title: Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs.
abstract: Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness study. Outcomes included 12 indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. A total of 21 SNPs satisfied this criterion. The top finding indicated that a SNP in Meis homeobox 2 (MEIS2) mediated the effects of risperidone on hip circumference (q=0.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q=0.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as in several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement, and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.
authors.affiliation: Center for Biomarker Research and Personalized Medicine, School of Pharmacy, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA 23223, USA. deadkins@vcu.edu
authors.forename: D E
authors.initials: DE
authors.lastname: Adkins
authors.forename: K
authors.initials: K
authors.lastname: Aberg
authors.forename: J L
authors.initials: JL
authors.lastname: McClay
authors.forename: J
authors.initials: J
authors.lastname: Bukszár
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.forename: P
authors.initials: P
authors.lastname: Jia
authors.forename: T S
authors.initials: TS
authors.lastname: Stroup
authors.forename: D
authors.initials: D
authors.lastname: Perkins
authors.forename: J P
authors.initials: JP
authors.lastname: McEvoy
authors.forename: J A
authors.initials: JA
authors.lastname: Lieberman
authors.forename: P F
authors.initials: PF
authors.lastname: Sullivan
authors.forename: E J C G
authors.initials: EJ
authors.lastname: van den Oord
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000145:classification; D001794:Blood Pressure / Q000187:drug effects; D015992:Body Mass Index; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006615:Hip; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000139:chemically induced* / Q000235:genetics; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome; D055105:Waist Circumference / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D018398:Homeodomain Proteins; C491172:MEIS2 protein, human; D014157:Transcription Factors; D002784:Cholesterol