title: Pleckstrin homology domain containing 6 protein (PLEKHA6) polymorphisms are associated with psychopathology and response to treatment in schizophrenic patients.
abstract: Pleckstrin homology domain (PH domain) comprises approximately 120 amino acids and is integrated in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phosphatidylinositol (3,4,5)-triphosphate and phosphatidylinositol (4,5)-biphosphate and proteins such as the βγ-subunits of heterotrimeric G proteins and protein kinase C. Associations with psychiatric diseases have not been investigated yet. To identify genes involved in response to antipsychotics, mice were treated with haloperidol (1mg/kg, n = 11) or saline (n = 12) for one week. By analyzing microarray data, we observed an increase of pleckstrin homology domain containing 6 (PLEKHA6) gene expression. Furthermore, we genotyped 263 schizophrenic patients, who were treated monotherapeutically with different antipsychotics within randomized-controlled trials. Psychopathology was measured weekly using the PANSS for a minimum of four and a maximum of twelve weeks. Correlations between PANSS subscale scores at baseline and PANSS improvement scores after four weeks of treatment and genotypes were calculated by using a linear model for all investigated SNPs. We found associations between four PLEKHA6 polymorphisms (rs17333933 (T/G), rs3126209 (C/T), rs4951338 (A/G) and rs100900571 (T/C)) and different PANSS subscales at baseline. Furthermore two different polymorphisms (rs7513240 (T/C), rs4951353 (A/G)) were found to be associated with therapy response in terms of a significant correlation with different PANSS improvement subscores after four weeks of antipsychotic treatment. Our observation of an association between genetic polymorphisms of a protein of the PH domain and psychopathology data in schizophrenic patients might be indicative for an involvement of PLEKHA6 in the pathophysiology of schizophrenia and the therapy response towards antipsychotics.
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy. Electronic address: ilja.spellmann@bkh-kaufbeuren.de.
authors.forename: Ilja
authors.initials: I
authors.lastname: Spellmann
authors.affiliation: Martin Luther University of Halle (Saale), Department of Psychiatry and Psychotherapy.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy.
authors.forename: Richard
authors.initials: R
authors.lastname: Musil
authors.forename: Sebastian
authors.initials: S
authors.lastname: Meyerwas
authors.affiliation: Martin Luther University of Halle (Saale), Department of Psychiatry and Psychotherapy.
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.affiliation: LVR-Hospital Essen, Department of Psychiatry and Psychotherapy.
authors.forename: Just
authors.initials: J
authors.lastname: Genius
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy.
authors.forename: Peter
authors.initials: P
authors.lastname: Zill
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Dehning
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy.
authors.forename: Anja
authors.initials: A
authors.lastname: Cerovecki
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy.
authors.forename: Florian
authors.initials: F
authors.lastname: Seemüller
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schennach
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Hartmann
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy.
authors.forename: Martin
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy.
authors.forename: Norbert
authors.initials: N
authors.lastname: Müller
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Bezirkskrankenhaus Kaufbeuren, Department of Psychiatry and Psychotherapy.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Möller
authors.affiliation: Ludwig Maximilians University of Munich, Department of Psychiatry and Psychotherapy and Vinzenz-von-Paul-Hospital Rottweil.
authors.forename: Michael
authors.initials: M
authors.lastname: Riedel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006220:Haloperidol / Q000494:pharmacology / Q000627:therapeutic use; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D051381:Rats; D020318:Rats, Long-Evans; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000593112:PLEKHA6 protein, human; D006220:Haloperidol
keywords: Antipsychotics; Intracellular signaling; Pharmacogenetics; Pleckstrin homology domain; Schizophrenia; Therapy response