Format

Send to

Choose Destination
Nat Commun. 2018 Oct 16;9(1):4285. doi: 10.1038/s41467-018-06540-3.

Phenome-wide association studies across large population cohorts support drug target validation.

Author information

1
Merck Sharp & Dohme, Boston, MA, 02115, USA. dorothee.diogo@merck.com.
2
23andMe Inc, Mountain View, CA, 94041, USA.
3
Genomics plc, Oxford, OX1 1JD, UK.
4
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Helsinki, Finland.
5
The Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, 19104, USA.
6
National Institute for Health and Welfare, FI-00271, Helsinki, Finland.
7
Merck Sharp & Dohme, Boston, MA, 02115, USA.
8
Nimbus Therapeutics, Cambridge, MA, 02139, USA.
9
Celgene, Cambridge, MA, 02140, USA.
10
McKinsey & Co., Boston, MA, 02210, USA.
11
Vertex Pharmaceuticals, Boston, MA, 02210, USA.
12
Biogen, Research and Early Development, Cambridge, MA, 02142, USA.
13
Eisai, Andover, MA, 01810, USA.
14
Pfizer, Cambridge, MA, 02139, USA.
15
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
16
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
17
Department of Public Health, University of Helsinki, Helsinki, Finland.
18
Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
19
Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
20
Merck Sharp & Dohme, Boston, MA, 02115, USA. heiko.runz@gmail.com.
21
Biogen, Research and Early Development, Cambridge, MA, 02142, USA. heiko.runz@gmail.com.

Abstract

Phenome-wide association studies (PheWAS) have been proposed as a possible aid in drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we select 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease indications. We interrogate these SNPs by PheWAS in four large cohorts with extensive health information (23andMe, UK Biobank, FINRISK, CHOP) for association with 1683 binary endpoints in up to 697,815 individuals and conduct meta-analyses for 145 mapped disease endpoints. Our analyses replicate 75% of known GWAS associations (P < 0.05) and identify nine study-wide significant novel associations (of 71 with FDR < 0.1). We describe associations that may predict ADEs, e.g., acne, high cholesterol, gout, and gallstones with rs738409 (p.I148M) in PNPLA3 and asthma with rs1990760 (p.T946A) in IFIH1. Our results demonstrate PheWAS as a powerful addition to the toolkit for drug discovery.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center