Largest Study to Date Identifies Hundreds of Genes for MDD

The largest and most ethnically diverse study of its kind has identified 697 genetic variants linked to major depressive disorder (MDD). The research also highlights potential therapies for repurposing, such as pregabalin, commonly used for pain and anxiety, and modafinil, prescribed for daytime sleepiness.

However, at least one genetics expert questions whether the research adds to the current knowledge base.

While this research may not have an immediate clinical impact, it provides valuable insights into the underlying mechanisms of depression and could influence future research directions, study investigator Andrew M. McIntosh, MD, professor of psychiatry at the Center for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, told Medscape Medical News.

A better understanding of depression can also remove some of the stigma attached to the disorder, said McIntosh. “Mental illnesses are still heavily stigmatized, in the way that conditions like tuberculosis or cancer were stigmatized in the past.”

The findings were published online on January 14, 2025, in Cell.

Ethnically Diverse 

MDD affects about 15% of the global population at some point in their lives, with early adulthood as the most common age of onset. Despite advancements in pharmacological and psychological treatments, MDD frequently leads to long-term disability.

Evidence suggests MDD has a heritability of about 37%. Since 2013, genome-wide association studies (GWAS) have provided major insights into the polygenic nature of MDD and related genetic risk factors.

However, the molecular, cellular, and neurobiological mechanisms of MDD remain largely unidentified, limiting the development of disease models and mechanism-informed drug treatments.

The study was conducted by the Psychiatric Genomics Consortium MDD Working Group. The investigators carried out a GWAS meta-analysis of 688,808 individuals with MDD and 4,364,225 controls.

Data on individuals came from various sources, including previous studies that collected genetic data and electronic health records.

Unlike most previous GWAS research, McIntosh and his colleagues included individuals of non-European ancestry. Of the total samples, 160,611 cases and 1,001,890 controls had African, East Asian, South Asian, or South American ancestry.

“Most of the world isn’t White, and most people suffering from depression don’t come from rich and high–income countries where people are mostly of European ancestry,” said McIntosh. “We have begun to appreciate the need to include people who are of non–European ancestry.”

Using a range of methods to gain insight into the associated variants, genes, and pathways that may be dysregulated in MDD, researchers identified 697 significant independent single-nucleotide polymorphisms in 635 genomic regions. Approximately half (46%) of the identified loci were novel.

“Many of the 697 variants that we discovered, we only discovered because we included ancestrally diverse participants,” noted McIntosh.

One gene that was linked to MDD is CYP7B1, which is involved in conversion to neurosteroids. “We thought that was an interesting discovery because it’s related to cholesterol; it kind of ties in metabolism and lipids with depression,” said McIntosh.

Another gene linked to depression is DRD2, the dopamine D2 receptor being the site of action of almost all antipsychotic medications. “You wouldn’t necessarily think that schizophrenia and depression would share many genetic risk factors but, they do”, said McIntosh.

Using diverse research datasets, including brain cells from postmortem samples and animal tissue, the researchers found evidence supporting the amygdala’s involvement in major depression. This aligns with previous findings from human brain imaging studies and animal models of depression.

“People with very different training, using very different approaches, and using very different tissues and techniques and technologies, have come to the same conclusion that the amygdala is somehow involved in depression,” said McIntosh.

Researchers also conducted a drug target enrichment analysis. This essentially involved cross-checking a list of genes affected by depression against a list of genes activated or deactivated by specific therapies.

They developed a list of 16 of the most enriched drugs, which included cancer drugs, osteoporosis therapies, and antipsychotics as well as antidepressants.

The findings suggest that certain medications, such as pregabalin and modafinil could be repurposed for MDD. Because sleep disturbances are common in depression and other mental illnesses, it’s certainly plausible that addressing sleepiness could influence depression, said McIntosh.

However, the only way to know if these drugs work in depression is to conduct randomized controlled trials, he said. “We think there’s emerging evidence to suggest that conducting such clinical trials would be useful.”

Limitations of the research include the fact that more than 75% of study participants with MDD were of European ancestry which could potentially reduce the power to reveal or test, cross-ancestry transferability of genetic variants.

“Without larger and more globally representative samples, it is not clear whether (or to what extent) the genetic architecture of MDD differs by ancestry or whether there are genetic differences between ancestral populations recruited from their regional origin vs those recruited from diasporas”, the researchers noted.

Nothing New? 

Commenting for Medscape Medical News, Jonathan Flint, MD, professor in the Department of Psychiatry and Biobehavioral Sciences and endowed chair in Psychiatry and Neuroscience at the Center for Neurobehavioral Genetics, Los Angeles, shared his insights on the study.

Flint has been a pivotal figure in advancing the understanding of the genetic basis of behavior. Notably, he and his colleagues developed the first genome-wide association strategy to identify genes and sequence variants linked to complex behavioral traits, including depression, in mammals. They were also the first to uncover robust genetic associations for MDD in humans.

However, Flint expressed some concerns about the new study, particularly regarding the origin of MDD diagnoses. “To recruit such a large sample, the study relies on brief assessments and electronic health records, which result in questionable diagnoses,” he said.

In a paper published in Molecular Psychiatry, Flint said in general, results from GWAS studies “derive from the analysis of cohorts in which most cases are diagnosed by minimal phenotyping, a method that has low specificity.”

Evidence indicates “there is a large genetic component unique to MDD that remains inaccessible to minimal phenotyping strategies and that the majority of genetic risk loci identified with minimal phenotyping approaches are unlikely to be MDD risk loci,” he said.

Flint doesn’t believe the new paper adds significantly to current knowledge surrounding depression genetics. “I don’t think we learn much about the biology of the disorder from the large sample size that we didn’t know already.”

Asked to respond to Flint’s comments, McIntosh said he agrees ideal datasets “are both large and include many features that define depression and can be used to explore its variability.”

However, he noted that because the current study includes 37,314 depressed individuals evaluated using structured assessments, “we were well-placed to directly test the value and validity of the pragmatic approach of including cohorts where depression is identified through self-report (N = 140,553), electronic health records (N = 414,577), or symptom questionnaires (N = 96,364).”

This current study demonstrates that adding these individuals improves prediction in the clinical cases, and that genetics of the ‘lower depth’ measures of depression are very highly correlated with assessments made using structured patient interviews, said McIntosh.

“These findings, and others presented in the paper, suggest that the current work is adding significantly to our knowledge of the biology of depression,” he added.

This study was funded by National Institutes of Health, Wellcome, and the National Institute for Health and Care Research Maudsley Biomedical Research Centre.

McIntosh and Flint reported no relevant disclosures.