Novel genetic associations with anxiety unveiled in comprehensive study of over 1.2 million people

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In a recent study posted to the medRxiv* preprint server, an international team of researchers conducted a large-scale genome-wide association study across five ancestral groups to understand the genetic basis of anxiety disorders, identify genetic loci, and calculate polygenic risk scores for anxiety.

Study: Gene Discovery and Biological Insights into Anxiety Disorders from a Multi-Ancestry Genome-wide Association Study of >1.2 Million Participants. Image Credit: zimmytws/Shutterstock.comStudy: Gene Discovery and Biological Insights into Anxiety Disorders from a Multi-Ancestry Genome-wide Association Study of >1.2 Million Participants. Image Credit: zimmytws/Shutterstock.com

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

Anxiety disorders are some of the most prevalent forms of mental health disorders and have a long-lasting impact on overall health, contributing to all-cause mortality.

Furthermore, while the diagnostic criteria are distinct for the various anxiety disorders, the substantial phenotypic overlap across these disorders results in 48% to 68% of individuals with one anxiety disorder having the symptoms for at least one more anxiety disorder.

Anxiety disorders are known to be polygenic, with different subtypes exhibiting a 20% to 60% heritability in twin studies. Genome-wide association studies have identified ten genetic loci that can be used to determine the risk of anxiety disorders.

However, these studies have been on populations that are largely of European descent, making the results difficult to generalize for people of other ancestries.

Furthermore, compared to other mental health disorders, such as post-traumatic stress disorder and major depressive disorders, the progress of research on anxiety disorders has been less diverse and not as rapid.

About the study

In the present study, the team conducted a large-scale genome-wide association study among a study population of over 1.2 million individuals of diverse ancestry, using data from previous studies and new cohorts.

The participants were of European, South Asia, Admixed-American, African, and East Asian ancestral groups.

The data was obtained from six cohorts, spanning various projects such as the All of Us Research Program (AoU) and Million Veteran Project (MVP) from the United States, the United Kingdom Biobank, and the FinnGen Project.

The AoU cohort was genetically the most diverse, consisting of participants from all the five ancestries included in this study.

Electronic health records were used to identify cases with lifetime diagnoses of panic disorder, generalized anxiety disorder, chronic stress disorder, phobic disorder, mixed anxiety and depressive disorder, and obsessive-compulsive disorder.

The control group consisted of participants who were not diagnosed with any of these disorders.

Various criteria for quality control, including those pertaining to Hardy-Weinberg equilibrium, minor allele frequency, and call rate, were used while conducting the genome-wide association analysis stratified for ancestry.

Additionally, covariates for age, sex, and ancestry-related principal components were considered while estimating the genetic associations.

The genetic architecture of the different anxiety definitions was compared by calculating linkage disequilibrium scores, which were then used for regression analyses to estimate the pairwise genetic correlations and single-nucleotide polymorphism (SNP)-based heritability.

Phenotype dilution and genetic correlation analyses were also performed in cases that did not exhibit significant SNP-based heritability.

Additionally, polygenic risk scores for anxiety were calculated using data from one cohort and tested on populations from other cohorts to determine polygenic risk scores that were valid across different ancestries.

Furthermore, the scientists also conducted a brain transcriptome-wide association study. They investigated the proteome-wide association to understand how genetically regulated variations in transcriptions and protein synthesis impact the pathogenesis of anxiety.

Results

The study found 39 novel anxiety-associated genetic loci and identified a total of 51 loci that were associated with anxiety.

The results also showed that polygenic risk scores identified using the European cohort showed associations with anxiety across different ancestral groups such as Admixed-American, East Asian, and African populations.

The genes that were expressed in the cerebellum, limbic system, metencephalon, cerebral cortex, brain stem, and entorhinal cortex showed enrichment in heritability of anxiety.

The proteome and transcriptome analysis further revealed 115 genes that were linked to anxiety through cross-tissue and brain-specific regulations.

The polygenic architecture of anxiety was also found to be correlated locally and globally with other mental health disorders such as schizophrenia, depression, and bipolar disorder.

Putative causal associations were also found between genetic mechanisms of anxiety and physical disorders such as myalgia, cystitis, periapical and pulp tissue diseases, and five cardiovascular and circulatory system diseases.

Conclusions

To summarize, a team of scientists from across the globe conducted a large-scale genome-wide association study involving numerous cohorts spanning five diverse ancestral groups to identify genetic loci associated with anxiety disorders.

The findings reported 39 novel genetic loci that were directly associated with anxiety disorders and 115 genes that were linked to anxiety through various brain and tissue-specific pathways.

Furthermore, the study also showed that the genetic mechanisms of anxiety disorders had overlaps with other mental health disorders, as well as physical health conditions such as cardiovascular disease.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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