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

TitleGenome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response.
Publication TypeJournal Article
Year of Publication2021
AuthorsMarshe VS, Maciukiewicz M, Hauschild A-C, Islam F, Qin L, Tiwari AK, Sibille E, Blumberger DM, Karp JF, Flint AJ, Turecki G, Lam RW, Milev RV, Frey BN, Rotzinger S, Foster JA, Kennedy SH, Kennedy JL, Mulsant BH, Reynolds CF, Lenze EJ, Müller DJ
JournalTransl Psychiatry
Date Published2021 02 15
KeywordsAged, Antidepressive Agents, Depressive Disorder, Major, Genome-Wide Association Study, Humans, Ion Channels, Male, Multifactorial Inheritance, Venlafaxine Hydrochloride

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) and intergenic rs6916777 (Beta = 14.03 [8.47, 19.59], p = 1.25 × 10), 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, 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). 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.

Alternate JournalTransl Psychiatry
PubMed ID33589590
PubMed Central IDPMC7884410