Brief reportG-protein β3 subunit genetic variation moderates five-year depressive symptom trajectories of primary care attendees
Introduction
Heterotrimeric guanine nucleotide-binding proteins (G proteins) consist of three subunits, α, β, and γ that are attached to the cell surface plasma membrane and serve as a signalling link between numerous ligands (e.g., neurotransmitters), their receptors (i.e. G protein-coupled receptors), and downstream effectors (Neves et al., 2002). Upon receptor activation, signalling can occur by way of the Gα protein or Gβγ protein complex. Although Gα proteins regulate the majority of this cell signalling, neurotransmitters associated with mood (e.g., serotonin, dopamine, epinephrine, and acetylcholine) have receptors that signal through the Gβγ protein complex. In addition, many effector proteins of the Gβγ protein complex such as phosphatidylinositol 3-kinase (PI3Kβ), phospholipase C-β (PLCβ), glycogen synthase kinase-3 (GSK3), and calcium channels have been implicated in the pathophysiology of affective disorders (Kim et al., 2005, Tanis and Duman, 2007).
To date, a synonymous polymorphism [rs5433 (C825T)] in exon 10 of the β3 subunit of the heterotrimeric G-protein (GNB3) has received considerable attention since it was first identified in 1998 (Siffert et al., 1998). The T allele of this polymorphism has been associated with a splice variant that is linked to increased signal transduction (Siffert et al., 1998) and major depressive disorder (MDD) (Lopez-Leon et al., 2008). However, no other polymorphisms in or near GNB3 have been examined for their association with depression phenotypes and no study to our knowledge has assessed the effect of GNB3 genetic variation on depressive symptom trajectories.
The present study aimed to examine whether genetic variation in GNB3 moderates depressive symptom trajectories. The main hypothesis was that carriers of the rs5443 T allele would have greater rates of major depressive disorder and more severe depressive symptom trajectories over a five-year observation period compared to CC carriers. We also sought to explore variation in the 5-prime region, a region that has not been examined in depression, of the GNB3 gene.
Section snippets
Study population
Participants were enrolled in the Diagnosis, Management and Outcomes of Depression in Primary Care (diamond) study, an ongoing prospective cohort that commenced in 2005 (Gunn et al., 2008). Details of the methods have been published elsewhere (Gunn et al., 2008, Gunn et al., 2013, Potiriadis et al., 2008). Briefly, primary care patients were eligible for the diamond cohort if they were: (a) aged 18–75 years, (b) able to read English, (c) not terminally ill, (d) did not reside in a nursing home
Results
A total of 306 participants consented and were genotyped. We excluded from the present analysis, five participants for whom genotyping failed for one or both of the GNB3 SNPs examined. This resulted in a sample of 301 participants included in the analysis (Table 1). Power calculations showed this sample size was sufficient for detection of an interaction effect of moderate magnitude (eta squared>0.08).
Both htSNPs were in HWE (rs5443: p=0.195; rs5440: p=0.689) and MAFs were >10% (rs5443: T=29%;
Discussion
Our findings suggest that genetic variation in GNB3 moderates five-year depressive symptom trajectories among primary care attendees. Carriers of the rs5440 GG genotype showed a more favourable depressive symptom trajectory than carriers of the GA or AA genotypes but we did not observe an effect for rs5443 (C825T).
The rs5440 polymorphism is located approximately 500 bp upstream from the 5-prime end of GNB3 within the 3-prime untranslated region of the neighbouring leprecan-like 2 (LEPREL2) gene.
Role of funding source
No funding body had a role in study design, the collection, analysis, and interpretation of data, the writing of the manuscript, or the decision to submit this manuscript for publication.
Conflict of interest
None.
Acknowledgements
The diamond study is funded by the National Health and Medical Research Council (IDs 299869, 454463, 566511 and 1002908) and the Victorian Centre for Excellence in Depression and Related Disorders, an initiative between beyondblue and the Victorian Government. The collection of DNA and genotyping was funded by the LEW Carty Chartable Fund (ID 7284). No funding body had a role in the study design, the collection, analysis, and interpretation of data, or the writing of the manuscript for
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