- My primary expertise is in the investigation of the hereditary causes of human inherited disorders, focusing on the r... moreMy primary expertise is in the investigation of the hereditary causes of human inherited disorders, focusing on the reasons behind treatment failure. After conducting my PhD research in the Medical Research Council (Toxicology Unit, Carshalton, United Kingdom), I worked as a junior Lecturer in the University of the Balearic Islands (Majorca, Spain), before moving back to the UK to work in the Institute of Psychiatry (King´s College London) for over 18 years. During that time, I made significant contributions to the search for genes related to variability in response to drugs, particularly of CNS medications. My team published several leading papers in the field, and produced the first test for the prediction of response to antipsychotics using genetic information (Arranz et al., Lancet, 2000), and later developed two more prediction tests for olanzapine and risperidone. I co-funded, with colleagues from the Institute of Psychiatry (King's College London), a spin-out company focused on the development of prediction tests that operated from 2006 to 2009, when it was bought by Avacta.
Since 2011, I am the head of a research laboratory unit at the Hospital Universitari Mútua Terrassa (Barcelona, Spain), where I am leading several research projects in psychiatry, oncology, immunology and cardiovascular disorders using candidate gene, GWAs and EWAs strategies. With the support of several national and international teams we are investigating the genetic determinants of response and side effects associated with pharmacological treatments in mental disorders and other medical areas. I have also supervised 5 PhD theses and more than 15 Master theses, and contribute to several masters and post-graduate courses in Genomics and Pharmacogenomics. I have published more than 130 articles and reviews in international publications (h index=41) and frequently present our work in national and international conferences. Finally, I have funded a second spin-out company (Personalised Medicine Gene Experts, PMGexperts, www.pmgenexperts.com) dedicated to consulting on genetic and pharmacogenetic tests, directed to health professionals and users, in collaboration with leading Spanish geneticists.edit
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The pathogenesis of IPD remains unknown, especially among middle-aged individuals without risk factors (WRF). The aim of the present study was to investigate the role of single nucleotide polymorphisms (SNP) within key genes involved in... more
The pathogenesis of IPD remains unknown, especially among middle-aged individuals without risk factors (WRF). The aim of the present study was to investigate the role of single nucleotide polymorphisms (SNP) within key genes involved in innate immune response on IPD susceptibility. Forty-three SNPs within 10 immunological genes were investigated in a cohort of 144 Caucasian IPD patients and 280 ethnically matched controls. The allele distribution of the NFKBIA rs1050851 and NFKBIE rs2282151 variants were associated with IPD susceptibility (χ = 4.23, p = 0.04 and χ = 5.13, p = 0.02, respectively). Additionally, the genotype distribution of NFKBIZ rs645781 (χ = 8.25, p = 0.02) and IL1R1 rs3917254 (χ = 6.70, p = 0.04) were also associated with IPD risk. When only IPD-WRF patients were considered; the allele distribution of IL1R1 rs2160227 (χ = 5.62, p = 0.03), rs13020778 (χ = 5.73, p = 0.02), rs3917267 (χ = 3.72, p = 0.05) and IL4 rs2227284 (χ = 3.76, p = 0.05) and the genotype distrib...
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Wolfram syndrome (DIDMOAD syndrome; MIM 222300) is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy. Previous linkage analysis of multiply affected families... more
Wolfram syndrome (DIDMOAD syndrome; MIM 222300) is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy. Previous linkage analysis of multiply affected families indicated that the gene for Wolfram syndrome is on chromosome 4p, and it produced no evidence for locus heterogeneity. We have investigated 12 U.K. families with Wolfram syndrome, and we report confirmation of linkage to chromosome 4p, with a maximum two-point LOD score of 4.6 with DRD5, assuming homogeneity, and of 5.1, assuming heterogeneity. Overlapping multipoint analysis using six markers at a time produced definite evidence for locus heterogeneity: the maximum multipoint LOD score under homogeneity was <2, whereas when heterogeneity was allowed for an admixture a LOD of 6.2 was obtained in the interval between D4S432 and D4S431, with the peak close to the marker D4S3023. One family with an atypical phenotype was definitely unlinked to the reg...
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Interest exists in identifying the factors that specifically contribute to the increased prevalence of cardiovascular disease observed in psychiatric disease. The apolipoprotein-E (APOE) gene codes for a protein that has a key role in... more
Interest exists in identifying the factors that specifically contribute to the increased prevalence of cardiovascular disease observed in psychiatric disease. The apolipoprotein-E (APOE) gene codes for a protein that has a key role in metabolism of cholesterol and triglycerides, with increased levels of apoE found in specific areas of post-mortem schizophrenic brains. This study investigated whether apoE variants influence the prevalence of cardiovascular risk factors (obesity, diabetes and dyslipidaemia), in patients receiving antipsychotic treatment, due to extension of the risk seen in the general population, but also due to the role of the APOE gene in mediating antipsychotic-induced side effects. Seven polymorphisms (rs741780, rs483082, rs429358, rs7412, rs10119, rs439401 and rs405509) were genotyped in 427 American Caucasian patients who were either receiving, or had been prescribed risperidone. Our results support the hypothesis that APOE gene variants influence the prevalenc...
Research Interests: Cardiovascular disease, Cardiovascular Risk, Humans, Internal Medicine, Hypertension, and 15 moreDiabetes mellitus, Hypercholesterolemia, Apolipoprotein E, Body Mass Index, Genotype, Cross Section, Cardiovascular Risk Factor, Cardiovascular Diseases, Antipsychotic, General Population, alleles, Antipsychotic agents, european psychiatry, Medical and Health Sciences, and Hyperlipidemias
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Background:GAP(genesandpsychosis) is a case-control studyof first episode psychosis conducted in London and Cambridge, which aims to identify genes conferring susceptibility to psychosis, and associated phenotypes including cognitive... more
Background:GAP(genesandpsychosis) is a case-control studyof first episode psychosis conducted in London and Cambridge, which aims to identify genes conferring susceptibility to psychosis, and associated phenotypes including cognitive dysfunction and cerebral morphology. Methods:First episode psychosis cases have been recruited in South London and Maudsley NHS Trust and in Cambridge. A variety of demographic and clinical data have been collected. In a subset of these, neurocognitive assessments and MRIs have been performed. Samples have been taken for DNA, and in a subset for RNA and proteomic analysis. Genetic association analysis is being undertaken using a candidate gene approach. The genes chosen for the first wave of analysis include the current most promising candidates for suscept-ibility to psychosis (NRG1, dysbindin, DISC1, G72, etc) as well as candidates for susceptibility to cannabis misuse (COMT), cognitive dysfunction, dysregulation of brain morphology or susceptibility to bipolar disorder (e.g. LIS1), and candidates in the dopamine and serotonin neurotransmitter systems. Results:DNA has been collected from 302 patients to date. Of these, 72%aremale, and themeanage is 25 years; 187 areCaucasian; 115 are of black origin; and the rest are of other ormixed ethnicity. Genotyping is being undertaken in this sample and in matched controls. Conclusions:Data is being reported separately for a number of phenotypes forwhich there is already somedata. This presentationwill report the overall genetic association results
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Research Interests: Wiley and NMDA receptor
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Borderline personality disorder (BPD) is a severe and highly prevalent psychiatric disorder, more common in females than in males and with notable differences in presentation between genders. Recent studies have shown that epigenetic... more
Borderline personality disorder (BPD) is a severe and highly prevalent psychiatric disorder, more common in females than in males and with notable differences in presentation between genders. Recent studies have shown that epigenetic modifications such as DNA methylation may modulate gene × environment interactions and impact on neurodevelopment. We conducted an epigenome wide study (Illumina Infinium HumanMethylation450k beadchip) in a group of BPD patients with (N = 49) and without (N = 47) childhood traumas and in a control group (N = 44). Results were confirmed in a replication cohort (N = 293 BPD patients and N = 114 controls) using EpiTYPER assays. Differentially methylated CpG sites were observed in several genes and intragenic regions in the X chromosome (PQBP1, ZNF41, RPL10, cg07810091 and cg24395855) and in chromosome 6 (TAP2). BPD patients showed significantly lower methylation levels in these CpG sites than healthy controls. These differences seemed to be increased by th...
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Disorders of the brain exhibit considerable epidemiological comorbidity and frequently share symptoms, provoking debate about the extent of their etiologic overlap. We quantified the genetic sharing of 25 brain disorders based on summary... more
Disorders of the brain exhibit considerable epidemiological comorbidity and frequently share symptoms, provoking debate about the extent of their etiologic overlap. We quantified the genetic sharing of 25 brain disorders based on summary statistics from genome-wide association studies of 215,683 patients and 657,164 controls, and their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders show substantial sharing of common variant risk, while neurological disorders appear more distinct from one another. We observe limited evidence of sharing between neurological and psychiatric disorders, but do identify robust sharing between disorders and several cognitive measures, as well as disorders and personality types. We also performed extensive simulations to explore how power, diagnostic misclassification and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a source of risk for brain diso...
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Clozapine response and genetic variation in neurotransmitter receptor targets David A. Collier1, Maria J. Arranz2, Sarah Osborne2, Katherine J. Aitchison2 ... and 549C/T plus changes resulting in Gly272Asp and Prol6Leu in the coding... more
Clozapine response and genetic variation in neurotransmitter receptor targets David A. Collier1, Maria J. Arranz2, Sarah Osborne2, Katherine J. Aitchison2 ... and 549C/T plus changes resulting in Gly272Asp and Prol6Leu in the coding region (Erdmann et aL, 1995; Nakhai et aL ...
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We have performed a case-control analysis of dopamine D2-like receptor (DRD2, DRD3 and DRD4) gene polymorphisms in 118 Han Chinese cases with bipolar affective disorder and 196 control subjects, and replication analysis in 157 English... more
We have performed a case-control analysis of dopamine D2-like receptor (DRD2, DRD3 and DRD4) gene polymorphisms in 118 Han Chinese cases with bipolar affective disorder and 196 control subjects, and replication analysis in 157 English cases and 143 control subjects. We found association between a functional DRD2 promoter variant (P = 0.03 by allele) and the DRD2 taq1A polymorphism (P = 0.001 by allele) in Chinese bipolar disorder patients. However, this finding was not replicated in the Caucasian subjects, indicating that the significant association we observed in the Chinese population is a false positive finding. An alternative explanation is that these polymorphisms are risk factors in Chinese but not Caucasian populations, a hypothesis which seems unlikely in view of the similarity of the clinical characteristics of bipolar disorder in the two populations. We also report a novel, rare one-repeat variant of the DRD4 exon 3 VNTR repeat in Chinese populations, which appears to be absent in Caucasians and is not associated with disease.
Research Interests: Genetics, Bipolar Disorder, Humans, Female, Genetic determinism, and 15 moreGene, Aged, Gene Polymorphism, Gen, Genotype, Adult, European Continental Ancestry Group, Asian Continental Ancestry Group, Genetic variation, Chi Square Distribution, Bipolar Affective Disorder, Case Control Studies, Association Analysis, False Positive, and alleles
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Preterm birth is associated with a range of neurodevelopmental deficits, including corpus callosum (CC) abnormalities, which persist into late adolescence and early adulthood. A common single-nucleotide polymorphism in the... more
Preterm birth is associated with a range of neurodevelopmental deficits, including corpus callosum (CC) abnormalities, which persist into late adolescence and early adulthood. A common single-nucleotide polymorphism in the catechol-o-methyl transferase (COMT) gene (Val158Met) is associated with cognition and brain structure and may play a role in neurodevelopment. It is not known whether this polymorphism is associated with CC morphometry in individuals born preterm. Structural MRI scans were acquired in 33 adults born very preterm (before 33 weeks&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; gestation) and 29 healthy controls. DNA was collected and COMT Val158Met polymorphism status determined using standard available assays. The mid-sagittal area of four antero-posterior subdivisions of the CC was measured. The effect of COMT Val158Met polymorphism on cross-sectional CC areas was studied using multivariate analysis and generalised linear models, adjusted for the effects of the clinical sample group (preterm vs. control), age and sex. The COMT Val/Val homozygous genotype was observed to be significantly associated with reduced size of the total corpus callosum, and this relationship was present for the anterior, midposterior and posterior quarters of the CC. The COMT Val158Met polymorphism possibly influences the morphometry of the corpus callosum associated with very preterm births. Further studies with larger sample sizes are warranted to conclusively establish the effects of individual genotypes of the COMT gene on corpus callosum in preterm born adults.
Research Interests: Polymorphism, Neurodevelopment, Adolescent, DNA, Humans, and 15 moreCorpus Callosum, Female, Neuroimage, Male, Genes, Newborn Infant, Gene Polymorphism, Genotype, Brain Structure, Amino Acid Substitution Rates, Preterm Birth, COMT, Psychology and Cognitive Sciences, Patient selection, and Medical and Health Sciences
Research Interests: Psychology, Polymorphism, Linear models, Psychological Medicine, Endophenotypes, and 15 moreHumans, Psychological, Female, Male, Aged, Middle Aged, Family Health, Adult, Auditory evoked Potentials, Psychotic Disorders, Psychol, Neurosciences, Logistic Models, Clinical Psychopharmacology, and Pharmacology and pharmaceutical sciences
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There is evidence to suggest that the alpha(2A)-adrenergic receptor may be involved in schizophrenia. With attention directed at the upstream regulatory region of the gene which codes for this receptor (ADRA2A), we proposed that single... more
There is evidence to suggest that the alpha(2A)-adrenergic receptor may be involved in schizophrenia. With attention directed at the upstream regulatory region of the gene which codes for this receptor (ADRA2A), we proposed that single nucleotide polymorphisms (SNPs) within this region influences susceptibility to schizophrenia by altering the expression of this receptor. We opted to test for an influence on susceptibility by association study using 112 schizophrenic/schizoaffective disorder patients and 159 controls. The region of interest was screened for SNPs using a combination of bioinformatic searches and sequencing. A total of nine SNPs were discovered, of which four (-5972-G/A, -2211-A/T, -1291-C/G and -261-G/A) were genotyped in the entire clinical sample. No associations were evident, suggesting no influence for these SNPs in susceptibility to schizophrenia.