Associations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis

Dimitrios Andreou,Erik Söderman,Tomas Axelsson,Göran C Sedvall,Lars Terenius,Ingrid Agartz,Erik G Jönsson

doi:10.1016/j.neulet.2016.03.005

Abstract

Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder.We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls.We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia.

Highlights

Dopaminergic innervation is prominent in the central nervous system and is critically implicated in many central and peripheral functions [5]
We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., dopamine receptor D1 gene (DRD1), dopamine receptor D2 gen (DRD2), dopamine receptor D3 gene (DRD3), dopamine receptor D4 gene (DRD4) and dopamine receptor D5 gene (DRD5), and the cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations in 74 patients with psychotic disorder
The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia

Summary

Introduction

Dopaminergic innervation is prominent in the central nervous system and is critically implicated in many central and peripheral functions [5]. The catecholaminergic neurotransmitter dopamine is Abbreviations: HVA, homovanillic acid; DRD2, dopamine receptor D2 gen; CSF, cerebrospinal fluid; CNS, central nervous system; DRD1, dopamine receptor D1 gene; DRD3, dopamine receptor D3 gene; DRD4, dopamine receptor D4 gene; DRD5, dopamine receptor D5 gene; SNPs, single nucleotide polymorphisms. D. Andreou et al / Neuroscience Letters 619 (2016) 126–130 association between dopaminergic gene variants and measurable biological markers may be more robust and consistent than the associations between gene variants and the disorder itself. Andreou et al / Neuroscience Letters 619 (2016) 126–130 association between dopaminergic gene variants and measurable biological markers may be more robust and consistent than the associations between gene variants and the disorder itself This approach can shed further light to the understanding of genotype-phenotype associations

Methods

Discussion

Conclusion