Plenge Lab
Date posted: December 28, 2017 | Author: | No Comments »

Categories: Drug Discovery Embedded Genomics Human Genetics

Over the holidays my family participated in an Escape Room, a live puzzle adventure game. We worked as a team to solve riddles, find clues and, over the course of 60-minutes, complete an old town bank heist. Many of the successful clues came from unexpected places – coordinates on maps, numbers inscribed in hidden places, and physical features of the room itself. Other clues seemed promising, but ultimately led to dead ends. In the end, everything came together and we escaped with only seconds to spare.

And so it goes with the invention of new medicines. The approval of a new medicine is an Escape Room of sorts, but over the course of decades not minutes. And like an Escape Room, clues can come from unexpected places, with some leading to new insights and others leading to dead ends.

I was in an Escape Room state-of-mind as I read a Science Translational Medicine article that developed a system to differentiate blood cells into microglia-like cells to study gene variants implicated in neurodegenerative disorders (here). In this blog, I provide a brief summary of the study, and then describe the potentially interesting phenomenon of genetically driven tissue-specific pathogenicity.…

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Date posted: December 19, 2017 | Author: | No Comments »

Categories: Drug Discovery Embedded Genomics Human Genetics Precision Medicine

A new genetics initiative was announced today: the creation of FinnGen (press release here). FinnGen’s goal is to generate sequence and GWAS data on up to 500,000 individuals with linked clinical data and consented for recall. There are many applications for such a resource, including drug discovery and development. In this blog, I want to first describe the application of PheWAS for drug discovery and development, and then introduce FinnGen as a new PheWAS resource (see FinnGen slide deck here).

[Disclaimer: I am an employee of Celgene. The views expressed here are my own.]

PheWAS

PheWAS turns GWAS on its head. While GWAS tests millions of genetic variants for association to a single trait, PheWAS does the opposite: tests hundreds (if not thousands) of traits for association with a single genetic variant. This approach is primarily relevant for those genetic variants with an unambiguous functional consequence – for example, a variant associated with disease risk or a variant that completely abrogates gene function. There are useful online resources (see here), as well as several nice recent reviews by Josh Denny and colleagues, which provide additional background on PheWAS (see here, here).

Work that originated from my academic lab represents the first example of PheWAS for drug discovery – in particular, how to use PheWAS to predict on-target adverse drug events (ADEs) and to select indications for clinical trials (see 2015 PLoS One publication here).…

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