Dopamine Genetics: Substance Use Disorders vs. Parkinson’s Disease

Summary. It is established that Substance use disorders (SUDs) and Parkinson’s Disease (PD) among many other neuropsychiatric disorders are dopamine (DA)-related brain disorders with strong heritability. However, it is unclear whether DA-associated genetic risks share commonality across these disorders. This study utilizes the Genotype and Phenotype Database (dbGaP), by downloading related genome-wide association studies (GWAS) for individual genotype/phenotypes. According to our results DA pathways are significantly implicated in the genetic etiology of both SUDs and PD but much more in the former. Epistatic effects may represent a major portion of missing heritability observed in current main effect-oriented GWAS analyses.


MATERIALS & METHODS
This study utilizes the Genotype and Phenotype Database (dbGaP), by downloading related genomewide association studies (GWAS) for individual genotype/phenotypes. First, genomic controlling was performed to ensure unrelatedness among subjects [13]; secondly, linkage-based imputation procedures were conducted to capture genotypes for these 22 DA system genes including serotonin and norepinephrine transporters' genes as controls; thirdly, association analyses for main effects and Logistic regressionbased epistasis analyses for intergenic effects on neuropsychiatric etiologies; and, finally meta-analyses of these association results. Genetic manipulations of gene activity in animal models were carried out to determine causality of these genetic associations.

RESULTS
Overall three SUD GWAS datasets and three PD datasets were utilized for the meta-analysis. After genomic and quality control, data from more than 6500 unrelated subjects with each disease were used in the analysis.
Specifically data from four SUD [12] cohorts were obtained from the three datasets: Collaborative Study on the Genetics of Alcoholism (COGA, dbGaP accession#: phs000125.v1.p1), Study of Addiction: Genetics and Environment (SAGE, polysubstance abuse but mainly with cigarette smoking, dbGaP accession#: phs000092.v1.p1), and the Australian twin-family study of alcohol use disorder (OZALC, dbGaP accession#: phs000181.v1.p1). After COGA data quality control (QC), data from the US Caucasians of European (EA) descent and African Americans (AA) were split into these 2 separate ethnic cohorts. Individuals found in both the COGA and SAGE studies, were removed from the SAGE datasets. The OZALC study used family genotype but only unrelated individuals were extracted for the purpose of epistasis analysis. After QC, data from 6,596 subjects remained: 1,368 from COGA_EA, 753 from COGA_AA, 2,063 from the OZALC study, and 2,412 from the SAGE study.
After initial analyses, only one of the 22 genes, SNCA, showed a significant main effect for PD which is consistent with the established literature. After Bonferroni corrections, none of the target genes resulted in a significant main effect for SUDs. However, epistasis analysis uncovered extensive and significant association signals between gene variants and SUDs or, to less extent, PD.
For SUDs, the strongest significant interaction was SNCA with the developmentally expressed vesicular monoamine transporter 1 gene SLC18A1 and our recently discovered TFs. The greatest number of significant interactions were between the DA transporter gene SLC6A3 and 21 of the 22 genes including two DR genes, DRD3 and DRD5. For PD, DRD3 interacted with the tyrosine hydroxylase gene TH and the dopadecarboxylase gene DDC; SLC6A3 interacted with 6 of the 22 target genes. Interestingly, the interaction between DRD3 and the NET gene (SLC6A2) was implicated in both diseases. Importantly, the significant association between SLC6A3 and SUD was confirmed by findings from mouse modeling. [14] CONCLUSIONS DA pathways are significantly implicated in the genetic etiology of both SUDs and PD but much more in the former. Epistatic effects may represent a major portion of missing heritability observed in current main effect-oriented GWAS analyses.