Rxivist logo

Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 55,041 bioRxiv papers from 254,018 authors.

Phenome-wide association studies (PheWAS), which assess whether a genetic variant is associated with multiple phenotypes across a phenotypic spectrum, have been proposed as a possible aid to drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we evaluate whether PheWAS can inform target validation during drug development. We selected 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease therapeutic indications. We independently interrogated these SNPs through PheWAS in four large real-world data cohorts (23andMe, UK Biobank, FINRISK, CHOP) for association with a total of 1,892 binary endpoints. We then conducted meta-analyses for 145 harmonized disease endpoints in up to 697,815 individuals and joined results with summary statistics from 57 published GWAS. Our analyses replicate 70% of known GWAS associations and identify 10 novel associations with study-wide significance after multiple test correction (P<1.8x10-6; out of 72 novel associations with FDR<0.1). By leveraging directionality and point estimate of the effect sizes, we describe new associations that may predict ADEs, e.g., acne, high cholesterol, gout and gallstones for rs738409 (p.I148M) in PNPLA3; or asthma for rs1990760 (p.T946A) in IFIH1. We further propose how quantitative estimates of genetic safety/efficacy profiles can be used to help prioritize candidate targets for a specific indication. Our results demonstrate PheWAS as a powerful addition to the toolkit for drug discovery.

Download data

  • Downloaded 2,913 times
  • Download rankings, all-time:
    • Site-wide: 958 out of 55,041
    • In genetics: 95 out of 3,183
  • Year to date:
    • Site-wide: 6,401 out of 55,041
  • Since beginning of last month:
    • Site-wide: 8,276 out of 55,041

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide

Sign up for the Rxivist weekly newsletter! (Click here for more details.)