In a groundbreaking worldwide study led by UCL researchers, over 200 genes linked to depression have been newly identified (1). This extensive research, documented in Nature Genetics, not only sheds light on the complex genetics of major depression but also opens avenues for drug repurposing and the development of novel treatments. The study marks a significant departure from previous research limitations, focusing on diverse ancestry groups and emphasizing the need for a global perspective in understanding depression.

Is Depression Genetic?

The research revealed more than 50 new genetic loci and 205 novel genes associated with depression, making it the first large-scale global study on the genetics of major depression with participants from diverse ancestry groups. The identification of these genes not only deepens our understanding of the genetic basis of depression but also offers potential targets for drug development.

Link Between Metformin and Reduced Depression and Anxiety

One of the identified genes encodes a protein targeted by a common diabetes drug, opening doors for drug repurposing in depression treatment. The gene NDUFAF3, linked to mood instability and targeted by metformin, the primary drug for type 2 diabetes, emerged as a promising candidate. Animal studies suggesting a link between metformin and reduced depression and anxiety further underscore the potential of this finding.

Global Perspective on Depression Genetics

While depression is a widespread condition, its development remains poorly understood. Previous genetic research primarily focused on individuals of European ancestry, limiting the breadth of insights into this complex condition. The current study addressed this shortcoming by involving nearly one million participants of African, East Asian, South Asian, and Hispanic/Latin American descent. The diversity in the study participants strengthens the relevance and applicability of the findings across different populations.

The study employed advanced genetic research methods, including genome-wide association studies, a meta-analysis of previously published data, and a transcriptome-wide association study. The comprehensive analysis incorporated genetic data from 21 study cohorts worldwide, including 88,316 people with major depression. The inclusion of diverse ancestry groups enriched the dataset, providing a more nuanced understanding of depression genetics.

Potential Implications for Drug Development for Depression Treatment

Besides NDUFAF3, the study identified other genes with plausible links to depression, such as those linked to neurotransmitters involved in goal-directed behavior and proteins associated with various neurological conditions. These findings not only deepen our understanding of the biological underpinnings of depression but also offer potential targets for future drug development.

Ancestry-Specific Insights about Depression

Surprisingly, the study found less overlap in the genetic hits for depression across ancestry groups than anticipated. Approximately 30% overlap, as determined by a new method developed by the research team, underscores the importance of studying depression in diverse samples. Ancestry-specific findings highlight the need for a global approach in genetic research to ensure inclusivity and relevance.

Led by Professor Karoline Kuchenbaecker and a collaborative team, this study represents a significant leap forward in understanding the genetic intricacies of depression. The identification of over 200 genes associated with depression, especially in diverse ancestry groups, not only contributes to our knowledge of depression genetics but also paves the way for targeted drug development. As we navigate the complexities of mental health, this research emphasizes the necessity of a global and inclusive approach to unravel the mysteries of depression and advance treatment options for individuals of all ancestries.

References:

1. Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference
   
   Meng, X., Navoly, G., Giannakopoulou, O. et al. Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference. Nat Genet (2024). https://doi.org/10.1038/s41588-023-01596-4

Source-Medindia