TY - JOUR
T1 - Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response
AU - Marshe, Victoria S.
AU - Maciukiewicz, Malgorzata
AU - Hauschild, Anne Christin
AU - Islam, Farhana
AU - Qin, Li
AU - Tiwari, Arun K.
AU - Sibille, Etienne
AU - Blumberger, Daniel M.
AU - Karp, Jordan F.
AU - Flint, Alastair J.
AU - Turecki, Gustavo
AU - Lam, Raymond W.
AU - Milev, Roumen V.
AU - Frey, Benicio N.
AU - Rotzinger, Susan
AU - Foster, Jane A.
AU - Kennedy, Sidney H.
AU - Kennedy, James L.
AU - Mulsant, Benoit H.
AU - Reynolds, Charles F.
AU - Lenze, Eric J.
AU - Müller, Daniel J.
N1 - Funding Information:
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).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85101432105&partnerID=8YFLogxK
U2 - 10.1038/s41398-021-01248-3
DO - 10.1038/s41398-021-01248-3
M3 - Article
C2 - 33589590
AN - SCOPUS:85101432105
SN - 2158-3188
VL - 11
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 127
ER -