Plenge Lab
Date posted: February 13, 2016 | Author: | No Comments »

Categories: Drug Discovery Embedded Genomics Human Genetics Precision Medicine

A study published last week in Science described a large-scale genetic association study of Neandertal-derived alleles with clinical phenotypes from electronic health records (EHRs). Here, I focus less on the Neandertal aspect of the study – which to me is really just a gimmick and not medically relevant – and more on the ability to use EHR data for unbiased association studies against a large number of clinical traits captured in real-world datasets. I also provide some thoughts on how this same approach could be used for drug discovery.

[Disclaimer: I am a Merck/MSD employee. The opinions I am expressing are my own and do not necessarily represent the position of my employer.]

The study used clinical data from the Electronic Medical Records and Genomics (eMERGE) Network, a consortium that unites EHR systems linked to patient genetic data from nine sites across the United States. The clinical data was primarily from ICD9 billing codes, an imperfect but decent way to capture clinical data from EHRs. In total, a set of 28,416 adults of European ancestry from across the eMERGE sites had both genotype data and sufficient EHR data to define clinical phenotypes (n=13,686 in the Discovery set; n=14,730 in the replication set).…

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There was an eruption in Iceland last week. No, this was not another volcanic eruption. Rather, there was a seismic release of human genetic data that provides a glimpse into the future of drug discovery. The studies were published in Nature Genetics (the issue’s Table of Contents can be found here), with insightful commentary from Carl Zimmer / New York Times (here), Matthew Herper / Forbes (here), and others (here, here).

[Disclaimer: I am a Merck/MSD employee. The opinions I am expressing are my own and do not necessarily represent the position of my employer.]

As I have commented before, human genetics represent a very powerful approach to identify new drug targets (see here, here). I have articulated a 4-step process (see slide #5 from this deck): (1) select a phenotype that is relevant for drug discovery; (2) identify a series of genetic variants (or “alleles”) that is associated with the phenotype; (3) assess the biological function of phenotype-associated alleles; and (4) determine if those same alleles are associated with other phenotypes that may be considered adverse drug events.

There is an important assumption about this model: genes with an “allelic series” will be identified from large-scale genetic studies, and these phenotype-associated alleles will serve as an estimate of function-phenotype dose-response curves.…

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Date posted: August 20, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Uncategorized

In this post I will build on previous blogs (here, here, here) about genetics for target ID and validation (TIDVAL).  Here, I argue that new targets with unambiguous promotable advantage will emerge from studies that focus on genetic pathways rather than single genes.

This is not meant to contradict my previous post about the importance of genetic studies of single genes to identify new targets.  However, there are important assumptions about the single gene “allelic series” approach that remain unknown, which ultimately may limit its application. In particular, how many genes exist in the human genome have a series of disease-associated alleles?  There are enough examples today to keep biopharma busy.  Moreover, I am quite confident that with deep sequencing in extremely large sample sizes (>100,000 patients) such genes will be discovered (see PNAS article by Eric Lander here).  Given the explosion of efforts such as Genomics England, Sequencing Initiative Suomi (SISu) in Finland, Geisinger Health Systems, and Accelerating Medicines Partnership, I am sure that more detailed genotype-phenotype maps will be generated in the near future.

[Note: Sisu is a Finnish word meaning determination, bravery, and resilience; it is about taking action against the odds and displaying courage and resoluteness in the face of adversity. …

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Date posted: August 8, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Uncategorized

phe·no·type  n.

1.The observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences.

2. An individual or group of organisms exhibiting a particular phenotype.

 

There are many different phenotypes: strength in the face of adversity (see here); self-reflection in a time of uncertainty (see here); and creativity amidst a sea of sameness (see here).

Phenotypes also refer to disease states such as risk of disease, response to therapy, a quantitative biomarker of medical relevance, or a physical trait such as height (as in the figure above).

For drug discovery, I have put forth the premise that human genetics is a useful tool to uncover novel drug targets that are likely to have unambiguous promotable advantage (see here).  The starting point in a genetic study is to pick the right phenotype, one that is an appropriate surrogate for drug efficacy.

And phenotype matters!

Two illustrative examples are the autoimmune diseases type 1 diabetes and rheumatoid arthritis. In type 1 diabetes the immune system destroys the pancreas, thereby preventing insulin secretion and the control of blood glucose levels.

Human genetics has identified many alleles associated with the risk of type 1 diabetes, nearly all of which act on the immune system (see here). …

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