The association of ARRB1 polymorphisms with response to antidepressant treatment in depressed patients

Kenneth Chappell, Abd El Kader Ait Tayeb, Romain Colle, Jérôme Bouligand, Khalil El-Asmar, Florence Gressier, Séverine Trabado, Denis Joseph David, Bruno Feve, Laurent Becquemont, Emmanuelle Corruble, Céline Verstuyft, Kenneth Chappell, Abd El Kader Ait Tayeb, Romain Colle, Jérôme Bouligand, Khalil El-Asmar, Florence Gressier, Séverine Trabado, Denis Joseph David, Bruno Feve, Laurent Becquemont, Emmanuelle Corruble, Céline Verstuyft

Abstract

Introduction: β-arrestin 1, a protein encoded by ARRB1 involved in receptor signaling, is a potential biomarker for the response to antidepressant drug (ATD) treatment in depression. We examined ARRB1 genetic variants for their association with response following ATD treatment in METADAP, a cohort of 6-month ATD-treated depressed patients. Methods: Patients (n = 388) were assessed at baseline (M0) and after 1 (M1), 3 (M3), and 6 months (M6) of treatment for Hamilton Depression Rating Scale (HDRS) changes, response, and remission. Whole-gene ARRB1 variants identified from high-throughput sequencing were separated by a minor allele frequency (MAF)≥5%. Frequent variants (i.e., MAF≥5%) annotated by RegulomeDB as likely affecting transcription factor binding were analyzed using mixed-effects models. Rare variants (i.e., MAF<5%) were analyzed using a variant set analysis. Results: The variant set analysis of rare variants was significant in explaining HDRS score changes (T = 878.9; p = 0.0033) and remission (T = -1974.1; p = 0.034). Rare variant counts were significant in explaining response (p = 0.016), remission (p = 0.022), and HDRS scores at M1 (p = 0.0021) and M3 (p=<0.001). rs553664 and rs536852 were significantly associated with the HDRS score (rs553664: p = 0.0055 | rs536852: p = 0.046) and remission (rs553664: p = 0.026 | rs536852: p = 0.012) through their interactions with time. At M6, significantly higher HDRS scores were observed in rs553664 AA homozygotes (13.98 ± 1.06) compared to AG heterozygotes (10.59 ± 0.86; p = 0.014) and in rs536852 GG homozygotes (14.88 ± 1.10) compared to AG heterozygotes (11.26 ± 0.95; p = 0.0061). Significantly lower remitter rates were observed in rs536852 GG homozygotes (8%, n = 56) compared to AG heterozygotes (42%, n = 105) at M6 (p = 0.0018). Conclusion: Our results suggest ARRB1 variants may influence the response to ATD treatment in depressed patients. Further analysis of functional ARRB1 variants and rare variant burden in other populations would help corroborate our exploratory analysis. β-arrestin 1 and genetic variants of ARRB1 may be useful clinical biomarkers for clinical improvement following ATD treatment in depressed individuals. Clinical Trial Registration: clinicaltrials.gov; identifier NCT00526383.

Keywords: ARRB1; high-throughput sequencing; major depressive disorder; pharmacogenetics; β Arrestin.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Chappell, Ait Tayeb, Colle, Bouligand, El-Asmar, Gressier, Trabado, David, Feve, Becquemont, Corruble and Verstuyft.

Figures

FIGURE 1
FIGURE 1
Timeline of β-arrestin 1 findings in psychopharmacology. Findings pertaining to β-arrestin 1 and ARRB1 across time. Colored boxes denote broad β-arrestin 1 findings (grey), β-arrestin 1 protein findings in the context of depression and/or antidepressants (blue), or genetic associations in the context of neuropsychiatric disorders (orange). Distance from timeline denotes whether studies were conducted entirely in human participants (furthest), partly (between), or in other models (closest).
FIGURE 2
FIGURE 2
ARRB1 transcript isoforms. Graphical representations of the two ARRB1 transcript isoforms along chromosome 11 (genomic position, x-axis). Exons and 5′- and 3′-untranslated regions are represented by vertical lines and arrows. Intronic sequences are represented by the intervening horizontal lines. Data were obtained from NCBI Genome Data Viewer, assembly GRCh37. p13 (accessed 15 August 2022).
FIGURE 3
FIGURE 3
ARRB1 genetic variant selection pipeline. Flowchart for ARRB1 genetic variant selection. Gray boxes correspond to analyzed variants. Indel, insertion/deletion; MAF, minor allele frequency; SNP, single nucleotide polymorphism.
FIGURE 4
FIGURE 4
Association of MAF (A) the probability of response, (B) the probability of remission, (C) the HDRS score at M1, and (D) the HDRS score at M3 (y-axis) according to the MAF<5% variant count (x-axis). HDRS, 17-item Hamilton Depression Rating Scale; M1, 1 month after beginning antidepressant treatment; M3, 3 months after beginning antidepressant treatment; MAF, minor allele frequency.
FIGURE 5
FIGURE 5
Average HDRS scores according to rs553664 and rs536852 genotypes over the course of antidepressant treatment. Average HDRS scores (y-axis) according to rs553664 (A) and rs536852 (B) genotypes (see legend) are shown across time (x-axis) after controlling for age, sex, antidepressant class, ethnicity, and significantly different demographic factors (see Supplementary Table S3). Error bars correspond to the standard error estimates from mixed-effects models. *: p < 0.0056 (0.05/9) **: p < 0.0011 (0.01/9). HDRS, 17-item Hamilton Depression Rating Scale; M0, baseline, prior to beginning antidepressant treatment; M1, 1 month after beginning antidepressant treatment; M3, 3 months after beginning antidepressant treatment; M6, 6 months after beginning antidepressant treatment.
FIGURE 6
FIGURE 6
Remission rates according to rs536852 genotypes over the course of antidepressant treatment. The probability of remission (y-axis) according to rs536852 genotypes (see legend) are shown across time (x-axis) after controlling for age, sex, antidepressant class, ethnicity, and significantly different demographic factors (see Supplementary Table S2). Error bars correspond to the standard error estimates from mixed-effects models. **: p < 0.0011 (0.01/9). M1, 1 month after beginning antidepressant treatment; M3, 3 months after beginning antidepressant treatment; M6, 6 months after beginning antidepressant treatment.

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