ABSTRACT: There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined 2,000 individuals for each of 7 major diseases and a shared set of 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 10-7: 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10-5 and 5 10-7) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.
  Nature 06/2007; 447(7145):661-678. · 36.28 Impact Factor