NEW YORK – Using genetic data for millions of individuals from more than two dozen countries, an international team led by investigators in the UK has identified hundreds of genes and genetic variants associated with major depression, including a subset of genetic contributors found in specific human populations.
"Together, these findings highlight the value of ancestrally diverse genetic studies to prioritize the study of pathophysiological processes in [major depression]," the authors wrote in Cell on Tuesday, adding that the results "suggest genetic associations will point to new drug targets and more effective therapies that may reduce the considerable disability caused by depression."
Starting with multi-ancestry data for some 686,000 individuals with major depression and more than 4.3 million unaffected control individuals from 29 countries, members of the Psychiatric Genomics Consortium's Major Depressive Disorder Working Group performed a genome-wide association study meta-analysis that unearthed 697 SNPs with new or known ties to depression.
With the help of gene prioritization and pathway enrichment analyses that included fine-mapping, expression quantitative trait locus (eQTL) data, and quantitative protein trait locus clues, the team focused in on 308 depression-related genes, while highlighting enrichment for depression-associated risk variants or genes in the neuron cell types in the brain, particularly at receptor and post-synaptic sites.
"Our study identifies hundreds of additional genetic variants that play a role in depression," co-corresponding author Cathryn Lewis, a genetic epidemiology and statistics researcher with King's College London's Institute of Psychiatry, Psychology and Neuroscience, said in a statement. "These findings show depression is highly polygenic and open up downstream pathways to translate these findings into better care for people with depression."
With the help of published human tissue RNA sequencing data and single-cell RNA-seq data on individual cells in central- and peripheral nervous system samples from mice and humans, meanwhile, the researchers saw signs that excitatory, inhibitory, and medium spiny neurons were also enriched for enhanced major depression-related variant or gene activity, as were neurons in the brain's amygdala region.
"Our results confirm and extend previous findings showing the enrichment of expression signals in excitatory and inhibitory neurons," the authors reported, adding that "the increased power in this genetic analysis provided additional evidence of involvement of amygdala and hippocampal excitatory neurons, including granule cells and medium spiny neurons."
The team went on to establish polygenic risk scores for depression using data for European participants or participants from non-European populations, with the European depression PRS accounting for some 5.8 percent of depression risk in that group. Even so, the results suggested that polygenic risk scores for major depression cannot be easily transferred across different populations, since distinct risk contributors turned up in African populations and other non-European populations.
The investigators also turned to a web interface tool called Drug Targetor to pin down possible antidepressant therapy targets, identifying targets for existing treatments as well as potential drug repurposing approaches. For example, the latter analysis suggested drugs approved to treat conditions such as chronic pain and narcolepsy may also help to treat depression.
Though the authors noted that such repurposing is "supported by sparse, non-randomized evidence supporting their efficacy in depression and related conditions," they cautioned that randomized clinical trials are needed to explore that possibility further.
"There are huge gaps in our understanding of clinical depression that limit opportunities to improve outcomes for those affected," co-corresponding author Andrew McIntosh, chair of biological psychiatry at the University of Edinburgh's Centre for Clinical Brain Sciences and the Centre for Genomic and Experimental Medicine, said in a statement.
"Larger and more globally representative studies are vital to provide the insights needed to develop new and better therapies and prevent illness in those at higher risk of developing the condition," McIntosh added.