PMID- 31964963
OWN - NLM
STAT- MEDLINE
DCOM- 20201217
LR  - 20210120
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 10
IP  - 1
DP  - 2020 Jan 21
TI  - Pharmacological enrichment of polygenic risk for precision medicine in complex 
      disorders.
PG  - 879
LID - 10.1038/s41598-020-57795-0 [doi]
LID - 879
AB  - Individuals with complex disorders typically have a heritable burden of common 
      variation that can be expressed as a polygenic risk score (PRS). While PRS has 
      some predictive utility, it lacks the molecular specificity to be directly 
      informative for clinical interventions. We therefore sought to develop a 
      framework to quantify an individual's common variant enrichment in clinically 
      actionable systems responsive to existing drugs. This was achieved with a metric 
      designated the pharmagenic enrichment score (PES), which we demonstrate for 
      individual SNP profiles in a cohort of cases with schizophrenia. A large 
      proportion of these had elevated PES in one or more of eight clinically 
      actionable gene-sets enriched with schizophrenia associated common variation. 
      Notable candidates targeting these pathways included vitamins, antioxidants, 
      insulin modulating agents, and cholinergic drugs. Interestingly, elevated PES was 
      also observed in individuals with otherwise low common variant burden. The 
      biological saliency of PES profiles were observed directly through their impact 
      on gene expression in a subset of the cohort with matched transcriptomic data, 
      supporting our assertion that this gene-set orientated approach could integrate 
      an individual's common variant risk to inform personalised interventions, 
      including drug repositioning, for complex disorders such as schizophrenia.
FAU - Reay, William R
AU  - Reay WR
AD  - School of Biomedical Sciences and Pharmacy, The University of Newcastle, 
      Callaghan, NSW, Australia.
AD  - Centre for Brain and Mental Health Research, Hunter Medical Research Institute, 
      Newcastle, NSW, Australia.
FAU - Atkins, Joshua R
AU  - Atkins JR
AD  - School of Biomedical Sciences and Pharmacy, The University of Newcastle, 
      Callaghan, NSW, Australia.
AD  - Centre for Brain and Mental Health Research, Hunter Medical Research Institute, 
      Newcastle, NSW, Australia.
FAU - Carr, Vaughan J
AU  - Carr VJ
AD  - School of Psychiatry, University of New South Wales, Randwick, NSW, Australia.
AD  - Neuroscience Research Australia, Sydney, NSW, Australia.
AD  - Department of Psychiatry, Monash University, Melbourne, VIC, Australia.
FAU - Green, Melissa J
AU  - Green MJ
AD  - School of Psychiatry, University of New South Wales, Randwick, NSW, Australia.
AD  - Neuroscience Research Australia, Sydney, NSW, Australia.
FAU - Cairns, Murray J
AU  - Cairns MJ
AD  - School of Biomedical Sciences and Pharmacy, The University of Newcastle, 
      Callaghan, NSW, Australia. Murray.cairns@newcastle.edu.au.
AD  - Centre for Brain and Mental Health Research, Hunter Medical Research Institute, 
      Newcastle, NSW, Australia. Murray.cairns@newcastle.edu.au.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200121
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
SB  - IM
MH  - Antipsychotic Agents/*pharmacology
MH  - Basic Helix-Loop-Helix Transcription Factors/genetics
MH  - Cohort Studies
MH  - Drug Repositioning
MH  - Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - Humans
MH  - Multifactorial Inheritance
MH  - Pharmacogenomic Testing/*methods
MH  - Polymorphism, Single Nucleotide
MH  - Precision Medicine/methods
MH  - Risk Factors
MH  - Schizophrenia/*drug therapy/*genetics
MH  - Transcriptome
PMC - PMC6972917
COIS- The authors declare no competing interests.
EDAT- 2020/01/23 06:00
MHDA- 2020/12/18 06:00
PMCR- 2020/01/21
CRDT- 2020/01/23 06:00
PHST- 2019/09/12 00:00 [received]
PHST- 2020/01/03 00:00 [accepted]
PHST- 2020/01/23 06:00 [entrez]
PHST- 2020/01/23 06:00 [pubmed]
PHST- 2020/12/18 06:00 [medline]
PHST- 2020/01/21 00:00 [pmc-release]
AID - 10.1038/s41598-020-57795-0 [pii]
AID - 57795 [pii]
AID - 10.1038/s41598-020-57795-0 [doi]
PST - epublish
SO  - Sci Rep. 2020 Jan 21;10(1):879. doi: 10.1038/s41598-020-57795-0.