The advent of genetic and genomics research has transformed our understanding of thousands of human diseases, with our abilities ever increasing following the completion of the Human Genome Project.
Mental health research has been no exception. From early studies indicating that certain mental illnesses run in families, to the easy use of whole genome sequencing to identify associations, genomics has played a crucial role in our understanding of these disorders. In this feature, we take a look at the current state of genomics in mental health research and provide you with a comprehensive overview of the past, present and future of the field, so that you can understand the evolution of the research landscape.
Mental health research has been ongoing for centuries, although the outcomes have been mixed. Patients suffering from a range of mental illnesses have been historically misunderstood and mistreated, owing to a lack of knowledge about their underlying conditions. The stigma surrounding these types of illness highlight an ongoing need for better understanding of the molecular basis and potential treatments. Despite this, ‘mental health’ as a concept does not appear in any literature prior to the 1940s.
The earliest genetic studies into mental health were generally family or twin studies. Researchers noted that these diseases tended to appear in relatives, but this can be due to genes or environmental factors. Early twin studies, dating back as far as the 1800s, indicated that suicidal tendencies (linked to depression) were more common in monozygotic than dizygotic twins, implying a significant hereditary component. Twin studies remained a cornerstone of mental health research until the late 20th century, with a highly cited study from 1986 suggesting that around one-third to a half of depression and anxiety symptoms are genetic, with depression having a higher heritable component.
The advent of molecular biology techniques allowed for more refined analysis. Early linkage studies showed that manic depression was associated with different loci in different populations, and another study from the same year stated that manic depression was linked to variation in the coagulation factor IX gene. Additionally, a 1990 linkage study presented brief, but ultimately inconclusive, evidence that panic disorder (more commonly referred to today as anxiety disorder) was linked to variation in the alpha-haptoglobin locus. Studies of affective disorders in general were also common, and findings from around the same time linked bipolar disorder to a number of different loci, including the HRAS1 gene. However, a 1989 workshop highlighted the complexities of genetic research into affective disorders such as depression, anxiety and bipolar disorder, such as a lack of consensus of definitions and comorbidity with other disorders.
The genomics revolution of the early 2000s following the completion of the Human Genome Project led to a new dawn for mental health research. The availability of accessible genomic data, better computational techniques and, crucially, a reference human genome, allowed for more effective molecular analysis of mental health disorders. Perhaps the most effective new technology was genome-wide association studies (GWAS). A highly cited 2009 GWAS and meta-analysis revealed a number of genetic variants linked to bipolar disorder and a 2010 study identified variants linked to major depression in the UK. However, as with all GWAS, effect sizes are typically very small, and as such, further work was necessary.
With the advent of even more novel technology in the last few years, we are closer than ever to implementing genomic medicine for mental health in the clinic. As the availability of more data and better ways to process such data have been invented, even classic GWAS has been revolutionised. For example, in a 2019 study, the largest of its kind, over 200,000 samples were assessed from patients with one of eight common psychiatric disorders. The findings led to the identification of over 100 common variants linked to mental health disorders. Other -omics are also now at the forefront of mental health research, with a 2020 study using transcriptomics in prefrontal cortex tissue to assess gene expression in major depressive disorder patients.
With the potential of genomics technology increasing exponentially, there are thousands of novel studies we could discuss. Let’s take a look at some of the biggest developments from the last year:
Genome-wide analysis of a model-derived binge eating disorder phenotype identifies risk loci and implicates iron metabolism: A genome-wide association study identified genetic variants associated with binge-eating disorder. The historically understudied illness was linked to three independent loci and the study implicated iron metabolism in the condition (Burstein et al., 2023).
Epidemiologic and Genetic Associations of Endometriosis With Depression, Anxiety, and Eating Disorders: A genetic association study revealed that women who suffer from endometriosis are more likely to be genetically predisposed to a number of mental health conditions including depression, anxiety and eating disorders (Koller et al., 2023).
Systematic review of genome-wide association studies of anxiety disorders and neuroticism: As part of a systematic review, researchers attempted to replicate a number of genetic association studies for anxiety and neuroticism. Most were not replicable, and the authors suggested that larger sample sizes and more ancestral diversity are key going forward (Van der Walt et al., 2022).
Using phenotype risk scores to enhance gene discovery for generalized anxiety disorder and posttraumatic stress disorder: This 2022 study used phenotype risk scores to mitigate the lack of responders to UK Biobank’s Mental Health questionnaire. The study aimed to increase the amount of data available for mental health research by carefully assessing phenotypes in those who had not responded. A genetic association study and transcriptomic analysis of these individuals revealed novel genetic loci and biomarkers linked to generalised anxiety disorder and PTSD (Wendt et al., 2022).
A sex-specific genome-wide association study of depression phenotypes in UK Biobank: This genetic association study was the first of its kind to implicate sex-specific pathways in major depressive disorder. The researchers identified a number of pathways specific to both males and females and calculated polygenic risk scores that supported their findings (Silveria et al., 2023).
Emerging roles of long non-coding RNA in depression: The role of long-non-coding RNAs (lncRNAs) in mental health has been a hot topic recently. This paper summaries the emerging role of these lncRNAs in depression and suggests pathways that may be implicated such as neurotransmission (Hao et al., 2022).
Genetic network structure of 13 psychiatric disorders in the general population: This study aimed to assess the genetic networks underpinning 13 common psychiatric disorders including substance use disorders, OCD and depression. They calculated polygenic scores to understand the networks at play between the conditions to explain the comorbidity often seen within the general population. They identified four robust ‘communities’ of disorders (Ihm et al., 2023).
Comorbidity of Novel CRHR2 Gene Variants in Type 2 Diabetes and Depression: This 2022 study investigates genetic comorbidity of depression and type II diabetes. The study revealed novel variants within the CRHR2 gene that could explain the comorbidity in families with both disorders (Amin et al., 2022).
Assessing a multivariate model of brain-mediated genetic influences on disordered eating in the ABCD cohort: Published in July 2023, this study investigated the relationship between genetics, brain structure and eating disorders in adolescents. The work revealed that genetic risk factors for high BMI and altered cortical brain thickness were linked to the onset of eating disorders, earlier than previously thought (Westwater et al., 2023).
In the spotlight
Below, we look at some crucial recent research that is worthy of being in the spotlight.
‘Plasma proteomics discovery of mental health risk biomarkers in adolescents’ – de Sousa Maciel et al., 2023.
This study, published in July 2023 in the journal Nature Mental Health, used plasma proteomics to identify biomarkers for mental health disorders in adolescents. This age group is worthy of considerable attention, given the early risks of developing mental health conditions in later life coupled with a large percentage (10-20%) of adolescents already suffering from some form of psychiatric disorder.
The study aimed to assess plasma proteome data (that is, proteins in the plasma and serum) from young people aged 11-16, primarily from the Spanish WALNUTs cohort using liquid chromatography-tandem mass spectrometry. Risk phenotypes were generated via responses to a self-reported ‘Strengths and Difficulties’ questionnaire. The study revealed proteome alterations in a number of pathways associated with future risk of mental health conditions, including those involved in blood coagulation and neuronal degeneration.
The authors concluded that the self-reported questionnaire was a robust measurement of phenotype, although noted that the study would have to be further validated due to a small cohort size and limitations of the sampling methods due to the ethics of working with adolescents.
An interview with Gerome Breen
Below is an excerpt from an interview conducted with Gerome Breen, Professor of Psychiatric Genetics at King’s College London. Gerome sat down with Front Line Genomics in January 2023 to discuss the Genetic Links to Anxiety and Depression (GLAD) study. You can read the full interview here.
“FLG: Could you talk us through the Genetic Links to Anxiety and Depression study and explain what the main goals of the study are?
Gerome Breen: GLAD or the Genetic Links to Anxiety and Depression Study is a research project where we aim to recruit 40,000 or more people who have experienced anxiety or depression during their lifetime. The goal is to recruit these individuals into an NIHR BioResource supported framework that will allow us to gather questionnaire information about their mental health, link to their medical records, and to collect DNA samples for genome-wide association studies and potentially whole genome sequencing of the dataset. In addition to genetics, we also focus on social and environmental risk factors.
Our goal is to recruit a very large sample not just for the discovery of specific risk factors, but also to make the study participants available for follow-up studies based on their genetics, polygenic risk scores, clinical features, and response to treatments. By creating the study, we aim to make translational research in depression and anxiety more affordable and provide the largest contactable resource for depression and anxiety research in the world.”
“FLG: How do you measure the nurture aspect of anxiety and depression in the GLAD study?
Gerome Breen: Measuring the environment is not as straightforward as measuring genetic variation. We ask people about their demographics, education, socio-economic status, and experiences of interpersonal trauma and other life events. We then integrate this information into our studies of genetics or do joint genetic and social-environmental risk factor studies.”
“FLG: The GLAD study is currently only in the UK. Do you think it’s important to carry out studies like these on a global scale? That would be a big undertaking.
Gerome Breen: Yes, we think it’s very important to carry out studies on a global scale. The environment affects our genetic results, and this is often overlooked. For example, we find that 15-20% of the genetic variants associated with depression in European samples are related to BMI. However, studies in East Asia have revealed that these genetic associations are probably mediated by the environment.
To take that further, if we gather large samples from different populations around the globe, we can develop a good understanding of the core biology of depression. Social and environmental risk factors vary across different countries, and to understand the core biology of depression, we need samples from different ethnicities, populations, and countries at a very large scale. This is even before considering global equity in research and addressing the fact that almost no studies have been done on depression genetics in African populations.
Along with investigators in Edinburgh and Cardiff, we have initiated a project called Depression Genetics in Africa (Dec. Gen. Africa) in collaboration with investigators in Ethiopia, Malawi, Nigeria and South Africa with funding from the Wellcome Trust. Our goal is to recruit 10,000 people from these countries with severe depression to carry out the first large-scale depression genetics study in Africa. The project will also train African investigators in psychiatric genetics and set up the local infrastructure to allow larger studies to take place.”
“FLG: How can genomics improve the clinical trial approaches that are currently used in mental health?
Gerome Breen: I think one of the key areas that interests us is the ability to recruit participants based on their genetic makeup. For example, we could recruit people with high or low polygenic risk scores and use different trial designs that focus on genetic selection (of participants) rather than phenotypic clinical variables. Another example would be if a drug company is developing a therapeutic, and they know that a specific genetic variant is important for the drug’s target or response, they could recruit participants based on that genetic variation.”
With omics technology continuing to increase exponentially in potential, mental health research is likely to benefit significantly in the coming years. However, there are still a number of caveats to consider. Diversity in genomics research is perhaps the biggest pitfall for both mental and physical health research, and many of the studies we have cited here focus primarily or exclusively on European populations. This is now beginning to change, but with the largest available resources still suffering from homogeneity, there will be a significant effort needed to change this. Another crucial yet often overlooked point is diversity between sexes. Typically, animal studies focus on male specimens, but many illnesses, mental or otherwise, differ between the sexes at a molecular level. In fact, a recent study has revealed that, in mice, the stress response differs between males and females. These findings could contribute to better targeted research and therapy for women.
By diversifying mental health research and applying new technologies as they become available, we may in time see the introduction of genomic medicine for mental health in the clinic. This could take a variety of forms, such as predictive treatments when a condition runs in a family or more targeted treatments for those suffering from a certain condition based on their own molecular profile.
We hope you enjoyed this whistlestop tour through the evolution of the mental health research landscape!