title: Genome-wide association study identifies common variants associated with pharmacokinetics of psychotropic drugs.
abstract: Individual variation in pharmacokinetics of psychotropic drugs, particularly metabolism, is an important factor to consider in pharmacological treatment in psychiatry. A large proportion of this variance is still not accounted for, but evidence so far suggests the involvement of genetic factors. We performed a genome-wide association study (GWAS) with concentration dose ratio (CDR) as sub-phenotype to assess metabolism rate of psychotropic drugs in a homogenous Norwegian sample of 1334 individuals diagnosed with a severe mental disorder. The GWAS revealed one genome-wide significant marker (rs16935279, p-value=3.95×10(-10), pperm=7.5×10(-4)) located in an intronic region of the lncRNA LOC100505718. Carriers of the minor allele have a lower metabolism rate of antiepileptic drugs compared to major allele carriers. In addition, several nominally significant associations between single nucleotide polymorphisms (SNPs) and CDR for antipsychotic, antidepressant and antiepileptic drugs were disclosed. We consider standardised CDR to be a useful measure of the metabolism rate of a drug. The present findings indicate that common gene variants could affect the metabolism of psychotropic drugs. This warrants further investigations into the functional mechanisms involved as it may lead to identification of predictive markers as well as novel drug targets.
authors.affiliation: Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway Department of Medical Genetics, Oslo University Hospital, Oslo, Norway lavinia.athanasiu@medisin.uio.no.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Athanasiu
authors.affiliation: Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, Oslo University, Oslo, Norway.
authors.forename: Lisa-Lena H
authors.initials: LL
authors.lastname: Smorr
authors.affiliation: Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, Oslo University, Oslo, Norway.
authors.forename: Martin
authors.initials: M
authors.lastname: Tesli
authors.affiliation: Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, Oslo University, Oslo, Norway.
authors.forename: Jan I
authors.initials: JI
authors.lastname: Røssberg
authors.affiliation: Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Ida E
authors.initials: IE
authors.lastname: Sønderby
authors.affiliation: Department of Clinical Pharmacology, St Olav University Hospital, Trondheim, Norway Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Olav
authors.initials: O
authors.lastname: Spigset
authors.affiliation: Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.affiliation: Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
mesh_terms: D000328:Adult; D015415:Biomarkers; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy* / Q000235:genetics*; D008875:Middle Aged; D009664:Norway; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011619:Psychotropic Drugs / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D011619:Psychotropic Drugs
keywords: Genome-wide association study; concentration dose ratio; metabolism; pharmacogenomics; psychotropic; serum level; single nucleotide polymorphism