Association of neurotransmitter-based polygenic scores with antidepressant treatment outcomes in patients with major depressive disorder
- 1Adelaide Medical School, Adelaide University, Adelaide, SA 5000, Australia
Abstract
Biologically informed polygenic scores (PGSs) may help interpret genetic associations with treatment outcomes. Here, we computed neurotransmitter-based PGSs (NeuroPGSs) for patients with major depressive disorder (MDD) and assessed their association with SSRI treatment outcomes. By targeting genetic variants involved in key neurotransmission pathways, we developed PGSs for serotonergic (5228), gamma-aminobutyric acid (GABA, 4103), dopaminergic (7061), and glutamatergic (5690) variants. We leveraged data from two cohorts of patients who received SSRIs for at least 4 weeks: the International SSRI Pharmacogenomics Consortium (ISPC) and the Pharmacogenomics Research Network Antidepressants Medication Pharmacogenomics Study (PGRN-AMPS). Treatment response was defined as [≥]50% reduction from baseline depression symptoms, measured using 17-item Hamilton Rating Scale for Depression (HRSD-17) in ISPC and 16-item Quick Inventory of Depressive Symptomatology (QIDS-C16) in PGRN-AMPS. Remission was defined as HRSD-17 [≤]7 (ISPC) or QIDS-C16[≤]5 (PGRN-AMPS). The association between each NeuroPGS and antidepressant response or remission was evaluated using logistic regression models, adjusting for age, sex and five genetic principal components, with statistical significance determined at Benjamini-Hochberg-adjusted p<0.05. The GABAergic-based PGS was associated with SSRI response (aOR per SD = 1.45, 95%CI: 1.14-1.85). Patients with the highest GABAergic PGS (10th decile) had 2.59-fold higher odds of response (95%CI: 1.46-4.60) compared to those with the lowest decile (1st decile). These exploratory findings support further evaluation of NeuroPGSs; independent replication and assessment of incremental predictive value are needed before clinical application.
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BibTeX
@misc{sharew2026association,
title = {{Association of neurotransmitter-based polygenic scores with antidepressant treatment outcomes in patients with major depressive disorder}},
author = {N. T. Sharew and S. R. Clark and V. Arolt and J. Brockmoller and C.-H. Chen and K. Domschke and D. K. Hall-Flavin and A. Illi and O. Kampman and E. Leinonen and Y.-J. Liou and T. Mushiroda and J. C. Stingl and A. Benjaponpitak and S. Mahasirimongkol and L. Wang and M. Kato and Y.-L. Liu and W. V. Bobo and S.-J. Tsai and M. Kubo and R. M. Weinshilboum and D. A. Mrazek and J. M. Biernacka and B. T. Baune and K. O. Schubert and A. T. Amare},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.18.26365850},
url = {https://www.medrxiv.org/content/10.64898/2026.10.18.26365850v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Association of neurotransmitter-based polygenic scores with antidepressant treatment outcomes in patients with major depressive disorder
AU - N. T. Sharew
AU - S. R. Clark
AU - V. Arolt
AU - J. Brockmoller
AU - C.-H. Chen
AU - K. Domschke
AU - D. K. Hall-Flavin
AU - A. Illi
AU - O. Kampman
AU - E. Leinonen
AU - Y.-J. Liou
AU - T. Mushiroda
AU - J. C. Stingl
AU - A. Benjaponpitak
AU - S. Mahasirimongkol
AU - L. Wang
AU - M. Kato
AU - Y.-L. Liu
AU - W. V. Bobo
AU - S.-J. Tsai
AU - M. Kubo
AU - R. M. Weinshilboum
AU - D. A. Mrazek
AU - J. M. Biernacka
AU - B. T. Baune
AU - K. O. Schubert
AU - A. T. Amare
PY - 2026
DA - 2026/10/18
PB - medRxiv
DO - 10.64898/2026.10.18.26365850
UR - https://www.medrxiv.org/content/10.64898/2026.10.18.26365850v1
AB - Biologically informed polygenic scores (PGSs) may help interpret genetic associations with treatment outcomes. Here, we computed neurotransmitter-based PGSs (NeuroPGSs) for patients with major depressive disorder (MDD) and assessed their association with SSRI treatment outcomes. By targeting genetic variants involved in key neurotransmission pathways, we developed PGSs for serotonergic (5228), gamma-aminobutyric acid (GABA, 4103), dopaminergic (7061), and glutamatergic (5690) variants. We leveraged data from two cohorts of patients who received SSRIs for at least 4 weeks: the International SSRI Pharmacogenomics Consortium (ISPC) and the Pharmacogenomics Research Network Antidepressants Medication Pharmacogenomics Study (PGRN-AMPS). Treatment response was defined as [≥]50% reduction from baseline depression symptoms, measured using 17-item Hamilton Rating Scale for Depression (HRSD-17) in ISPC and 16-item Quick Inventory of Depressive Symptomatology (QIDS-C16) in PGRN-AMPS. Remission was defined as HRSD-17 [≤]7 (ISPC) or QIDS-C16[≤]5 (PGRN-AMPS). The association between each NeuroPGS and antidepressant response or remission was evaluated using logistic regression models, adjusting for age, sex and five genetic principal components, with statistical significance determined at Benjamini-Hochberg-adjusted p<0.05. The GABAergic-based PGS was associated with SSRI response (aOR per SD = 1.45, 95%CI: 1.14-1.85). Patients with the highest GABAergic PGS (10th decile) had 2.59-fold higher odds of response (95%CI: 1.46-4.60) compared to those with the lowest decile (1st decile). These exploratory findings support further evaluation of NeuroPGSs; independent replication and assessment of incremental predictive value are needed before clinical application.
ER -