Talking Migraine Genetics: An Interview with Lyn Griffiths

“My career has spanned decades, and I’m still surprised by how far things have come. When I first started, it took six to eight weeks just to investigate one variation in a particular gene. Now, you can do a whole genome – or multiple genomes – in a day.” – Lyn Griffiths

Distinguished Professor Lyn Griffiths, PhD, is a molecular geneticist and director of the Centre for Genomics and Personalised Health at the Queensland University of Technology in Australia. The Centre aims to discover better methods of diagnosing disease, develop targeted treatments based on genetic information, and train the next generation of translational genomics scientists. Professor Griffiths’ own research into familial migraine, ataxia, epilepsy, and hereditary stroke has resulted in multiple diagnosis breakthroughs for these conditions.

In this MSC interview, she chats with Lincoln Tracy, PhD, a researcher and writer from Melbourne, Australia, to discuss her career path to molecular genetics, key findings from migraine genetics research, links between migraine genes and the response to head trauma, and more. This interview has been edited for clarity and length.

What was your path to becoming a molecular geneticist?

I did a bit of genetics during my undergraduate and honors degree in biochemistry and molecular biology. Molecular genetics was really starting to take off around this time, as it was becoming obvious you could look at DNA in relation to disease. We knew about the structure of DNA, as well as rare mutations and chromosomal abnormalities, but there hadn’t been much work done into the genetics underlying more common individual disorders.

I felt that you could get more of an understanding of the molecular basis of a disorder if you studied the DNA, rather than looking at the repercussions of the disorder, which tended to be more about the proteins throughout the body. In addition to wanting to understand the genetic cause, I had a strong interest in diagnostics – to be able to translate the genetics into something that made it easier for people to understand what was causing their disorder, which in turn makes it much easier to determine the best treatment for them.

After my undergraduate degree, I decided to pursue a PhD in molecular genetics at the University of Sydney, which focused on identifying the genes involved in a neurological disorder called Charcot-Marie-Tooth disease. At the time, we thought it was a single-gene disorder, but through my doctoral research we were able to show that it is due to multiple different genes in different families.

How did you transition into researching other conditions, such as migraine?

The experiences from my PhD got me thinking about other disorders I could work on that were not simple, single-gene disorders. And it didn’t take me long to start thinking about migraine. It was pretty obvious that it ran through families – I only had to look at my own family history to know that – but at that stage there hadn’t been many genetic studies. Migraine was mostly treated as a neurological disorder. We started several studies investigating the potential role of genetics in migraine during the 1990s, looking at topics such as serotonin receptor and nitric oxide gene variation, as well as undertaking family linkage studies to map migraine genes.

Since then, we’ve collected large case and control populations, including over a hundred multigenerational families. We’ve done a lot of work looking at neurogenetic disorders, including migraine, but have also looked at other neurovascular disorders. Importantly, we’ve been able to translate this into diagnostic testing, and have been undertaking diagnostic testing for migraine gene disorders since 1999. We do all the diagnostic testing for Australia and New Zealand for the familial hemiplegic migraine genes, but also genes with overlapping symptoms and overlapping disorders, including episodic ataxias, spinocerebellar ataxias, and CADASIL, which is the most common hereditary stroke disorder and presents initially with migraine symptoms.

Lyn Griffiths

Why is it important to understand the genetic mechanisms underlying migraine?

Migraine is, without a doubt, the most common neurological disorder in the world. We now know that migraine isn’t caused by one gene. Rather, it’s caused by multiple genes, and probably by different genes in different people. In the more common types of migraine, there could also be a threshold effect of multiple different genes – where the additive effect of mutations in multiple genes leads to migraine rather than being caused by a single mutation. But for rarer types of migraine, like familial hemiplegic migraine, we know there are specific mutations in single genes that cause the disorder. We also know that if you can identify mutations in individual genes, this really helps direct the best treatment for a particular individual.

What are some of the key things we’ve learned about the genetics of migraine?

There are three known ion channel genes that cause monogenic [single gene] forms of migraine. The first one identified was a calcium channel gene, CACNA1A; the second one was an ATPase gene, ATP1A2; and the third was a sodium channel gene, SCN1A. We’ve just published a paper implicating two other calcium channel genes – CACNA1H and CACNA1I – in migraine, where we showed that people with familial hemiplegic migraine who didn’t have mutations in the known familial hemiplegic migraine genes carried an excess of variants in these two other calcium channel genes, indicating these genes may also play a role in hemiplegic migraine. In addition, there have been several other genes implicated in neurovascular or ion channel pathways, and now we test for 15 of these when we get any cases of suspected familial hemiplegic migraine or CADASIL.

It’s trickier when you consider the more common types of migraine. While these don’t always run through families, about 90% of cases have a close relative who suffers from migraine. The International Headache Genetics Consortium we are involved with has identified more than 120 different genes that contribute to migraine. Some genes relate to neurotransmitters, some relate to vascular genes, and others relate to hormones. It is expected that there are other genes involved, and it will take a while to track all of them down and work out the best way to use this information. We’ve been involved in studies that have implicated a specific single mutation in the potassium channel gene, TRESK, in a typical migraine family indicating that private mutations can occur in different families, in addition to polygenic risk genes that contribute to migraine.

How are the genetics of migraine linked to the response to head trauma?

There are obviously differences between mild and very severe traumatic brain injury, but migraine is the most common symptom resulting from head trauma, regardless of injury severity. Sometimes it can be a short-term thing where people recover quite well, and in other cases it can last for months – we call this post-traumatic migraine.

We started thinking about this in the context of familial hemiplegic migraine, and we and others discovered that a particular mutation in the CACNA1A gene makes people highly susceptible to poor outcomes even after very minor instances of head trauma. We’ve found multiple instances where, for example, a child will bump their head on the corner of a table, and instead of picking themselves straight back up and getting better, they can go on to develop severe migraine, lose consciousness, and so on. That got us thinking about whether there are other genes involved in migraine that play a role in the response to head trauma.

This led to undertaking whole exome sequencing [sequencing the protein-coding regions of genes] on people with multiple notable concussions, and even some families where multiple generations had concussion issues. We’ve only just started publishing the results, but we’ve published on the CACNA1A gene and its potential role in concussion, as well as a potential role for another gene, ATP1A2. We noted that a third of people with mutations in that gene had also noted common problems associated with mild traumatic brain injury resulting in really severe concussion. We are currently investigating the role of other ion channel genes in post-traumatic migraine.

Do you have any theories about how the genetic susceptibility causes poorer outcomes?

We’re not exactly sure, but our current hypothesis is that the two already-implicated ion channel genes are responsible for controlling ion flow across neuronal cells, and it is possible that mutations in these genes create a threshold level where the functioning of the ion channels isn’t quite normal. Then, the injury triggers the abnormal release and movement of ions across neuronal cells, which in turn goes on to cause a cascade of other events that results in pain. But, as it’s hard to pull someone’s brain apart while this is happening, we can only infer these kinds of things. However, there are other imaging-based studies exploring the outcomes associated with traumatic brain injury, and I expect that bringing the genetics and imaging perspectives together will help improve this understanding.

What projects are you and your team currently working on?

Familial hemiplegic migraine is a key area of interest. We’ve been collecting diagnostic samples since 2000, but only about 25% of these cases have had a genetic cause identified, despite the fact that we’ve increased the number of genes we’re investigating. So we’re currently doing whole exome sequencing on the other 75% of people, because there must be other genes contributing to their migraines that we haven’t identified yet. We’ve identified a number of new genes that have bumped the diagnostic rate up to about 35%, but we still need to go further.

We’re also interested in the more common types of migraine. We’re set up to do whole genome sequencing with the inhabitants of Norfolk Island, a genetically isolated population who we have been working with for around 20 years. That line of work started after we hired someone whose parents lived on Norfolk Island [a small island in the South Pacific Ocean, off the east coast of Australia], and, like all good ideas, it came from having a drink at the pub. He spoke about his family and his ancestry, and it sounded like a fascinating population to explore from a genetic perspective. The ancestral history goes back to the mutiny on the Bounty, so much so that about 80% of today’s population can trace their ancestry back to the original mutineers.

There have been maybe 15 visits to the island, with three major collections as part of the longitudinal studies in 2000, 2010, and 2021-2022. We’ve done a genome-wide association study in the past, and we’re currently doing whole genome sequencing as well as sequencing of the methylome [chemical modifications throughout the genome in which methyl groups are attached to DNA; this is a type of epigenetic mechanism that turns genes on or off]. We’ve found several genes that contribute to disease in this population, some of which relate to migraine. It’s been a great population to live and work with.

What are some of the challenges associated with your line of research?

There are the usual challenges of getting enough funding and recruiting participants; you can’t really do research unless you have the funds to do it and the people coming forward to help you out. Despite migraine being the most common neurological disorder, affecting a minimum of 12% of the Australian population, migraine has been second-to-last on the list in terms of medical and research funding in Australia. Only ear infection – which you can more easily fix with antibiotics – had less money allocated to it. It’s bizarre to think that migraines can affect such an enormous number of people, but that people don’t take migraine seriously. Migraines can prevent people from doing their normal jobs or living their normal lives, but people just think things like, ‘Oh, I had a big night out on Friday.’ But it’s a very serious and nasty disorder.

When you started your career, did you ever think molecular genetic technology would advance as much as it has?

My career has spanned decades, and I’m still surprised by how far things have come. When I first started, it took six to eight weeks just to investigate one variation in a particular gene. Now, you can do a whole genome – or multiple genomes – in a day. But despite the technology growing, and the costs of using it decreasing, the trick at the moment is being able to find a way to store the data properly and access it with consent so it can be used for diagnosing future disorders without needing to recollect and re-sequence samples from everyone.

Sequencing a whole genome leaves you with a huge amount of data. You need to keep anything you use for diagnostic purposes for a long time, but it’s much more challenging to store research data. When people consent to being in a research project, they often consent for their data to be used for a specific purpose. And in most cases, people would be happy for their data to be used in other research studies, but based on how consent forms are currently written, there are a lot of data that can go to waste. There’s a bit of serious thinking we need to do about how we could better consent, store, and access DNA-related data.

Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia. Follow him on Twitter @lincolntracy.

Additional Reading
Whole exome sequencing of hemiplegic migraine patients shows an increased burden of missense variants in CACNA1H and CACNA1I genes.
Maksemous et al.
Mol Neurobiol. 2023 Jun;60(6):3034-43.

Exploring neuronal vulnerability to head trauma using a whole exome approach.
Ibrahim et al.
J Neurotrauma. 2020 Sep 1;37(17):1870-9.

The role of the MTHFR gene in migraine.
Stuart et al.
Headache. 2012 Mar;52(3):515-20.

Heritability and genome-wide linkage analysis of migraine in the genetic isolate of Norfolk Island.
Cox et al.
Gene. 2012 Feb 15;494(1):119-23.

A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura.
Lafrenière et al.
Nat Med. 2010 Oct;16(10):1157-60.