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Large-Scale Depression Genetic Study Uncovers Additional Risk Loci, Ties to Potential Drugs

NEW YORK — Through a genome-wide association study of more than a million individuals, researchers have identified dozens of additional genetic loci linked to depression.

Depression affects about one of every five people at some point in their life, and recent studies have begun to tease out the genetic underpinnings of the condition. To identify additional genetic loci associated with depression, a team led by researchers at Yale University conducted a GWAS using data from the Million Veteran Program, a project aimed at uncovering genes related to health and disease using data from US veterans.

Following a meta-analysis that included additional large-scale GWAS data from other efforts and replication in an independent sample, the researchers uncovered 178 genetic risk loci and 223 SNPs associated with depression — more than has been linked to the condition previously, which the researchers said underscores the genetic complexity of depression, as they reported in Nature Neuroscience.

"That's why we weren't surprised by how many variants we found," co-senior author Joel Gelernter, a genetics and neuroscience professor at Yale, said in a statement. "And we don't know how many more there are left to discover — hundreds? Maybe even thousands?"

The researchers conducted two GWAS using MVP data, one with more than 250,000 individuals of European ancestry and the other with 59,600 participants of African ancestry.

They combined their European ancestry MVP cohort with GWAS summary statistics from the Psychiatric Genomics Consortium and the UK Biobank, FinnGen, and 23andMe research cohorts, all of European ancestry. In this combined cohort of 1.15 million individuals — which included 340,591 cases — the researchers identified 223 SNPs at 178 genomic risk loci associated with depression.

However, a GWAS based on the MVP participants of African ancestry uncovered no findings of genome-wide significance. When the researchers tested whether the SNPs from their European analysis might also have an effect in their African ancestry cohort, they found many had a similar direction of effect, and a transancestral meta-analysis further noted 233 SNPs at 183 genomic loci associated with depression.

They then replicated their findings using an independent cohort of 1.3 million individuals from 23andMe, finding concordance in the direction of effect for 99 percent of the 211 variants that could be tested.

Following transcriptome-wide and other analyses, the researchers further prioritized risk loci and related genes. For instance, they noted that one SNP they uncovered maps close to the NEGR1 gene, which encodes a neural growth regulator and is expressed in the hypothalamus. Mice lacking this gene show changes in social behavior, including depression-like and anxiety-like features.

As new treatments for depression are needed, the researchers explored whether the Manually Annotated Targets and Drugs Online Resource database was enriched for any of the genes they tied to depression. Through this, they found potential links between drugs that affect glutamatergic function and depression, including riluzole, a drug used to treat amyotrophic lateral sclerosis that is currently in trials as part of a combination therapy for treatment-resistant depression.

"One of the real goals of the research is bringing forward new ways to treat people suffering from depression," co-senior author Murray Stein, a psychiatrist at the VA San Diego Healthcare System and a professor at the University of California, San Diego, said in a statement.

The researchers added that their findings could additionally be used to develop a polygenic risk score to identify individuals at increased risk of developing depression.