Cookie policy: This site uses cookies (small files stored on your computer) to simplify and improve your experience of this website. Cookies are small text files stored on the device you are using to access this website. For more information please take a look at our terms and conditions. Some parts of the site may not work properly if you choose not to accept cookies.

Join

Subscribe or Register

Existing user? Login

Drug discovery

Disease risk influenced by entire genome, researchers suggest

Analysis of genome-wide association studies shows that how genes interact with each other has a bigger impact on disease than single-gene effects which makes drug discovery a more difficult task.

human genome

Source: Shutterstock.com

Researchers analysed data from genome-wide association studies — that link genetic variants with disease — and found that for a given trait there are thousands of genes exerting tiny and indirect effects making the chances of drug discovery ‘hits’ less likely

A recent study[1] could change the way that researchers use data on genetic variation to inform drug discovery.

The researchers analysed data from genome-wide association studies (GWAS) — a method that links genetic variants to disease — and found that for a given trait there are thousands of genes exerting tiny and indirect effects.

They showed that the collective influence of these genes on a trait is actually greater than that of genes with direct effects, which have traditionally been the focus of research into human disease genetics.

The researchers say it calls into question the role of GWAS for drug discovery as ‘hits’ found using the method wouldn’t necessarily make good drug targets.

“If this model is right, it’s telling us something profound about how cells work that we don’t really understand very well,” says lead author Jonathan Pritchard from Stanford University School of Medicine. “And so maybe that puts us a little bit further away from using genome-wide association studies for therapeutics. But in terms of understanding how genetics encodes disease risk, it’s really important.”

Pritchard and his team re-analysed large datasets from past GWAS of height, Crohn’s disease, rheumatoid arthritis and schizophrenia.

GWAS involve scanning the genome for common genetic variants between people with the same trait, the idea being that shared variants are likely to play a role in the development of the trait, such as a disease.

Greater role for entire genome

In the past, it was thought that the most important variants would be those in biological pathways directly related to a particular disease. But the research suggested a greater role for variants spread throughout the genome in regions that do not encode proteins, but are involved in a complex network of regulation.

“Because the total set of expressed genes may outnumber core genes by 100:1 or more, the sum of small effects across peripheral genes can far exceed the genetic contribution of variants directly affecting the core genes themselves,” the authors explain, reporting in Cell.

Pritchard and colleagues say that GWAS research will continue to be important but their findings raise the imperative of also mapping regulatory networks within cells, if we are to ever fully understand human disease biology.

Jason Moore, professor of informatics at the Perelman School of Medicine, who was not involved in the research, says that the concept of genes impacting disease through complex, interacting systems is not new. But the current paper is important as it challenges the prevailing GWAS paradigm.

“GWAS has assumed a simple genetic architecture made up of lots of genetic variants that each impact disease susceptibility independently of the rest of the genome and our environmental exposures,” he explains.

Moore says that the approach to analysing GWAS data should be revised to reflect the complex interactions at play within the genome including gene-gene interaction and gene-environment interaction, something which will likely be assisted by machine learning and artificial intelligence.

“Instead of thinking about a drug impacting a single gene or gene product we need to understand the context of that gene in the rest of the genome,” he says.

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2017.20203060

Have your say

For commenting, please login or register as a user and agree to our Community Guidelines. You will be re-directed back to this page where you will have the ability to comment.

Recommended from Pharmaceutical Press

  • Workplace Drug Testing

    Workplace Drug Testing

    Explains drug testing regulatory frameworks and all aspects of drug analysis. Case studies of successful programmes are included.

    £79.00Buy now
  • Stockley's Drug Interactions

    Stockley's Drug Interactions

    Now in its eleventh edition, Stockley’s Drug Interactions is still the most comprehensive and authoritative international source of drug interaction information.

    £205.00Buy now
  • Stockley's Drug Interactions Pocket Companion

    Stockley's Drug Interactions Pocket Companion

    The 2016 pocket guide to drug interactions and their management, for the busy healthcare professional.

    £29.95Buy now
  • Clarke's Analysis of Drugs and Poisons

    Clarke's Analysis of Drugs and Poisons

    Clarke's Analysis of Drugs and Poisons is the definitive reference source of analytical data for drugs and poisons.

    £520.00Buy now
  • Disease Management

    Disease Management

    Disease Management covers the diseases commonly encountered in primary care by system, with common therapeutic issues. Includes case studies and self-assessment sections.

    £52.00Buy now
  • Drugs and the Liver

    Drugs and the Liver

    Drugs and the Liver assists practitioners in making pragmatic choices for their patients. It enables you to assess liver function and covers the principles of drug use in liver disease.

    £37.00Buy now

Search an extensive range of the world’s most trusted resources

Powered by MedicinesComplete
  • Print
  • Share
  • Comment
  • Save
  • Print Friendly Version of this pagePrint Get a PDF version of this webpagePDF

Supplementary images

  • human genome

Newsletter Sign-up

Want to keep up with the latest news, comment and CPD articles in pharmacy and science? Subscribe to our free alerts.