PMID- 36055211
OWN - NLM
STAT- MEDLINE
DCOM- 20220908
LR  - 20230308
IS  - 1537-6605 (Electronic)
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 109
IP  - 9
DP  - 2022 Sep 1
TI  - Genetics-informed precision treatment formulation in schizophrenia and bipolar 
      disorder.
PG  - 1620-1637
LID - S0002-9297(22)00315-9 [pii]
LID - 10.1016/j.ajhg.2022.07.011 [doi]
AB  - Genetically informed drug development and repurposing is an attractive prospect 
      for improving patient outcomes in psychiatry; however, the effectiveness of these 
      endeavors is confounded by heterogeneity. We propose an approach that links 
      interventions implicated by disorder-associated genetic risk, at the population 
      level, to a framework that can target these compounds to individuals. 
      Specifically, results from genome-wide association studies are integrated with 
      expression data to prioritize individual "directional anchor" genes for which the 
      predicted risk-increasing direction of expression could be counteracted by an 
      existing drug. While these compounds represent plausible therapeutic candidates, 
      they are not likely to be equally efficacious for all individuals. To account for 
      this heterogeneity, we constructed polygenic scores restricted to variants 
      annotated to the network of genes that interact with each directional anchor 
      gene. These metrics, which we call a pharmagenic enrichment score (PES), identify 
      individuals with a higher burden of genetic risk, localized in biological 
      processes related to the candidate drug target, to inform precision drug 
      repurposing. We used this approach to investigate schizophrenia and bipolar 
      disorder and reveal several compounds targeting specific directional anchor genes 
      that could be plausibly repurposed. These genetic risk scores, mapped to the 
      networks associated with target genes, revealed biological insights that cannot 
      be observed in undifferentiated genome-wide polygenic risk score (PRS). For 
      example, an enrichment of these partitioned scores in schizophrenia cases with 
      otherwise low PRS. In summary, genetic risk could be used more specifically to 
      direct drug repurposing candidates that target particular genes implicated in 
      psychiatric and other complex disorders.
CI  - Copyright (c) 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Reay, William R
AU  - Reay WR
AD  - Centre for Complex Disease and Precision Medicine, School of Biomedical Sciences 
      and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia; Precision 
      Medicine Research Program, Hunter Medical Research Institute, Newcastle, NSW, 
      Australia.
FAU - Geaghan, Michael P
AU  - Geaghan MP
AD  - Kinghorn Centre for Clinical Genomics, Garvan Medical Research Institute, 
      Darlinghurst, NSW, Australia.
FAU - Atkins, Joshua R
AU  - Atkins JR
AD  - Centre for Complex Disease and Precision Medicine, School of Biomedical Sciences 
      and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.
FAU - Carr, Vaughan J
AU  - Carr VJ
AD  - Discipline of Psychiatry and Mental Health, School of Clinical Medicine, 
      University of New South Wales, Randwick, NSW, Australia; Neuroscience Research 
      Australia, Sydney, NSW, Australia; Department of Psychiatry, Monash University, 
      Melbourne, VIC, Australia.
FAU - Green, Melissa J
AU  - Green MJ
AD  - Discipline of Psychiatry and Mental Health, School of Clinical Medicine, 
      University of New South Wales, Randwick, NSW, Australia; Neuroscience Research 
      Australia, Sydney, NSW, Australia.
FAU - Cairns, Murray J
AU  - Cairns MJ
AD  - Centre for Complex Disease and Precision Medicine, School of Biomedical Sciences 
      and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia; Precision 
      Medicine Research Program, Hunter Medical Research Institute, Newcastle, NSW, 
      Australia. Electronic address: murray.cairns@newcastle.edu.au.
LA  - eng
GR  - MC_PC_17228/MRC_/Medical Research Council/United Kingdom
GR  - MC_QA137853/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
SB  - IM
MH  - *Bipolar Disorder/drug therapy/genetics
MH  - Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - Humans
MH  - Multifactorial Inheritance/genetics
MH  - Risk Factors
MH  - *Schizophrenia/drug therapy/genetics
PMC - PMC9502060
OTO - NOTNLM
OT  - bipolar disorder
OT  - drug repurposing
OT  - genetics
OT  - polygenic scoring
OT  - precision medicine
OT  - proteomic imputation
OT  - schizophrenia
OT  - transcriptomic imputation
COIS- Declaration of interests W.R.R. and M.J.C. have filed a patent related to the use 
      of the pharmagenic enrichment score framework in complex disorders (WIPO Patent 
      Application WO/2020/237314), an approach used in a section of this study. W.R.R. 
      and M.J.C. also are directors of a company that aims to commercialize the 
      pharmagenic enrichment score platform (PolygenRx Pty Ltd).
EDAT- 2022/09/03 06:00
MHDA- 2022/09/09 06:00
PMCR- 2022/09/01
CRDT- 2022/09/02 18:32
PHST- 2022/05/11 00:00 [received]
PHST- 2022/07/13 00:00 [accepted]
PHST- 2022/09/02 18:32 [entrez]
PHST- 2022/09/03 06:00 [pubmed]
PHST- 2022/09/09 06:00 [medline]
PHST- 2022/09/01 00:00 [pmc-release]
AID - S0002-9297(22)00315-9 [pii]
AID - 10.1016/j.ajhg.2022.07.011 [doi]
PST - ppublish
SO  - Am J Hum Genet. 2022 Sep 1;109(9):1620-1637. doi: 10.1016/j.ajhg.2022.07.011.