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Researchers Link 17 Loci to Depression-Related Phenotypes

NEW YORK (GenomeWeb) – In a genome-wide association study, researchers have identified 17 loci linked to different depression-related phenotypes.

Using data from UK Biobank participants, a University of Edinburgh-led team conducted a genome-wide association study of broad depression, likely major depressive disorder, and diagnosed major depressive disorder. In the US in 2016, 10.3 million adults, or about 6.7 percent, were affected by at least one episode of major depression, according to the National Institute of Mental Health.

As the team reported in Nature Communications yesterday, they teased out 17 loci associated with those depression phenotypes, and these loci included ones near genes involved in neurotransmission and synapse function.

"This study identifies genes that potentially increase our risk of depression, adding to the evidence that it is partly a genetic disorder," first author David Howard from the University of Edinburgh's Center for Clinical Brain Sciences said in a statement. "The findings also provide new clues to the causes of depression, and we hope it will narrow down the search for therapies that could help people living with the condition."

The researchers drew upon the UK Biobank cohort, which has undergone extensive phenotyping, to identify individuals who reported seeking help in the past for depression or related symptoms, those who reported symptoms of depression and related impairment, and those with major depressive disorder, as gauged from hospital admission records. In up to 322,580 UK Biobank participants, the researchers tested whether more than 7.6 million gene variants were associated with those depression-related phenotypes.

Seventeen variants, they reported, reached genome-wide significance across these categories.

To replicate these variants, Howard and his colleagues turned to data from a previous GWAS of major depression using research participants from 23andMe. In 2016, that study linked 15 loci to major depression risk. In that cohort, 16 of the 17 variants Howard and his colleagues uncovered had an effect in the same direction and seven reached significance. In a meta-analysis, all 17 remained significant. The researchers noted that 14 of their 17 variants were novel.

Of these variants, 14 were linked to broad depression, while two were associated with likely major depressive disorder and one was associated with the narrowest depression phenotype of ICD-coded major depressive disorder.

Using Linkage Disequilibrium Score Regression and the LD Hub resource, Howard and his colleagues examined the genetic correlations between these depression phenotypes and 235 other traits. For instance, they noted a significant genetic correlation between the three phenotypes and schizophrenia, while broad depression and probable major depressive disorder were correlated with bipolar disorder. This, the researchers noted, is in agreement with findings reported by the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.

The researchers also examined the roles of the genes located near these loci to identify five gene sets. Four were linked to cellular components, particularly nerve cell components like the excitatory synapse, neuron spine, and dendrite. As imbalances in the excitation and inhibition of neurons have been linked to other psychiatric disorders like schizophrenia and autism spectrum disorder, the researchers said that the role of excitatory synapses in depression should be explored further.

The fifth was linked to mechanosensory pathways, which suggests that people with depression may respond differently to pain.

However, Howard and his colleagues noted that their study is limited by its reliance on self-report of depression-linked symptoms, rather than formal structured interviews. Still, they said their findings indicate that a broad depression phenotype could be a useful tool for genetic studies.