Anxiety and fear are normal responses to threats, but when they become chronic, they can interfere with daily life. Anxiety disorders, such as panic disorder, social anxiety disorder, or specific phobias, are not rare. Millions of people suffer from an anxiety disorder and women are more likely to be affected than men.
If we look at US numbers, roughly one-third of US citizens will experience an anxiety disorder at some point in their lives. On a yearly basis, one-fifth of US adults deal with an anxiety problem every day, and over half of them report moderate to serious impairments in their daily lives.
The causes of anxiety are complex and can be influenced by a combination of genetic, environmental, and psychological factors. Effective treatments for anxiety disorders are available, including anxiolytic medication, therapy, and lifestyle changes. While these treatments help a lot of people, they don’t work for everyone and some of the available medications come with adverse side effects.
However, in an exciting development, new genetic insights may help us untangle the complex roots of anxiety, and, hopefully, lead to more personalised and effective treatments. But first, we need to meet a few mice.
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Anxiety with whiskers
Stress is often a major trigger for anxiety disorders. Because humans and rodents share similarities in their physiological stress response and the involved brain circuits, many anxiety disorders are studied in animal models, with mice taking the largest slice of the cake.
Of course, non-human animal models will not cover the full clinical course and experience of anxiety in humans. Still, recent advances in transgenic, optogenetic, and chemogenetic techniques allow researchers to take a detailed look at the anxious brain in mice. This can then serve as a starting point for an improved understanding of our anxiety-riddled human selves.
Using lab mice to study anxiety has the advantage of researchers being able to control the experimental conditions, such as the environment and even the genetic background of the mice strains used. However, animal models can only get us so far. Humans are not mice, behaviourally or genetically speaking, and real life is a far cry from a lab environment.
Still, anxiety research in lab mice has taught three important lessons: Individual differences in behaviour are associated with different gene expression responses; The gene expression responses to stress vary between males and females; Genetic background plays an important role in susceptibility to anxiety. For example, the popular mice strain known as C57BL/6J appears to be quite resistant to anxiety, in contrast to the strain called DBA/2J.
Observation studies in humans confirm the importance of genetics with anxiety having a heritability of around 30–40%. (An important clarification here is that heritability is the amount of variation between people explained by genetic differences, not your personal chance of inheriting a certain trait.) Let’s dive into those human genetics.
Genome-wide association studies (GWAS)
Genome-wide association studies (GWAS) look at large populations to identify genetic variants correlated with specific traits. Those genetic variants often take the form of single-nucleotide polymorphisms or SNPs — differences in a single DNA letter at a certain position in the genome.
Thanks to cheaper gene sequencing, researchers now have the data and the tools to start looking for those SNPs, and they have done so in large datasets such as the Million Veteran Project, UK BioBank, and Danish iPSYCH cohort.
And… there are a lot of SNPs that correlate with increased odds for anxiety. That makes sense; most traits are the result of tiny nudges by dozens if not hundreds of genes. Anxiety is no exception.
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There is an intriguing aspect to anxiety genetics, however, most of the anxiety-related SNPs identified so far are in the introns of the relevant genes. Introns are regions of DNA that are removed halfway through the process of turning a gene into a protein. So, mutations in an intron don’t affect the final product, aka the protein. But, introns can act as gene expression regulators. The protein might not change, but how fast that protein is made and in which quantity, that is where intronic mutations come into play.
Anxiety, in other words, is shaping up to be an issue with gene expression in response to stress. Environmental and psychological stressors pull the trigger on the gene expression hijinks that lead to feelings of anxiety.
Of course, there is much left to learn about the genetics of anxiety disorders. SNPs are far from the only form of genetic variation. How large is the role of other forms, such as copy number variation, protein-truncating variants, and so on? What do the genes with altered expression do? What pathways are they involved in? To what extent can we see the different gene expression responses between human females and males? Does this translate to a different average resilience to certain environmental stressors?
The study of anxiety genetics is a complex and rapidly evolving field. While recent advances have provided important insights, we have to recognise the limitations of animal models and genome-wide association studies in fully capturing the complexity of anxiety in humans. Anxiety disorders are influenced by a multifaceted interplay of genetic, environmental, and psychological factors, and personalised treatment requires a more comprehensive understanding of these factors.
Nonetheless, the progress made in this field gives us reason to be optimistic about the future of anxiety research and treatment.