Abstract
BackgroundDepression is a common source of human disability for which etiologic insights remain limited. Although abnormalities of monoamine neurotransmission, including dopamine, are theorized to contribute to the pathophysiology of depression, evidence linking dopamine-related genes to depression has been mixed. The current study sought to address this knowledge-gap by examining whether the combined effect of dopamine polymorphisms was associated with depressive symptomatology in both healthy individuals and individuals with depression.MethodsData were drawn from three independent samples: (1) a discovery sample of healthy adult participants (n = 273); (2) a replication sample of adults with depression (n = 1,267); and (3) a replication sample of healthy adult participants (n = 382). A genetic risk score was created by combining functional polymorphisms from five genes involved in synaptic dopamine availability (COMT and DAT) and dopamine receptor binding (DRD1, DRD2, DRD3).ResultsIn the discovery sample, the genetic risk score was associated with depressive symptomatology (β = −0.80, p = 0.003), with lower dopamine genetic risk scores (indicating lower dopaminergic neurotransmission) predicting higher levels of depression. This result was replicated with a similar genetic risk score based on imputed genetic data from adults with depression (β = −0.51, p = 0.04). Results were of similar magnitude and in the expected direction in a cohort of healthy adult participants (β = −0.86, p = 0.15).ConclusionsSequence variation in multiple genes regulating dopamine neurotransmission may influence depressive symptoms, in a manner that appears to be additive. Further studies are required to confirm the role of genetic variation in dopamine metabolism and depression.
Highlights
Depression is one of the most prevalent and costly psychiatric conditions, estimated to affect 16.6% of US adults [1], knowledge of its etiology remains limited
Overview The main hypothesis we sought to test was that genetic variation in the dopamine system was significantly related to depressive symptoms, with genotypes corresponding to lower dopamine neurotransmission being associated with greater depressive symptomatology
In the Healthy Study (HS) sample, the dopamine genetic risk score was significantly associated with Center for Epidemiologic Studies Depression Scale (CES-D) score after adjusting for race/ethnicity (b = 20.80, p = 0.003), with lower genetic risk scores corresponding to greater levels of depression (Figure 1, Table 3)
Summary
Depression is one of the most prevalent and costly psychiatric conditions, estimated to affect 16.6% of US adults [1], knowledge of its etiology remains limited. The most commonly articulated theory regarding the pathophysiology of depression focuses on systems regulating monoamine neurotransmission [2]. Disturbances in limbic dopaminergic pathways may contribute to depressive symptoms in Parkinson’s disease (PD) [5], and dopaminergic therapy for PD can reduce depressive symptoms even in the absence of formal antidepressant treatment [6]. Based on such findings, dopaminergic targets have become a focus for depression therapies; one study found that the DRD2 agonist pramipexole was as effective as fluoxetine in the treatment of MDD [12].
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