Nick Craddock

Cardiff University, Cardiff, Wales, United Kingdom

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Publications (234)2213.35 Total impact

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    Jie Huang · Bryan Howie · Shane McCarthy · Yasin Memari · Klaudia Walter · Josine L. Min · Petr Danecek · Giovanni Malerba · Elisabetta Trabetti · Hou-Feng Zheng · [...] · Crispian Wilson · Scott G. Wilson · Kim Wong · ChangJiang Xu · Jian Yang · Gianluigi Zaza · Eleftheria Zeggini · Feng Zhang · Pingbo Zhang · Weihua Zhang
    Nature Communications 09/2015; · 11.47 Impact Factor
  • Rachel Upthegrove · Ian Jones · Nick Craddock
    The British journal of psychiatry: the journal of mental science 09/2015; 207(3):272. DOI:10.1192/bjp.207.3.272 · 7.99 Impact Factor
  • Sarah Knott · Liz Forty · Nick Craddock · Rhys H. Thomas
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    ABSTRACT: It is well recognized that mood disorders and epilepsy commonly co-occur. Despite this, our knowledge regarding the relationship between epilepsy and bipolar disorder is limited. Several shared features between the two disorders, such as their episodic nature and potential to run a chronic course, and the efficacy of some antiepileptic medications in the prophylaxis of both disorders, are often cited as evidence of possible shared underlying pathophysiology. The present paper aims to review the bidirectional associations between epilepsy and bipolar disorder, with a focus on epidemiological links, evidence for shared etiology, and the impact of these disorders on both the individual and wider society. Better recognition and understanding of these two complex disorders, along with an integrated clinical approach, are crucial for improved evaluation and management of comorbid epilepsy and mood disorders. Copyright © 2015 Elsevier Inc. All rights reserved.
    Epilepsy & Behavior 08/2015; DOI:10.1016/j.yebeh.2015.07.003 · 2.26 Impact Factor
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    ABSTRACT: Alcohol misuse (AM) is more common in bipolar disorder (BD) than within the general population but the mechanisms of this association are unclear. We hypothesized that certain affective temperaments (including hyperthymic, cyclothymic, anxious, depressive and/or irritability) might represent 'fundamental states' contributing to risk of both AM and BD and we aimed to assess whether extremes of these five affective temperaments were associated with BD and concomitant AM status. Our sample comprised 1420 individuals with BD who were recruited into a clinical-genetic study conducted by the Bipolar Disorder Research Network. Phenotypic assessments, including evaluation for AM and the 32-item TEMPS-A questionnaire, were conducted. Binary logistic regression was used to determine the effect of TEMPS-A scores on the likelihood of concomitant AM, with adjustment for confounders. Mean scores for four affective temperaments (hyperthymic, cyclothymic, depressive and irritable) were higher in cases (BD+AMs) than controls (BD only) (p<0.001). Hyperthymic and irritable temperaments in particular significantly increased the odds of concomitant AM within the BD sample after adjustment for potential confounders. The definition of AM was not directly based on formal diagnostic classification systems. A retrospective, cross-sectional design was used. Our findings may not generalize to other countries and cultures. Higher scores on measures of hyperthymic and irritable temperament may contribute to the association between AM and BD. Assessing affective temperaments early in the course of BD may help to predict the development of an AM problem in vulnerable individuals. Copyright © 2015. Published by Elsevier B.V.
    Journal of Affective Disorders 07/2015; 186:226-231. DOI:10.1016/j.jad.2015.07.027 · 3.38 Impact Factor
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    ABSTRACT: PsyCymru was initially established as a proof of concept to investigate the feasibility of linking a prospectively ascertained, well-characterised (linked clinical cohort) of people with psychosis in Wales, UK with large amounts of anonymised routinely collected health record data. We are now additionally linking genetic data. PsyCymru aims to create a research platform and infrastructure for psychosis research in Wales by the establishment of two cohorts. The first is a well characterised clinically-assessed cohort of 490 individuals aged 16 and over, including genetic data. Consented individuals underwent a structured interview using a series of well-validated questionnaires and gave blood for the purpose of DNA extraction for sequencing and candidate gene identification. This data was linked to routinely collected health and social datasets with identity encryption used to protect privacy. The second is a much larger (12,097 individuals) but less well characterised population-based e-cohort of prevalent psychosis cases created using a previously validated algorithm applied to anonymised routine data. Both cohorts can be tracked prospectively and retrospectively using anonymised routinely collected electronic health and administrative data in the Secure Anonymised Information Linkage (SAIL) databank. This unique platform pools data together from multiple sources; linking clinical, psychological, biological, genetic and health care factors to address a wide variety of research questions. This resource will continue to expand over the coming years in size, breadth and depth of data, with continued recruitment and additional measures planned. Copyright © 2015. Published by Elsevier B.V.
    Schizophrenia Research 06/2015; 166(1-3). DOI:10.1016/j.schres.2015.05.036 · 3.92 Impact Factor
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    ABSTRACT: Background North American studies show bipolar disorder is associated with elevated rates of problem gambling; however, little is known about rates in the different presentations of bipolar illness.AimsTo determine the prevalence and distribution of problem gambling in people with bipolar disorder in the UK.Method The Problem Gambling Severity Index was used to measure gambling problems in 635 participants with bipolar disorder.ResultsModerate to severe gambling problems were four times higher in people with bipolar disorder than in the general population, and were associated with type 2 disorder (OR = 1.74, P = 0.036), history of suicidal ideation or attempt (OR = 3.44, P = 0.02) and rapid cycling (OR = 2.63, P = 0.008).Conclusions Approximately 1 in 10 patients with bipolar disorder may be at moderate to severe risk of problem gambling, possibly associated with suicidal behaviour and a rapid cycling course. Elevated rates of gambling problems in type 2 disorder highlight the probable significance of modest but unstable mood disturbance in the development and maintenance of such problems. © The Royal College of Psychiatrists 2015.
    The British journal of psychiatry: the journal of mental science 06/2015; DOI:10.1192/bjp.bp.114.154286 · 7.99 Impact Factor
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    ABSTRACT: The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.
    Nature Communications 06/2015; 6. DOI:10.1038/ncomms8074 · 11.47 Impact Factor
  • Bipolar Disorders 06/2015; 17(5). DOI:10.1111/bdi.12314 · 4.97 Impact Factor
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    ABSTRACT: Obesity is strongly associated with major depressive disorder (MDD) and various other diseases. Genome-wide association studies have identified multiple risk loci robustly associated with body mass index (BMI). In this study, we aimed to investigate whether a genetic risk score (GRS) combining multiple BMI risk loci might have utility in prediction of obesity in patients with MDD. Linear and logistic regression models were conducted to predict BMI and obesity, respectively, in three independent large case-control studies of major depression (Radiant, GSK-Munich, PsyCoLaus). The analyses were first performed in the whole sample and then separately in depressed cases and controls. An unweighted GRS was calculated by summation of the number of risk alleles. A weighted GRS was calculated as the sum of risk alleles at each locus multiplied by their effect sizes. Receiver operating characteristic (ROC) analysis was used to compare the discriminatory ability of predictors of obesity. In the discovery phase, a total of 2,521 participants (1,895 depressed patients and 626 controls) were included from the Radiant study. Both unweighted and weighted GRS were highly associated with BMI (P <0.001) but explained only a modest amount of variance. Adding 'traditional' risk factors to GRS significantly improved the predictive ability with the area under the curve (AUC) in the ROC analysis, increasing from 0.58 to 0.66 (95% CI, 0.62-0.68; χ(2) = 27.68; P <0.0001). Although there was no formal evidence of interaction between depression status and GRS, there was further improvement in AUC in the ROC analysis when depression status was added to the model (AUC = 0.71; 95% CI, 0.68-0.73; χ(2) = 28.64; P <0.0001). We further found that the GRS accounted for more variance of BMI in depressed patients than in healthy controls. Again, GRS discriminated obesity better in depressed patients compared to healthy controls. We later replicated these analyses in two independent samples (GSK-Munich and PsyCoLaus) and found similar results. A GRS proved to be a highly significant predictor of obesity in people with MDD but accounted for only modest amount of variance. Nevertheless, as more risk loci are identified, combining a GRS approach with information on non-genetic risk factors could become a useful strategy in identifying MDD patients at higher risk of developing obesity.
    BMC Medicine 04/2015; 13(1):86. DOI:10.1186/s12916-015-0334-3 · 7.25 Impact Factor
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    ABSTRACT: Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10−9) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10−14). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10−9) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10−11). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.
    Nature Communications 03/2015; 6. DOI:10.1038/ncomms6681 · 11.47 Impact Factor
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    ABSTRACT: Defining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD. In this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset. We found an enrichment of Turner's syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79-33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002). After statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
    Biological psychiatry 02/2015; 54. DOI:10.1016/j.biopsych.2015.02.025 · 10.26 Impact Factor
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    ABSTRACT: Background There has been increasing interest in the association between childhood trauma and psychosis. Proposals for potential mechanisms involved include affective dysregulation and cognitive appraisals of threat. Aims To establish if, within bipolar disorder, childhood events show a significant association with psychosis, and in particular with symptoms driven by dysregulation of mood or with a persecutory content. Method Data on lifetime-ever presence of psychotic symptoms were determined by detailed structured interview with case-note review (n = 2019). Childhood events were recorded using a self-report questionnaire and case-note information. Results There was no relationship between childhood events, or childhood abuse, and psychosis per se. Childhood events were not associated with an increased risk of persecutory or other delusions. Significant associations were found between childhood abuse and auditory hallucinations, strongest between sexual abuse and mood congruent or abusive voices. These relationships remain significant even after controlling for lifetime-ever cannabis misuse. Conclusions Within affective disorder, the relationship between childhood events and psychosis appears to be relatively symptom-specific. It is possible that the pathways leading to psychotic symptoms differ, with delusions and non-hallucinatory symptoms being influenced less by childhood or early environmental experience. Royal College of Psychiatrists.
    The British journal of psychiatry: the journal of mental science 01/2015; 206(3). DOI:10.1192/bjp.bp.114.152611 · 7.99 Impact Factor
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    ABSTRACT: Background Individuals with a mental health disorder appear to be at increased risk of medical illness. Aims To examine rates of medical illnesses in patients with bipolar disorder (n = 1720) and to examine the clinical course of the bipolar illness according to lifetime medical illness burden. Method Participants recruited within the UK were asked about the lifetime occurrence of 20 medical illnesses, interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to DSM-IV criteria. Results We found significantly increased rates of several medical illnesses in our bipolar sample. A high medical illness burden was associated with a history of anxiety disorder, rapid cycling mood episodes, suicide attempts and mood episodes with a typically acute onset. Conclusions Bipolar disorder is associated with high rates of medical illness. This comorbidity needs to be taken into account by services in order to improve outcomes for patients with bipolar disorder and also in research investigating the aetiology of affective disorder where shared biological pathways may play a role.
    The British journal of psychiatry: the journal of mental science 10/2014; 205(6). DOI:10.1192/bjp.bp.114.152249 · 7.99 Impact Factor
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    ABSTRACT: Objectives Darier disease is an autosomal dominant skin disorder caused by mutations in the ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 (ATP2A2) gene and previously reported to cosegregate with bipolar disorder and schizophrenia in occasional pedigrees. It is, however, unknown whether these associations exist also in the general population, and the objective of this study was to examine this question. Methods We compared a national sample of individuals with Darier disease and their first-degree relatives with matched unexposed individuals from the general population and their first-degree relatives, respectively. To examine risks for bipolar disorder and schizophrenia, risk ratios and 95% confidence intervals (CIs) were estimated using conditional logistic regressions. Results Individuals with Darier disease had a 4.3 times higher risk of being diagnosed with bipolar disorder (95% CI: 2.6–7.3) and a 2.3 times higher risk of being diagnosed with schizophrenia (95% CI: 1.1–5.2) than matched individuals from the general population. Relatives of individuals with Darier disease had a 1.6 times higher risk of having bipolar disorder (95% CI: 1.1–2.5) than relatives of matched individuals from the general population, but no increased risk of schizophrenia (risk ratio = 0.8, 95% CI: 0.4–1.8). Conclusions The association between Darier disease and bipolar disorder is manifest also in the population, and our data suggest that genetic variability within the ATP2A2 gene that causes Darier disease also confers susceptibility for bipolar disorder. The Darier-causing mutations merit additional attention in molecular genetic research on bipolar disorder.
    Bipolar Disorders 09/2014; 17(3). DOI:10.1111/bdi.12257 · 4.97 Impact Factor
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    ABSTRACT: Background: Clinical, genetic and neuroimaging studies indicated strong evidence against traditional diagnostic separation of bipolar disorder from schizophrenia. In this study, we aimed to evaluate hypomanic symptoms and influence on general functioning among psychotic patients. Subjects and methods: Patients with schizophrenia and other psychotic disorders were assessed between June and September 2010. Positive and Negative Symptom Scale (PANSS), Hypomania Check List-32 (HCL-32), Mood Disorders Questionnaire (MDQ) and General Assessment of Functioning Scale (GAS) were applied to all 93 patients. Answers of self-rating scales were confirmed with hospital records. Results: Mean age was 35.7 ± 9.5 years, mean age of onset was 20.3 ± 5.3 years and duration of illness was 15.4 ± 9.2 years. 30.1% of the patients, had a history of mood stabilizer treatment taken at least one month while one five of the patients had different psychiatric diagnosis other than current diagnosis. 26.9% of the patients with psychotic disorders had positive scores on both MDQ and HCL-32 but there were no significant difference between patients in terms of general functioning (p = 0.82). Conclusions: As reported in this study, there is no simple, clear-cut between schizophrenia and bipolar affective disorder.
    Psychiatria Danubina 09/2014; 26(3):200-204. · 1.30 Impact Factor
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    Nature Communications 09/2014; 5:4871. · 11.47 Impact Factor
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    Nature Communications 09/2014; 5:4871. · 11.47 Impact Factor
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    ABSTRACT: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
    Nature 07/2014; 511(7510):421-427. DOI:10.1038/nature13595 · 41.46 Impact Factor
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    ABSTRACT: Epidemiological studies have recognized a genetic diathesis for suicidal behavior, which is independent of other psychiatric disorders. Genome-wide association studies (GWAS) on suicide attempt (SA) and ideation have failed to identify specific genetic variants. Here, we conduct further GWAS and for the first time, use polygenic score analysis in cohorts of patients with mood disorders, to test for common genetic variants for mood disorders and suicide phenotypes. Genome-wide studies for SA were conducted in the RADIANT and GSK-Munich recurrent depression samples and London Bipolar Affective Disorder Case-Control Study (BACCs) then meta-analysis was performed. A GWAS on suicidal ideation during antidepressant treatment had previously been conducted in the Genome Based Therapeutic Drugs for Depression (GENDEP) study. We derived polygenic scores from each sample and tested their ability to predict SA in the mood disorder cohorts or ideation status in the GENDEP study. Polygenic scores for major depressive disorder, bipolar disorder and schizophrenia from the Psychiatric Genomics Consortium were used to investigate pleiotropy between psychiatric disorders and suicide phenotypes. No significant evidence for association was detected at any SNP in GWAS or meta-analysis. Polygenic scores for major depressive disorder significantly predicted suicidal ideation in the GENDEP pharmacogenetics study and also predicted SA in a combined validation dataset. Polygenic scores for SA showed no predictive ability for suicidal ideation. Polygenic score analysis suggests pleiotropy between psychiatric disorders and suicidal ideation whereas the tendency to act on such thoughts may have a partially independent genetic diathesis. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2014; 165(5). DOI:10.1002/ajmg.b.32247 · 3.42 Impact Factor
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    ABSTRACT: Objectives: To compare rates of bipolar episodes following miscarriage and termination with those occurring in the postpartum period. Methods: Information in relation to pregnancy and childbirth was gathered retrospectively for 1,283 women with broadly defined bipolar disorder by interview and case-notes review. Results: Rates of mania or affective psychosis were significantly higher after full-term delivery than after termination (p < 0.001) or miscarriage (p < 0.001). Rates of non-psychotic major depression were similar following full-term deliveries, miscarriages (p = 0.362), and terminations (p = 0.301). Conclusions: While women with bipolar disorder and their clinicians should be aware of the possible onset of depression in the weeks following miscarriage or termination, episodes of mania or affective psychosis are less common in comparison with the high rates observed in the postpartum period.
    Bipolar Disorders 06/2014; 17(1). DOI:10.1111/bdi.12217 · 4.97 Impact Factor

Publication Stats

17k Citations
2,213.35 Total Impact Points


  • 2005–2015
    • Cardiff University
      • • MRC Centre for Neuropsychiatric Genetics & Genomics
      • • Department of Psychological Medicine and Neurology
      • • School of Medicine
      • • Centre for Neuropsychiatric Genetics and Genomics
      Cardiff, Wales, United Kingdom
  • 1999–2014
    • University of South Wales
      Понтиприте, Wales, United Kingdom
  • 2013
    • University of Oslo
      • Division of Mental Health and Addiction
      Kristiania (historical), Oslo, Norway
  • 2012
    • Royal College of Psychiatrists
      Londinium, England, United Kingdom
  • 2011
    • Ludwig-Maximilians-University of Munich
      • Department of Psychiatry
      München, Bavaria, Germany
  • 2009–2011
    • University of Bristol
      • School of Experimental Psychology
      Bristol, England, United Kingdom
    • McMaster University
      • Department of Psychiatry and Behavioural Neurosciences
      Hamilton, Ontario, Canada
  • 1993–2011
    • University of Wales
      • College of Medicine
      Cardiff, Wales, United Kingdom
    • Mandeville Regional Hospital
      Мандевиль, Manchester, Jamaica
  • 1998–2009
    • University of Birmingham
      • School of Clinical and Experimental Medicine
      Birmingham, England, United Kingdom
  • 2006
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
  • 2001
    • St. James's Hospital
      Dublin, Leinster, Ireland