"Our study provides a biological rationale to look at new uses for old drugs - drugs approved for other problems but that deserve a look in the context of depression," principal author Dr. Joel Gelernter of Yale University School of Medicine in New Haven told Reuters Health by email.
"Establishing whether these rationales might lead to new treatments requires many more steps, including clinical trials," he acknowledged. "But basing this analysis on drugs that are already approved for other uses makes it an easier process."
"It was a little surprising how effective the replication analysis was," lead author Dr. Daniel Levey, also of Yale, noted in the same email. "We're at the point where we have multiple powerful cohorts and, indeed, we are seeing that these results seem to be consistent."
As reported in Nature Neuroscience, the team analyzed the genomes of over 250,000 participants of European ancestry and nearly 60,000 veterans of African ancestry in the Million Veteran Program. Then they combined the findings with previous analyses from several other genetic repositories--the UK Biobank, FinnGen, and 23andMe - for a total of 1.2 million participants.
Of those, more than 340,000 of European American ancestry and close to 26,000 of African ancestry had depression.
Transcriptome-wide association study analyses of those with depression revealed significant associations with the expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others.
Further analyses identified 178 loci involved in depression risk, including 77 not detected in previous research, as well as 223 single nucleotide polymorphisms (SNPs) at the 178 locations that appear to affect a person's depression risk.
Additional analyses showed that 125 (61%) of the SNPs identified in the European ancestry group similarly affected the African ancestry participants' risk for depression.
An analysis of an independent cohort of more than 1,3000,000 samples provided by 23andMe, including more than 455,000 depression cases yielded "substantial replications" of the findings.
The team also uncovered genetic risk overlap between depression and several other psychiatric conditions, as suggested by other studies, including anxiety disorders, PTSD, risky behavior and cannabis use disorder. With regard to possible repurposing of existing drugs, a database search pinpointed, among others, riluzole, currently used to treat amyotrophic lateral sclerosis, as a candidate; riluzole is currently in trials for combination therapy in treatment-resistant depression.
Next steps, according to Dr. Levey, include a project that addresses the variance in genes that affect women versus men.
Dr. Anthony Rothschild, Professor of Psychiatry at the University of Massachusetts Medical School and Editor-in-Chief of the Journal of Clinical Psychopharmacology, commented in an email to Reuters Health. "The finding of the importance of DRD2 in the nucleus accumbens is important as it shows the role for dopaminergic function in symptoms of anhedonia."
"The finding of the importance of glutamatergic function is important, as that is the mechanism of ketamine and esketamine and other medications in development," he said. "The study also provides important clues for the repurposing of medications for the treatment of depression (e.g., estrogen)."
Nonetheless, he added, "one of the issues in genetic research of psychiatric disorders is that the phenotype (major depressive disorder; MDD) is a very broad category likely encompassing people with many different etiologies."
"With the current DSM-5 criteria, there are 227 possible ways to meet the symptom criteria for MDD," he noted. "There was also considerable variance in some of the samples, in part I think related to the broad definition of MDD."
"I would like to see replication of the findings and studies in non-European populations," he added.
SOURCE: https://go.nature.com/3iAQ8gh Nature Neuroscience, online May 27, 2021
By Marilynn Larkin
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