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. 2021 Feb 15;11(1):127.
doi: 10.1038/s41398-021-01248-3.

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

Victoria S Marshe  1   2 , Malgorzata Maciukiewicz  3 , Anne-Christin Hauschild  4 , Farhana Islam  2   5 , Li Qin  2 , Arun K Tiwari  2   6 , Etienne Sibille  2   5   6 , Daniel M Blumberger  1   2   6 , Jordan F Karp  7 , Alastair J Flint  1   6   8 , Gustavo Turecki  9 , Raymond W Lam  10 , Roumen V Milev  11 , Benicio N Frey  12   13 , Susan Rotzinger  8   14 , Jane A Foster  13   14 , Sidney H Kennedy  6   8   14   15 , James L Kennedy  1   2   6 , Benoit H Mulsant  1   2   6 , Charles F Reynolds 3rd  7 , Eric J Lenze  16 , Daniel J Müller  17   18   19   20
Affiliations

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

Victoria S Marshe et al. Transl Psychiatry. .

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.

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Conflict of interest statement

E.J.L. has received funding from Takeda, Lundbeck, Janssen, Alkermes, Aptynx, and PCORI, and is a consultant for Janssen and Jazz Pharmaceuticals. B.H.M. currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). He directly owns stocks of General Electric (less than $5,000). Within the past 3 years, he has also received research support from Eli Lilly (medications for an NIH-funded clinical trial) and Pfizer (medications for an NIH-funded clinical trial).

Figures

Fig. 1
Fig. 1. Analysis workflow.
The primary presented analysis is for the IRL-GREY European-ancestry sub-cohort (n = 307). Results for the African-ancestry sub-cohort and total, mixed cohort are presented in the Supplementary Tables.
Fig. 2
Fig. 2. Primary analysis results.
A Results from the SNP-based, genome-wide association study for remission status (top panel in blue) and percentage symptom improvement (bottom panel in grey). B Q–Q plots for association p-values with remission status. C Q–Q plots for association p-values with percentage symptom improvement. D Locus zoom plot of chromosome 6 top-associated locus surrounding rs6916777 (chr6:25251374:C:A). E Locus zoom plot of chromosome 16 top-associated locus surrounding rs12597726 (chr16: 88820301:G:A).
Fig. 3
Fig. 3. Secondary analysis results for top-associated SNPs, rs6916777 (chr6:25251374:C:A) and rs12597726 (chr16: 88820301:G:A).
A, B Mixed-effects analyses for rs6916777 and rs12597726, respectively. Values at each time-point denote mean per genotype, and error bars denote standard error of the mean. C, D Kaplan–Meier survival plots for rs6916777 and rs12597726, respectively. Risk tables denote the number of non-remitted or censored individuals at each time-point. Significance levels. ***p < 0.001, **p < 0.01, *p < 0.05, †p < 0.1.
Fig. 4
Fig. 4. GTEx tissue and geneset enrichment for nominally associated genes with remission status (n = 878) or percentage symptom improvement (n = 889).
A GTEx tissue (n = 54) enrichment. B Enrichment across Gene Ontology and curated genesets. For genesets, only the top 15 sets are shown across both remission status and percentage symptom improvement for brevity. No significant enrichment was observed for tissue or genesets. *Note. Pathways also among the top 15 associated for the second phenotype (either remission status or improvement, as indicated) but at a lower p-value.
Fig. 5
Fig. 5. Polygenic risk scores and prediction.
A Polygenic risk score effect sizes for remission status (blue, odds ratios) and percentage symptom improvement (yellow, unstandardized betas). Error bars denote standard error of the mean. B Variance in remission status explained by the polygenic risk score regression results for cardioembolic risk (Malik et al., 2018). C, D Receiver operating curves for prediction of C remission status and D symptom improvement comparing a base clinical model to a model including the 11 polygenic risk scores. E Variable importance from the best performing model for remission status.
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