Ian Richard Jones
Cardiff University
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Featured researches published by Ian Richard Jones.
Nature Genetics | 2008
Manuel A. Ferreira; Michael Conlon O'Donovan; Ian Richard Jones; Douglas M. Ruderfer; Lisa Jones; Jinbo Fan; George Kirov; Roy H. Perlis; Elaine K. Green; Jordan W. Smoller; Detelina Grozeva; Jennifer Stone; Ivan Nikolov; Marian Lindsay Hamshere; Vishwajit L. Nimgaonkar; Valentina Moskvina; Michael E. Thase; Sian Caesar; Gary S. Sachs; Jennifer Franklin; Katherine Gordon-Smith; Kristin Ardlie; Stacey Gabriel; Christine Fraser; Brendan Blumenstiel; Matthew DeFelice; Gerome Breen; Michael Gill; Derek W. Morris; Amanda Elkin
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 × 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 × 10−8, rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.
Molecular Psychiatry | 2002
Pamela Sklar; Stacey Gabriel; P. Bennett; Y-M Lim; G. Tsan; Stephen F. Schaffner; George Kirov; Ian Richard Jones; Michael John Owen; N. Craddock; J. R. DePaulo; Eric S. Lander
Identification of the genetic bases for bipolar disorder remains a challenge for the understanding of this disease. Association between 76 candidate genes and bipolar disorder was tested by genotyping 90 single-nucleotide polymorphisms (SNPs) in these genes in 136 parent-proband trios. In this preliminary analysis, SNPs in two genes, brain-derived neurotrophic factor (BDNF) and the alpha subunit of the voltage-dependent calcium channel were associated with bipolar disorder at the P<0.05 level. In view of the large number of hypotheses tested, the two nominally positive associations were then tested in independent populations of bipolar patients and only BDNF remains a potential risk gene. In the replication samples, excess transmission of the valine allele of amino acid 66 of BDNF was observed in the direction of the original result in an additional sample of 334 parent-proband trios (T/U=108/87, P=0.066). Resequencing of 29 kb surrounding the BDNF gene identified 44 additional SNPs. Genotyping eight common SNPs identified three additional markers transmitted to bipolar probands at the P < 0.05 level. Strong LD was observed across this region and all adjacent pairwise haplotypes showed excess transmission to the bipolar proband. Analysis of these haplotypes using TRANSMIT revealed a global P value of 0.03. A single haplotype was identified that is shared by both the original dataset and the replication sample that is uniquely marked by both the rare A allele of the original SNP and a novel allele 11.5 kb 3′. Therefore, this study of 76 candidate genes has identified BDNF as a potential risk allele that will require additional study to confirm.
Journal of Psychopharmacology | 2009
Guy M. Goodwin; Peter Haddad; I. N. Ferrier; Jeffrey Aronson; T R H Barnes; Andrea Cipriani; David Coghill; Seena Fazel; John Geddes; H. Grunze; Emily A. Holmes; Oliver Howes; S. Hudson; Neil Hunt; Ian Richard Jones; Iain Macmillan; H. McAllister-Williams; D. R. Miklowitz; Richard Morriss; Marcus R. Munafò; Carol Paton; B. J. Saharkian; Kate E. A. Saunders; J M A Sinclair; David Taylor; Eduard Vieta; Allan H. Young
The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.
Molecular Psychiatry | 2010
Elaine K. Green; Detelina Grozeva; Ian Richard Jones; Lisa Jones; George Kirov; Sian Caesar; Katherine Gordon-Smith; Christine Fraser; Liz Forty; E. Russell; Marian Lindsay Hamshere; Valentina Moskvina; Ivan Nikolov; Anne Farmer; Peter McGuffin; Peter Holmans; Michael John Owen; Michael Conlon O'Donovan; Nicholas John Craddock
Molecular genetic analysis offers opportunities to advance our understanding of the nosological relationship between psychiatric diagnostic categories in general, and the mood and psychotic disorders in particular. Strong evidence (P=7.0 × 10−7) of association at the polymorphism rs1006737 (within CACNA1C, the gene encoding the α-1C subunit of the L-type voltage-gated calcium channel) with the risk of bipolar disorder (BD) has recently been reported in a meta-analysis of three genome-wide association studies of BD, including our BD sample (N=1868) studied within the Wellcome Trust Case Control Consortium. Here, we have used our UK case samples of recurrent major depression (N=1196) and schizophrenia (N=479) and UK non-psychiatric comparison groups (N=15316) to examine the spectrum of phenotypic effect of the bipolar risk allele at rs1006737. We found that the risk allele conferred increased risk for schizophrenia (P=0.034) and recurrent major depression (P=0.013) with similar effect sizes to those previously observed in BD (allelic odds ratio ∼1.15). Our findings are evidence of some degree of overlap in the biological underpinnings of susceptibility to mental illness across the clinical spectrum of mood and psychotic disorders, and show that at least some loci can have a relatively general effect on susceptibility to diagnostic categories, as currently defined. Our findings will contribute to a better understanding of the pathogenesis of major psychiatric illness, and such knowledge should be useful in providing an etiological rationale for shaping psychiatric nosology, which is currently reliant entirely on descriptive clinical data.
Molecular Psychiatry | 2005
Jin Yan; Guiomar Oliveira; A. Coutinho; C. Yang; Jinong Feng; C. Katz; J. Sram; A. Bockholt; Ian Richard Jones; Nicholas John Craddock; Edwin H. Cook; Astrid M. Vicente; Steve S. Sommer
SIR—Jamain et al reported a frameshift and a mis sense mutation in the X-linked neuroligin 4 (NLGN4, MIM# 300427) and neuroligin 3 (NLGN3, MIM# 300336) genes, respectively, in Swedish families with autism. A frameshift mutation in NLGN4 appeared de novo in the mother, cosegregated with an affected brother with Asperger syndrome and was absent in a normal brother. This frameshift mutation was not present in 600 unrelated control X-chromosomes. A missense mutation in NLGN3, R451C, was found in the mother and two sibs, one with autism and another with Asperger syndrome, but no other relatives were studied. It was not found in 300 unrelated control X-chromosomes. Laumonnier et al reported a large French family in which 10 males had nonspecific X-linked mental retardation, two had autism and one had pervasive developmental disorder. All affected patients were found to have the same frameshift mutation (1253delAG) in the NLGN4 gene. One obligate female carrier had mild mental retardation. The NLGN3 and NLGN4 genes map to Xq13 and Xp22.3, respectively. The NLGN3 gene spans 32 kb, and the NLGN4 gene spans 338 kb. NLGN3 has eight exons, encoding two alternatively spliced isoforms of 828 and 848 amino acids. The NLGN4 gene contains six exons and codes for a protein of 816 amino acids. All neuroligins contain an N-terminal hydrophobic sequence with the characteristics of a cleaved signal peptide followed by a large esterase homology domain, a highly conserved single transmembrane region, and a short cytoplasmic domain. To better understand the relationship between the NLGN4 gene and autism, the coding regions and associated splice junctions of the NLGN4 gene were scanned for mutations with DOVAM-S (Detection of Virtually All Mutations-SSCP) and direct sequencing in the following subjects: 148 unrelated patients with autism (76 Midwest US Caucasians and 72 Portuguese Caucasians; 122 males and 26 females), 48 patients without autism, including 24 Midwest US Caucasian patients with attention deficit hyperactivity disorder (ADHD) and 24 UK Caucasian patients with DSM-IV Bipolar I Disorder (BPD), as well as 48 Portuguese healthy control subjects. The Portuguese autistic patients were diagnosed using DSM-IV criteria, the Autism Diagnostic Interview-Revised (ADI-R) and the Childhood Autism Rating Scale (CARS). Idiopathic subjects were included in the study after clinical assessment and screening for known medical and genetic conditions associated with autism (fragile X, chromosomal disorders, neurocutaneous syndromes, metabolic disorders, infectious diseases). Neuropsychological evaluation was performed using the Ruth Griffiths Mental Developmental Scales or the Wechsler Intelligence Scale for Children (WISC), depending on the patient’s age. The Midwest autistic patients were diagnosed as described previously. Putative missense mutations were identified once each in the NLGN4 gene in four separate autistic patients (Table 1). G99S and K378R were found in unrelated Portuguese patients. V403M and R704C were found in unrelated Midwest patients. G99, K378 and V403 are located in the esterase domain and R704 is located in the cytoplasmic domain. Three of the structural changes, K378R, V403M and R704C, occur in asymptomatic mothers, while G99S occurs in a mother with learning disability. Comprehensive mutation scanning of 48 Portuguese healthy controls and sequencing of the appropriate exons in 288 healthy controls including 96 Portuguese and 192 Midwest US Caucasians (144 males and 192 females; 528 X-chromosomes total) did not reveal these four missense variants or any other structural changes (4/148 vs 0/336, P1⁄4 0.009 or 4/174 vs 0/528, P1⁄4 0.004, when the Fisher exact test is performed with patients or X-chromosome alleles, respectively). In addition, no structural variants were found in a pilot experiment performed on patients with ADHD and BPD (24 of each). Patient #1 has a younger brother with a diagnosed language disability and a global developmental quotient below the mean (Ruth Griffiths Mental Developmental Scales score of 89), who also carries the G99S variation. Their mother, who is heterozygous for the variation, had a documented learning disability. As also found by Laumonnier et al, sequence variation in NLGN4 may be segregating with autism and cognitive disability in this family. Patient #3 had an affected brother with V403M. He had three other unaffected sibs, including a sister without the variant and two brothers with V403M who had normal social function (making friends easily), normal school performance and no attentional problems, consistent with an absence of cosegregation between this variant and any phenotype. The three unaffected children had Social Communication Questionnaire (SCQ) (Lifetime) scores of 0. Proband #3 was specifically of Irish descent. In all, 50 normal female controls of Irish descent were sequenced, none of them had V403M. Molecular Psychiatry (2005) 10, 329–335 & 2005 Nature Publishing Group All rights reserved 1359-4184/05
American Journal of Human Genetics | 2005
Matthew B. McQueen; Bernie Devlin; Stephen V. Faraone; Vishwajit L. Nimgaonkar; Pamela Sklar; Jordan W. Smoller; Rami Abou Jamra; Margot Albus; Silviu-Alin Bacanu; Miron Baron; Thomas B. Barrett; Wade H. Berrettini; Deborah Blacker; William Byerley; Sven Cichon; Willam Coryell; Nicholas John Craddock; Mark J. Daly; J. Raymond DePaulo; Howard J. Edenberg; Tatiana Foroud; Michael Gill; T. Conrad Gilliam; Marian Lindsay Hamshere; Ian Richard Jones; Lisa Jones; S H Juo; John R. Kelsoe; David Lambert; Christoph Lange
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American Journal of Psychiatry | 2010
Cathryn M. Lewis; Mandy Y.M. Ng; Amy W. Butler; Sarah Cohen-Woods; Rudolf Uher; Katrina Pirlo; Michael E. Weale; Alexandra Schosser; Ursula M. Paredes; Margarita Rivera; Nicholas John Craddock; Michael John Owen; Lisa A. Jones; Ian Richard Jones; Ania Korszun; Katherine J. Aitchison; Jianxin Shi; John P. Quinn; Alasdair MacKenzie; Peter Vollenweider; Gérard Waeber; Simon Heath; Mark Lathrop; Pierandrea Muglia; Michael R. Barnes; John C. Whittaker; Frederica Tozzi; Florian Holsboer; Martin Preisig; Anne Farmer
Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.
Molecular Psychiatry | 1998
George Kirov; Kieran C. Murphy; Maria Arranz; Ian Richard Jones; F McCandles; Hiroshi Kunugi; Robin M. Murray; P. McGuffin; D. A. Collier; Michael John Owen; N. Craddock
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.
Molecular Psychiatry | 2013
Marian Lindsay Hamshere; James Tynan Rhys Walters; Rhodri Smith; Alexander Richards; Elaine K. Green; Detelina Grozeva; Ian Richard Jones; Elizabeth Forty; Lisa A. Jones; Katherine Gordon-Smith; B. Riley; T. O'Neill; Kenneth S. Kendler; Pamela Sklar; S Purcell; J. Kranz; Derek W. Morris; Michael Gill; Peter Holmans; Nicholas John Craddock; Aiden Corvin; Michael John Owen; Michael Conlon O'Donovan
Catechol-O-methyltransferase (COMT) plays a major role in the breakdown of catecholamines.1 An amino acid polymorphism (val-108-met) determines high and low activity of the enzyme.2,3 A recent study in a small sample of patients with velo-cardio-facial syndrome who had bipolar affective disorder suggested that the Met (low activity) COMT allele might be associated with rapid-cycling in this population.4 We therefore tested the hypothesis that the Met allele might be associated with rapid cycling bipolar disorder in the wider population. We studied a sample of British Caucasian DSM-IV bipolar patients, of whom 55 met criteria for rapid cycling at some time during the illness and 110 met stringent criteria for a definite non-rapid cycling course. The COMT genotype was determined using a PCR assay. The low activity allele was more frequent in the group of rapid cyclers: 0.55 vs 0.42 (one-tailed χ2 = 5.12, d.f. = 1, P = 0.012), and bearers of low activity alleles showed a dose-dependent increased risk of lifetime occurrence of rapid cycling: χ2 test of linear association = 4.84, d.f. = 1, P = 0.014. Our data support the hypothesis that variation in the COMT gene modifies the course of bipolar disorder.
Archives of General Psychiatry | 2010
Detelina Grozeva; George Kirov; Dobril Ivanov; Ian Richard Jones; Lisa Jones; Elaine K. Green; David St Clair; Allan H. Young; Nicol Ferrier; Anne Farmer; Peter McGuffin; Peter Holmans; Michael John Owen; Michael C. O’Donovan; Nicholas John Craddock
The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78–100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.