Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response

Abstract

Antidepressant outcomes in older adults with depression is poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to understand the genetic architecture of antidepressant response. Our sample included 307 older adults (≥60 years) with current major depression, treated with venlafaxine extended-release for 12 weeks. A standard genome-wide association study (GWAS) was conducted for post-treatment remission status, followed by in silico biological characterization of associated genes, as well as polygenic risk scoring for depression, neurodegenerative and cerebrovascular disease. The top-associated variants for remission status and percentage symptom improvement were PIEZO1 rs12597726 (OR = 0.33 [0.21, 0.51], p = 1.42 × 10−6) and intergenic rs6916777 (Beta = 14.03 [8.47, 19.59], p = 1.25 × 10−6), respectively. Pathway analysis revealed significant contributions from genes involved in the ubiquitin-proteasome system, which regulates intracellular protein degradation with has implications for inflammation, as well as atherosclerotic cardiovascular disease (n = 25 of 190 genes, p = 8.03 × 10−6, FDR-corrected p = 0.01). Given the polygenicity of complex outcomes such as antidepressant response, we also explored 11 polygenic risk scores associated with risk for Alzheimer’s disease and stroke. Of the 11 scores, risk for cardioembolic stroke was the second-best predictor of non-remission, after being male (Accuracy = 0.70 [0.59, 0.79], Sensitivity = 0.72, Specificity = 0.67; p = 2.45 × 10−4). Although our findings did not reach genome-wide significance, they point to previously-implicated mechanisms and provide support for the roles of vascular and inflammatory pathways in LLD. Overall, significant enrichment of genes involved in protein degradation pathways that may be impaired, as well as the predictive capacity of risk for cardioembolic stroke, support a link between late-life depression remission and risk for vascular dysfunction.

Pathomechanisms of Vascular Depression in Older Adults

“…A GWAS provided support for the roles of vascular and inflammatory pathways in LLD. Significant enrichment of genes involved in protein degradation pathways as well as the predictive capacity of risk for cardioembolic stroke, however, support a link between LLD and risk for vascular dysfunction [ 198 ]. Other large GWAS data showed co-heritability between CRP levels and individual depressive symptoms [ 199 ] and that inflammatory markers are associated with neurovegetative symptoms of depression [ 200 ].…”

Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue

“…Although this project explored neurovasculature-related changes in two brain regions, many other areas involved in emotion regulation remain unexplored and we hypothesize that stress-induced BBB changes go beyond the NAc and PFC. It will also be intriguing to investigate if age-related neurovascular changes such as BBB breakdown, which has been linked to human cognitive dysfunction 72 , play a causal role in late-life depression 73 which is more prevalent in women 74 .…”

A Systematic Review and Analysis of the Use of Polygenic Scores in Pharmacogenomics

“…Half of the articles focusing on antipsychotic response reported significant associations between PGSs derived from schizophrenia or major depressive disorder risk GWASs and antipsychotic response 42,45,46,47,48,49 . Of the 12 studies examining antidepressant response outcomes, 4 reported significant associations 41,43,50,51 . Two articles found that lower major depressive disorder PGSs and schizophrenia PGSs were associated with improved lithium response in bipolar disorder 52,53 .…”

“…42,45,46,47,48,49 Of the 12 studies examining antidepressant response outcomes, 4 reported significant associations. 41,43,50,51 Two articles found that lower major depressive disorder PGSs and schizophrenia PGSs were associated with improved lithium response in bipolar disorder. 52,53 In addition, an association between an attention deficit hyperactivity disorder PGS and attention deficit hyperactivity disorder treatment response was reported, but this PGS was based on a small base cohort (n = 1,655).…”