Evaluating the dopamine hypothesis of schizophrenia in a large-scale genome-wide association study
Introduction
The first widely cited articulation of the dopamine (DA) hypothesis of schizophrenia (DHS) was by Matthysse in 1973 (Kendler and Schaffner, 2011a, Matthysse, 1973) when he suggested that schizophrenia might result from an “over-activity of dopaminergic transmission” (Matthysse, 1973). For several decades in the late 20th century, the DHS was the leading etiologic theory in psychiatry and generated an immense amount of both basic and clinical research.
Two prominent themes emerge from an analysis of the history of the DHS (Kendler and Schaffner, 2011a, Kendler and Schaffner, 2011b). First, the empirical track-record of the theory has been spotty, with a failure to verify robustly most—albeit probably not all—of its key empirical predictions. Second, its persistence over four decades is probably related to the protean nature of the theory undergoing a number of substantial revisions and re-interpretations. For example, Davis and colleagues proposed, in 1991, a major revision of the theory suggesting that “… schizophrenia can be characterized by hypodopaminergia in mesocortical and hyperdopaminergia in mesolimbic dopamine neurons …” (Davis et al., 1991). More recently, Howes and Kapur proposed another substantial modification of the DHS focusing on DA striatal dysfunction as a “final common pathway” for the etiopathogenesis of schizophrenia (Howes and Kapur, 2009). In addition, a review by Howes et al. (2015) described the extent of evidence implicating the dopaminergic system, ranging from antipsychotic efficacy to in vivo imaging. Furthermore, the authors elaborated on the interplay among glutamatergic and dopaminergic systems and their impact of schizophrenia etiology, demonstrating that the effects of dopamine do not act in isolation.
Given the central role of genetic factors in the etiology of schizophrenia, demonstrated both by classical genetic-epidemiologic methods (Sullivan et al., 2003) and by newer analytic methods applied to molecular data (Cross-Disorder Group of the Psychiatric Genomics et al., 2013), a plausible prediction of the DHS would be that variation in at least some genes critical to DA function would impact on risk for schizophrenia. Indeed, a large and inconclusive candidate gene literature emerged in the last several decades examining DA receptor genes and genes involved in the uptake, synthesis and metabolism of DA (Kendler and Schaffner, 2011a). As depicted in Table 1, quite large numbers of individual association studies have been reported for most of the core DA related genes. The percentage of positive reports for a number of them substantially exceeds the 5% expected under the null hypothesis although meta-analyses have not provided consistent positive evidence for association for any gene with the possible exception of DRD4. It is now clear from recent advances in complex disease genetics, as we have clarified the typical effect size of variants impacting multifactorial biomedical disorders, that these earlier candidate gene studies were unpowered which might explain the variability and inconsistency in findings. Furthermore, the potential for publication bias cannot be excluded, raising the possibility that more null results exist than are in the extant literature.
Advances in the field of schizophrenia genetics have now provided us with a much more powerful way to test the genetic predictions of the DHS. As a result of massive efforts, the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) has collected and made publically available GWAS results on 34,241 cases of schizophrenia and 45,604 controls (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). The PGC recently reported strong evidence of an association between variation in DRD2 and schizophrenia case-control status. In addition, they found signal enrichment in KEGG's dopaminergic synapse gene set. However, that category consists of > 100 genes (Kanehisa et al., 2016) whose functions are quite diverse and in many cases only indirectly related to dopamine function. Thus, in some ways the category reflects the diffuse nature of the DHS itself and may not represent a valid test of the core underlying theory.
In this paper, we selected, a priori, 11 genes directly related to DA function which have all been subject to prior candidate gene studies motivated by the DHS (Table 1). We ask a single, simple question: do common molecular variants in these genes, examined as a group, differ significantly in their frequency in cases and controls? A positive response to this question would provide confirmatory evidence for the DHS. By contrast, a negative response – in which the distributions of these variants in the two groups were consistent with chance effects – would provide evidence, although far from conclusive, against the importance of the etiologic role of DA dysfunction in schizophrenia.
Section snippets
Gene selection
We selected 11 genes that are directly involved in the synthesis, metabolism, or neurotransmission of dopamine: catechol-o-methyltransferase (COMT), dopamine beta-hydroxylase (DBH), the five dopamine receptors (DRD1–DRD5), dopa-decarboxylase (DDC), tyrosine hydroxylase (TH), monoamine oxidase A (MAOA), and the dopamine transporter (solute carrier member 6 carrier 3, known as SLC6A3 or DAT). Using positions from genome build hg37, we selected markers in the PGC's most recently publicly available
Simes tests
Using the Simes test, we first tested for evidence of enrichment (relative to background) in the form of a few signals of at least moderate effect size within or near DA-related genes (Table 2). For both ranges tested, we observed no significant enrichment of signals within the 11 genes tested. Given the strong signal mapping to near and within DRD2 in the PGC2 results, we further tested for enrichment near that locus versus among all non-DRD2 SNPs (Table 2). For both ranges tested, we observed
Discussion
In this study, we empirically tested whether core dopamine-related genes were enriched for signals associated with schizophrenia using the largest currently available dataset (PGC2). Our results indicate that, despite strong signal(s) within/near the DRD2 locus, overall there is no enrichment of signals within this core group of genes involved in the synthesis, metabolism, and primary neurotransmission of dopamine.
Given the strong evidence that the etiology of schizophrenia has a substantial
Funding body agreements and policies
This work was supported by the National Institutes of Health (grant numbers K01 AA021399, R21 MH100560, R21 AA022717, U01 MH094421).
Contributors
ACE and KSK designed the study and wrote the manuscript; ACE, SAB, TBB, and AM conducted statistical analyses.
Conflict of interest
The authors have declared that there are no conflicts of interest in relation to the subject of this study.
Acknowledgments
The summary statistics for PGC2 schizophrenia results were obtained from https://pgc.unc.edu/Sharing.php#SharingOpp; we are grateful to the investigators who produced and analyzed these datasets.
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