Expression of Dopamine-Related Genes in Four Human Brain Regions

Abstract

A better understanding of dopaminergic gene expression will inform future treatment options for many different neurologic and psychiatric conditions. Here, we utilized the National Institutes of Health’s Genotype-Tissue Expression project (GTEx) dataset to investigate genotype by expression associations in seven dopamine pathway genes (ANKK1, DBH, DRD1, DRD2, DRD3, DRD5, and SLC6A3) in and across four human brain tissues (prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus). We found that age alters expression of DRD1 in the nucleus accumbens and prefrontal cortex, DRD3 in the nucleus accumbens, and DRD5 in the hippocampus and prefrontal cortex. Sex was associated with expression of DRD5 in substantia nigra and hippocampus, and SLC6A3 in substantia nigra. We found that three linkage disequilibrium blocks of SNPs, all located in DRD2, were associated with alterations in expression across all four tissues. These demographic characteristic associations and these variants should be further investigated for use in screening, diagnosis, and future treatment of neurological and psychiatric conditions.

Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans

“…Taken together, the present findings, in conjunction with prior work in this area, provide compelling evidence that ESR1, DRD2, TRAF3, and DCC are highly plausible cross-ancestry candidate risk genes for SITB that should be targeted in future investigations of the biology of suicide. Gene-based tests identified 24 more unique cross-ancestry risk genes, including FURIN , TSNARE1 , and the NCAM1-TTC12-ANKK1-DRD2 gene cluster, which also represent promising avenues for future inquiry, as do the numerous FDR-significant cross-ancestry pathways identified through enrichment analyses, including dopaminergic, cyclic adenosine monophosphate, and mitogen-activated protein kinase signaling, axon guidance, and parathyroid hormone synthesis and action.…”

“…Estrogen has also been hypothesized to potentially help to explain sex differences in depression rates, and loss of ESR1 has been found to produce effects on brain tissue in men . Notably, rs6557168 was also recently identified as a likely causal variant for the ESR1 locus in relation to anxiety …”

Enhancing Research Through the Use of the Genotype-Tissue Expression (GTEx) Database

“…Genetic variations in this gene have been associated with a variety of conditions including stroke ( Stanfill et al, 2016 , 2017 ), Parkinson’s disease ( McGuire et al, 2011 ), weight gain ( Stanfill, Hathaway, et al, 2015 ; Stanfill, Conley, et al, 2015 ) and binge eating ( Kessler et al, 2016 ), with alcohol consumption ( Clarke et al, 2017 ), and substance addiction ( Buhler et al, 2015 ). Our work to date has focused mainly on genotypic changes in DRD2 , but it is reasonable to hypothesize that alterations in the sequence could alter this expression in the brain, whether they are directly involved in the coding itself, or whether these variants could act as regulatory variants that alter gene expression and/or splicing ( Kaalund et al, 2014 ; Stanfill & Cao, 2020 ; Zhang et al, 2007 ). Such information would provide a biological explanation of the association of the genotype variations with symptoms of neurological disease and could suggest further functional and mechanistic follow-up.…”

“…As mentioned previously, our team’s work is in neurologic injury and disease, and DRD2 variations are well-known to be associated with these conditions ( Buhler et al, 2015 ; Clarke et al, 2017 ; McGuire et al, 2011 ; Stanfill & Cao, 2020 ; Stanfill et al, 2016 , 2017 ). The information provided by the GTEx portal has enhanced our program of research by demonstrating how DRD2 is expressed across several different brain tissues that cannot be easily accessed in our living subjects.…”

Phenylalanine Rich Diet (Vicia faba L.) Enhances the Expression of Dopamine Receptor D3 (DRD3) Gene in Rabbits

“…Dopamine receptors are responsible for receiving dopamine and bound with it after its production inside the brain and it, also responsible for its transmission and distribution to the entire body by transferring it as nervous signals [2], [29]- [31]. The Dopamine receptor D3 (DRD3) gene is located in the nucleus accumbens in the human brain, and any defection in this gene leads to Schizophrenia disease [32], [33]. The cycle of dopamine biosynthesis begins with the phenylalanine transformation process by phenylalanine hydroxylase enzyme (PAH) and ends at the binding of dopamine to DRD3 in the brain.…”