TY - JOUR
T1 - The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression
AU - Amare, Azmeraw T.
AU - Schubert, Klaus Oliver
AU - Tekola-Ayele, Fasil
AU - Hsu, Yi Hsiang
AU - Sangkuhl, Katrin
AU - Jenkins, Gregory
AU - Whaley, Ryan M.
AU - Barman, Poulami
AU - Batzler, Anthony
AU - Altman, Russ B.
AU - Arolt, Volker
AU - Brockmöller, Jürgen
AU - Chen, Chia Hui
AU - Domschke, Katharina
AU - Hall-Flavin, Daniel K.
AU - Hong, Chen Jee
AU - Illi, Ari
AU - Ji, Yuan
AU - Kampman, Olli
AU - Kinoshita, Toshihiko
AU - Leinonen, Esa
AU - Liou, Ying Jay
AU - Mushiroda, Taisei
AU - Nonen, Shinpei
AU - Skime, Michelle K.
AU - Wang, Liewei
AU - Kato, Masaki
AU - Liu, Yu Li
AU - Praphanphoj, Verayuth
AU - Stingl, Julia C.
AU - Bobo, William V.
AU - Tsai, Shih Jen
AU - Kubo, Michiaki
AU - Klein, Teri E.
AU - Weinshilboum, Richard M.
AU - Biernacka, Joanna M.
AU - Baune, Bernhard T.
N1 - Publisher Copyright:
© 2019, Springer-Verlag GmbH Austria, part of Springer Nature.
PY - 2019/1/21
Y1 - 2019/1/21
N2 - Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different p value thresholds (PT) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC, N = 865), and in a replication cohort (STAR*D, N = 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including NEGR1, CADM2, PMAIP1, PARK2) that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2) with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.
AB - Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different p value thresholds (PT) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC, N = 865), and in a replication cohort (STAR*D, N = 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including NEGR1, CADM2, PMAIP1, PARK2) that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2) with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.
KW - Antidepressants
KW - Body mass index
KW - Coronary artery disease
KW - Major depression
KW - Obesity
KW - Pharmacogenomics
KW - Pleiotropy
KW - Polygenic score
KW - SSRIs
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U2 - 10.1007/s00702-018-01966-x
DO - 10.1007/s00702-018-01966-x
M3 - Article
C2 - 30610379
AN - SCOPUS:85059549800
SN - 0300-9564
VL - 126
SP - 35
EP - 45
JO - Journal of Neural Transmission
JF - Journal of Neural Transmission
IS - 1
ER -