In this blog post, we explore how researchers detect small genetic variations between individuals and bring them together into a single score. We’ll also look at how genetic differences can shape the way your body responds to medications—and why that matters for how well they work.
Background
Depression is a mood disorder characterised by continuous low mood, feelings of sadness or hopelessness, reduced interest or pleasure in doing things, as well as other physical and psychological symptoms. Around 15% of people experience depression at some point in their life. Available treatments include antidepressants, talking therapies, and social support, however people can respond differently to different treatments. Researchers in the AMBER project are specifically interested in why some people find antidepressants helpful, while others don’t.
One way to explore people’s individual differences to antidepressant response is through genetics. Our genes, inherited from our parents, help shape many aspects of our health and biology. Previous research has shown that genetics play a role in the risk of developing depression. However, we still don’t know if genetics also influences how well people respond to antidepressants.
1. Introducing Genome-Wide Association Studies (GWAS) 1
Genome-Wide Association Studies (GWAS) are one of the main ways researchers study the genetics of antidepressant response.
How does it work?
- Blood, saliva, or buccal [inside of cheek] samples are collected from participants, and their DNA is extracted.
- Using this DNA information, scientists scan across the whole genome (the complete set of genes in a cell) and attempt to identify whether tiny differences in people’s DNA affect how they respond to antidepressants. For example, they might ask: Do people with a particular genetic variation [small difference] respond better to a certain medication? Or experience fewer side effects?
We know from past studies that each genetic variation only contributes a small amount to how an individual responds to medications. Therefore, these studies usually require thousands of people to reliably identify genetic variations that might contribute to these individual differences.
What have we learned so far?
GWAS have shown that antidepressant response is influenced by many different genetic factors, each contributing a small piece to the puzzle. In the AMBER study, this approach can help to identify genetic variants that affect how the body processes medications and what side effects people might experience.
2. Introducing Polygenic Scores (PGS) 2
When researchers have completed a GWAS and identified genetic variants [small differences] linked to antidepressant response, they can take it one step further and create a polygenic score (PGS).
What is a PGS?
A PGS is like a summary score that combines information from many genetic variants into a single number. Instead of looking at each genetic difference one by one, researchers add them all together to estimate someone’s overall genetic likelihood of responding to antidepressants.
Genetics works a bit like a shopping bag of ingredients. Some items only hint at the final dish: for example, flour could become bread, cake or used to thicken a stew. But other items are very specific – birthday candles and sprinkles mean you’re making a birthday cake. In the same way, some genetic variants weakly suggest how someone might respond to treatment, while others are stronger indicators. A PGS combines all these clues together.
Researchers can then test if a particular PGS is associated with a particular outcome. For example, is PGS for antidepressant response linked to the likelihood of switching from one antidepressant medication to another?
Can PGS tell me which antidepressant to take?
Not yet. PGS are research tools and aren’t ready to guide treatment decisions in real-world clinical settings. However, it’s continually progressing with larger GWAS and more accurate calculation methods becoming available.
It’s also worth bearing in mind that having a particular genetic score doesn’t absolutely determine what will happen – genetics are just one piece of a much larger puzzle that interacts with life experiences, environment, and many other factors to shape an outcome.
3. Introducing Pharmacogenetics3
Pharmacogenetics is the study of how genes may affect the way our bodies interact with medications, including antidepressants.
How does it work?
Antidepressants are generally processed and broken down in the liver, by a family of special proteins called enzymes. This is a biological process called metabolism. Genetics control the amounts of these enzymes produced in our bodies, and affects the speed of metabolism.
From DNA samples, scientists can identify whether a person processes certain medications rapidly or slowly by examining specific genetic variations that affect the production of enzymes involved in metabolism.
Why does this matter?
Imagine two people are prescribed the same antidepressant at the same dose. One person might be a rapid metaboliser, and their body breaks down the antidepressant so quickly that it leaves their system before it has a chance to work. The other person might be a slow metaboliser. The antidepressant builds up in their system and causes uncomfortable side effects.
In the AMBER study, researchers are investigating whether genetic information like this could help doctors personalise treatment. Instead of trial and error, doctors might one day be able to match people to the antidepressants and doses that are most likely to work well for them right from the start.
Conclusion:
Each of these approaches provides a different piece of the puzzle.
- GWAS identify genetic variants,
- PGS combines them into a single measure,
- Pharmacogenetics examines how genes affect medication processing.
While genetics is important, it is just one part of the bigger picture, alongside life experiences, environment, and other factors. The goal of research like the AMBER study is to move toward personalised treatment, helping doctors match people to the antidepressants most likely to work well for them from the start.
Find out more:
- About GWAS: YouTube video [55 mins]
MPG Primer: GWAS design and interpretation (2016), Broad Institute of MIT and Harvard - About Polygenic Risk Scores: Overview that was printed in a journal: Polygenic Scores in Psychiatry: On the Road From Discovery to Implementation, Cathryn M.Lewis, Ph.D., EvangelosVassos, M.D., Ph.D.
- About Pharmacogenomics: An introduction designed for healthcare workers, which includes text and a video: https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/introduction-to-pharmacogenomics/
NHS England, National Genomics Education Programme | GeNotes
This is the second in a series of 3 blog posts.
Read the first post: The Genetics of Antidepressant Response: What We Know and What We Don’t Know
