title: Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity.
abstract: Ndel1 is a DISC1-interacting oligopeptidase that cleaves in vitro neuropeptides as neurotensin and bradykinin, and which has been associated with both neuronal migration and neurite outgrowth. We previously reported that plasma Ndel1 enzyme activity is lower in patients with schizophrenia (SCZ) compared to healthy controls (HCs). To our knowledge, no previous study has investigated the genetic factors associated with the plasma Ndel1 enzyme activity. In the current analyses, samples from 83 SCZ patients and 92 control subjects that were assayed for plasma Ndel1 enzyme activity were genotyped on Illumina Omni Express arrays. A genetic relationship matrix using genome-wide information was then used for ancestry correction, and association statistics were calculated genome-wide. Ndel1 enzyme activity was significantly lower in patients with SCZ (t=4.9; p<0.001) and was found to be associated with CAMK1D, MAGI2, CCDC25, and GABGR3, at a level of suggestive significance (p<10(-6)), independent of the clinical status. Then, we performed a model to investigate the observed differences for case/control measures. 2 SNPs at region 1p22.2 reached the p<10(-7) level. ZFPM2 and MAD1L1 were the only two genes with more than one hit at 10(-6) order of p value. Therefore, Ndel1 enzyme activity is a complex trait influenced by many different genetic variants that may contribute to SCZ physiopathology.
authors: Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, Brazil. Electronic address: aryararipe@yahoo.com.br.
authors: Ary
authors: A
authors: Gadelha
authors: Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, United Kingdom.
authors: Jonathan
authors: J
authors: Coleman
authors: Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, United Kingdom; National Institute of Health Research Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
authors: Gerome
authors: G
authors: Breen
authors: Department of Psychobiology, UNIFESP/EPM, São Paulo, Brazil.
authors: Diego Robles
authors: DR
authors: Mazzoti
authors: Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, Brazil; Department of Pharmacology, UNIFESP/EPM, São Paulo, Brazil.
authors: Camila M
authors: CM
authors: Yonamine
authors: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, United States.
authors: Renata
authors: R
authors: Pellegrino
authors: Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, Brazil; Department of Morphology and Genetics, UNIFESP/EPM, São Paulo, Brazil.
authors: Vanessa Kiyomi
authors: VK
authors: Ota
authors: Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, Brazil; Department of Morphology and Genetics, UNIFESP/EPM, São Paulo, Brazil.
authors: Sintia Iole
authors: SI
authors: Belangero
authors: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, United States.
authors: Joseph
authors: J
authors: Glessner
authors: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, United States; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
authors: Patrick
authors: P
authors: Sleiman
authors: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, United States; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
authors: Hakon
authors: H
authors: Hakonarson
authors: Department of Pharmacology, UNIFESP/EPM, São Paulo, Brazil. Electronic address: mhayashi@unifesp.br.
authors: Mirian A F
authors: MA
authors: Hayashi
authors: Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, Brazil.
authors: Rodrigo A
authors: RA
authors: Bressan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000097:blood / Q000235:genetics; D002352:Carrier Proteins / Q000097:blood* / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000097:blood / Q000235:genetics; D004268:DNA-Binding Proteins / Q000097:blood / Q000235:genetics; D004522:Educational Status; D005260:Female; D055106:Genome-Wide Association Study; D051528:Guanylate Kinases; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000097:blood* / Q000201:enzymology / Q000235:genetics*; D014157:Transcription Factors / Q000097:blood / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C501384:MAD1L1 protein, human; C421108:NDEL1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; C117427:ZFPM2 protein, human; C517601:CAMK1D protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D051528:Guanylate Kinases; C485777:MAGI2 protein, human
keywords: Biomarker; Enzyme activity; GWAS; Ndel1; Schizophrenia