title: Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach.
abstract: BACKGROUND
  Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia.
  
  
  METHODS
  We defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36 989 cases and 113 075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance.
  
  
  RESULTS
  We combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029).
  
  
  CONCLUSIONS
  Our results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism.
  
  
  BACKGROUND
  US National Institutes of Health.
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, New York, NY, USA; Institute for Genomics and Multiscale Biology, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: douglas.ruderfer@mssm.edu.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Ruderfer
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, New York, NY, USA; Institute for Genomics and Multiscale Biology, New York, NY, USA.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Charney
authors.affiliation: Institute for Genomics and Multiscale Biology, New York, NY, USA; Department of Genetics and Genomic Sciences, New York, NY, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Readhead
authors.affiliation: Institute for Genomics and Multiscale Biology, New York, NY, USA; Department of Genetics and Genomic Sciences, New York, NY, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kidd
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kähler
authors.affiliation: Department of Pharmacology and Systems Therapeutics, New York, NY, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kenny
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA; USA Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, CA, USA; Institute of Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keiser
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Moran
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hultman
authors.affiliation: Department of Genetics and Genomic Sciences, New York, NY, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Scott
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, New York, NY, USA; Institute for Genomics and Multiscale Biology, New York, NY, USA; Department of Genetics and Genomic Sciences, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Purcell
authors.affiliation: Institute for Genomics and Multiscale Biology, New York, NY, USA; Department of Genetics and Genomic Sciences, New York, NY, USA.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, New York, NY, USA; Institute for Genomics and Multiscale Biology, New York, NY, USA; Department of Genetics and Genomic Sciences, New York, NY, USA; Friedman Brain Institute, New York, NY, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Sklar
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D003024:Clozapine / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D020412:Multifactorial Inheritance / Q000235:genetics*; D012042:Registries; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*; D013548:Sweden; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine