Parkinson's Disease Risk Genes Research Articles

Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and Fine-mapping of causal gene sets (FOCUS), leveraging joint-tissue imputation (JTI) prediction models of 22 tissues to identify and prioritize putatively causal genes. We further conducted PWAS, SMR, TWAS, and FOCUS using a multi-trait analysis of GWAS (MTAG) to identify additional PD risk genes to boost statistical power. In this large-scale study, we identified 16 genes whose genetically regulated protein abundance levels were associated with Parkinson's disease risk. We undertook a large-scale analysis of PD and correlated traits, through TWAS and FOCUS studies, and discovered 26 casual genes related to PD that had not been reported in previous TWAS. 5 genes (CD38, GPNMB, RAB29, TMEM175, TTC19) showed significant associations with PD at both the proteome-wide and transcriptome-wide levels. Our study provides new insights into the etiology and underlying genetic architecture of PD.

Molecular profiling of human substantia nigra identifies diverse neuron types associated with vulnerability in Parkinson's disease.

Parkinson's disease (PD) is characterized pathologically by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Whether cell types beyond DA neurons in the SN show vulnerability in PD remains unclear. Through transcriptomic profiling of 315,867 high-quality single nuclei in the SN from individuals with and without PD, we identified cell clusters representing various neuron types, glia, endothelial cells, pericytes, fibroblasts, and T cells and investigated cell type-dependent alterations in gene expression in PD. Notably, a unique neuron cluster marked by the expression of RIT2, a PD risk gene, also displayed vulnerability in PD. We validated RIT2-enriched neurons in midbrain organoids and the mouse SN. Our results demonstrated distinct transcriptomic signatures of the RIT2-enriched neurons in the human SN and implicated reduced RIT2 expression in the pathogenesis of PD. Our study sheds light on the diversity of cell types, including DA neurons, in the SN and the complexity of molecular and cellular changes associated with PD pathogenesis.

Epigenetic associations of GPNMB rs199347 variant with alcohol consumption in Parkinson's disease.

Alcohol consumption can induce a neuroinflammatory response and contribute to the progression of neurodegeneration. However, its association with Parkinson's disease (PD), the second most common neurodegenerative disorder, remains undetermined. Recent studies suggest that the glycoprotein non-metastatic melanoma protein B (GPNMB) is a potential biomarker for PD. We evaluated the association of rs199347, a variant of the GPNMB gene, with alcohol consumption and methylation upstream of GPNMB. We retrieved genetic and DNA methylation data obtained from participants enrolled in the Taiwan Biobank (TWB) between 2008 and 2016. After excluding individuals with incomplete or missing information about potential PD risk factors, we included 1,357 participants in our final analyses. We used multiple linear regression to assess the association of GPNMB rs199347 and chronic alcohol consumption (and other potential risk factors) with GPNMB cg17274742 methylation. There was no difference between the distribution of GPNMB rs199347 genotypes between chronic alcohol consumers and the other study participants. A significant interaction was observed between the GPNMB rs199347 variant and alcohol consumption (p = 0.0102) concerning cg17274742 methylation. Compared to non-chronic alcohol consumers with the AA genotype, alcohol drinkers with the rs199347 GG genotype had significantly lower levels (hypomethylation) of cg17274742 (p = 0.0187). Alcohol consumption among individuals with the rs199347 GG genotype was associated with lower levels of cg17274742 methylation, which could increase expression of the GPNMB gene, an important neuroinflammatory-related risk gene for PD.

Distinct Patterns of Gene Expression Changes in the Colon and Striatum of Young Mice Overexpressing Alpha-Synuclein Support Parkinson's Disease as a Multi-System Process.

Evidence supports a role for the gut-brain axis in Parkinson's disease (PD). Mice overexpressing human wild type α- synuclein (Thy1-haSyn) exhibit slow colonic transit prior to motor deficits, mirroring prodromal constipation in PD. Identifying molecular changes in the gut could provide both biomarkers for early diagnosis and gut-targeted therapies to prevent progression. To identify early molecular changes in the gut-brain axis in Thy1-haSyn mice through gene expression profiling. Gene expression profiling was performed on gut (colon) and brain (striatal) tissue from Thy1-haSyn and wild-type (WT) mice aged 1 and 3 months using 3' RNA sequencing. Analysis included differential expression, gene set enrichment and weighted gene co-expression network analysis (WGCNA). At one month, differential expression (Thy1-haSyn vs. WT) of mitochondrial genes and pathways related to PD was discordant between gut and brain, with negative enrichment in brain (enriched in WT) but positive enrichment in gut. Linear regression of WGCNA modules showed partial independence of gut and brain gene expression changes. Thy1-haSyn-associated WGCNA modules in the gut were enriched for PD risk genes and PD-relevant pathways including inflammation, autophagy, and oxidative stress. Changes in gene expression were modest at 3 months. Overexpression of haSyn acutely disrupts gene expression in the colon. While changes in colon gene expression are highly related to known PD-relevant mechanisms, they are distinct from brain changes, and in some cases, opposite in direction. These findings are in line with the emerging view of PD as a multi-system disease.

Rotenone impairs brain glial energetics and locomotor behavior in bumblebees

Bumblebees are essential pollinators of both wildflowers and crops and face multiple anthropogenic stressors, particularly the utilization of pesticides. Rotenone is an extensively applied neurotoxic pesticide that possesses insecticidal activities against a wide range of pests. However, whether environmentally realistic exposure levels of rotenone can damage neurons in bumblebee brains is still uncertain. Using single-cell RNA-seq, we revealed that rotenone induced cell-specific responses in bumblebee brains, emphasizing the disruption of energy metabolism and mitochondrial dysfunction in glial cells. Correspondingly, the gene regulatory network associated with neurotransmission was also suppressed. Notably, rotenone could specially reduce the number of dopaminergic neurons, impairing bumblebee's ability to fly and crawl. We also found impaired intestinal motility in rotenone-treated bumblebees. Finally, we demonstrated that many differentially expressed genes in our snRNA-seq data overlapped with rotenone-induced Parkinson's disease risk genes, especially in glial cells. Although rotenone is widely used owing to its hypotoxicity, we found that environmentally realistic exposure levels of rotenone induced disturbed glial energetics and locomotor dysfunction in bumblebees, which may lead to an indirect decline in this essential pollinator.

Genetic insights into immune mechanisms of Alzheimer's and Parkinson's disease.

Microglia, the macrophages of the brain, are vital for brain homeostasis and have been implicated in a broad range of brain disorders. Neuroinflammation has gained traction as a possible therapeutic target for neurodegeneration, however, the precise function of microglia in specific neurodegenerative disorders is an ongoing area of research. Genetic studies offer valuable insights into understanding causality, rather than merely observing a correlation. Genome-wide association studies (GWAS) have identified many genetic loci that are linked to susceptibility to neurodegenerative disorders. (Post)-GWAS studies have determined that microglia likely play an important role in the development of Alzheimer's disease (AD) and Parkinson's disease (PD). The process of understanding how individual GWAS risk loci affect microglia function and mediate susceptibility is complex. A rapidly growing number of publications with genomic datasets and computational tools have formulated new hypotheses that guide the biological interpretation of AD and PD genetic risk. In this review, we discuss the key concepts and challenges in the post-GWAS interpretation of AD and PD GWAS risk alleles. Post-GWAS challenges include the identification of target cell (sub)type(s), causal variants, and target genes. Crucially, the prediction of GWAS-identified disease-risk cell types, variants and genes require validation and functional testing to understand the biological consequences within the pathology of the disorders. Many AD and PD risk genes are highly pleiotropic and perform multiple important functions that might not be equally relevant for the mechanisms by which GWAS risk alleles exert their effect(s). Ultimately, many GWAS risk alleles exert their effect by changing microglia function, thereby altering the pathophysiology of these disorders, and hence, we believe that modelling this context is crucial for a deepened understanding of these disorders.

Characterization of altered molecular mechanisms in Parkinson's disease through cell type-resolved multiomics analyses.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. However, cell type-dependent transcriptional regulatory programs responsible for PD pathogenesis remain elusive. Here, we establish transcriptomic and epigenomic landscapes of the substantia nigra by profiling 113,207 nuclei obtained from healthy controls and patients with PD. Our multiomics data integration provides cell type annotation of 128,724 cis-regulatory elements (cREs) and uncovers cell type-specific dysregulations in cREs with a strong transcriptional influence on genes implicated in PD. The establishment of high-resolution three-dimensional chromatin contact maps identifies 656 target genes of dysregulated cREs and genetic risk loci, uncovering both potential and known PD risk genes. Notably, these candidate genes exhibit modular gene expression patterns with unique molecular signatures in distinct cell types, highlighting altered molecular mechanisms in dopaminergic neurons and glial cells including oligodendrocytes and microglia. Together, our single-cell transcriptome and epigenome reveal cell type-specific disruption in transcriptional regulations related to PD.

Bacterial Butyrate in Parkinson's Disease Is Linked to Epigenetic Changes and Depressive Symptoms.

BackgroundThe gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers.ObjectivesHere, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons.MethodsStool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short‐chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome‐wide DNA methylation by targeted bisulfite sequencing.ResultsWe show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate‐associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate‐associated methylated‐DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases.ConclusionsDecreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyrate‐dependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Parkinson's disease risk genes act in glia to control neuronal α-synuclein toxicity

Idiopathic Parkinson's disease is the second most common neurodegenerative disease and is estimated to be approximately 30% heritable. Genome wide association studies have revealed numerous loci associated with risk of development of Parkinson's disease. The majority of genes identified in these studies are expressed in glia at either similar or greater levels than their expression in neurons, suggesting that glia may play a role in Parkinson's disease pathogenesis. The role of individual glial risk genes in Parkinson's disease development or progression is unknown, however. We hypothesized that some Parkinson's disease risk genes exert their effects through glia. We developed a Drosophila model of α-synucleinopathy in which we can independently manipulate gene expression in neurons and glia. Human wild type α-synuclein is expressed in all neurons, and these flies develop the hallmarks of Parkinson's disease, including motor impairment, death of dopaminergic and other neurons, and α-synuclein aggregation. In these flies, we performed a candidate genetic screen, using RNAi to knockdown 14 well-validated Parkinson's disease risk genes in glia and measuring the effect on locomotion in order to identify glial modifiers of the α-synuclein phenotype. We identified 4 modifiers: aux, Lrrk, Ric, and Vps13, orthologs of the human genes GAK, LRRK2, RIT2, and VPS13C, respectively. Knockdown of each gene exacerbated neurodegeneration as measured by total and dopaminergic neuron loss. Knockdown of each modifier also increased α-synuclein oligomerization. These results suggest that some Parkinson's disease risk genes exert their effects in glia and that glia can influence neuronal α-synuclein proteostasis in a non-cell-autonomous fashion. Further, this study provides proof of concept that our novel Drosophila α-synucleinopathy model can be used to study glial modifier genes, paving the way for future large unbiased screens to identify novel glial risk factors that contribute to PD risk and progression.

Genetic analysis of TRIM family genes for early-onset Parkinson's disease in Chinese population

IntroductionAmounting evidence has suggested the Tripartite Motif (TRIM) family proteins as related to Parkinson's disease (PD). However, many of the risk genes were still awaiting further explorations, and their genetic role in PD has not been investigated yet. MethodsHere, we aimed to systematically evaluate the genetic associations of TRIMs with PD in a large Chinese early-onset PD (EOPD, age at onset < 50 years) cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated EOPD patients using whole exome sequencing, and evaluated the association between rare variants and EOPD at allele and gene levels. ResultsTotally 123 rare variants were identified in 13 TRIM protein family members, including TRIM3, TRIM6, TRIM8, TRIM9, TRIM10, TRIM11, TRIM17, TRIM24, TRIM27, TRIM28, TRIM34, TRIM40 and TRIM41. At the allele level, three variants were nominally associated with PD, namely p.R65H in TRIM10, p.P467S in TRIM11, and p.I425V in TRIM24. Gene-based burden analysis showed a clear enrichment of rare variants of TRIM24 in EOPD. ConclusionThese results demonstrate TRIM24 as a potential risk gene for PD, provide a better understanding for the genetic involvement of TRIM protein family members in EOPD and broaden the current mutation spectrum of PD.

Mutation analysis of seven SLC family transporters for early-onset Parkinson's disease in Chinese population

The solute carrier (SLC) transporters have been suggested to play important roles in neurodegenerative disorders. Recently, seven SLC transporters were identified to be associated with Parkinson's disease (PD) by genome-wide association studies. However, few replications were conducted, and whether rare variants in these genes were associated with PD was not explored yet. To elucidate the genetic associations of these SLCs with PD, we investigated the rare variants in 743 Chinese early-onset PD (EOPD) patients using whole-exome sequencing, and evaluated the association between rare variants and PD at allele and gene levels. Totally, 58 rare variants were identified in SLC50A1, SLC41A1, SLC45A3, SLC44A4, SLC56A2, SLC2A13 and SLC38A1. At allele level, 6 variants were nominally associated with PD, namely p.S423G in SLC45A3, p.I551V, p.T435S, p.R323C and p.V101M in SLC2A13, and p.R285Q in SLC41A1. Gene-based burden analysis showed enrichment of rare variants of SLC2A13 in EOPD. Our study systematically analyzed the genetic involvement of SLCs in EOPD, identified SLC2A13 as a risk gene for PD, and broadened the current mutation spectrum of PD.

Single-cell brain atlas of Parkinson's disease mouse model

Parkinson's disease (PD) is a neurodegenerative disease, leading to the impairment of movement execution. PD pathogenesis has been largely investigated, either limited to bulk transcriptomic levels or at certain cell types, which failed to capture the cellular heterogeneity and intrinsic interplays among distinct cell types. Here, we report the application of single-nucleus RNA-seq on midbrain, striatum, and cerebellum of the α-syn-A53T mouse, a well-established PD mouse model, and matched controls, generating the first single cell transcriptomic atlas for the PD model mouse brain composed of 46,174 individual cells. Additionally, we comprehensively depicte the dysfunctions in PD pathology, covering the elevation of NF-κB activity, the alteration of ion channel components, the perturbation of protein homeostasis network, and the dysregulation of glutamatergic signaling. Notably, we identify a variety of cell types closely associated with PD risk genes. Taken together, our study provides valuable resources to systematically dissect the molecular mechanism of PD pathogenesis at the single-cell resolution, which facilitates the development of novel approaches for diagnosis and therapies against PD.

Assessment of the association between NUS1 variants and essential tremor

A recent study on early onset Parkinson's disease (PD) revealed that NUS1 is a risk gene for PD. Clinically, essential tremor (ET) is closely related to PD. In this study, we aimed to detect NUS1 variants and assess the effect of those variants on patients with ET. The 5 coding regions and the exon-intron boundaries of NUS1 were directly sequenced in 395 patients with ET and an equal number of healthy controls, matched for age and sex. The function of variants was assessed by pathogenic predictive software programs. Genetic analysis of variants was used to evaluate susceptibility to ET. A total of 6 exonic variants were identified, including 3 synonymous and 3 missense variants. The non-synonymous variants were predicted to be tolerable. No variants had significant association with ET (none of the p-values were less than 0.05, using Fisher's exact test). Our study suggested that NUS1 variants may not contribute to the risk of ET.

Molecular Signatures of Neuroinflammation Induced by αSynuclein Aggregates in Microglial Cells.

Alpha-synuclein (αSynAgg) are pathological hallmarks of Parkinson's disease (PD) and other synucleinopathies that induce microglial activation and immune-mediated neurotoxicity, but the molecular mechanisms of αSynAgg-induced immune activation are poorly defined. We performed quantitative proteomics by mass spectrometry coupled with PCR, immunohistochemical and functional validations studies to define the molecular characteristics of alpha synuclein mediated microglial activation. In mouse microglia, αSynAgg induced robust pro-inflammatory activation (increased expression of 864 genes including Irg1, Ifit1, and Pyhin) and increased nuclear proteins involved in RNA synthesis, splicing, and anti-viral defense mechanisms. Conversely, αSynAgg decreased expression several proteins (including Cdc123, Sod1, and Grn), which were predominantly cytosolic and involved in metabolic, proteasomal and lysosomal mechanisms. Pathway analyses and confirmatory in vitro studies suggested that αSynAgg partly mediates its effects via Stat3 activation. As predicted by our proteomic findings, we verified that αSynAgg induces mitochondrial dysfunction in microglia. Twenty-six proteins differentially expressed by αSynAgg were also identified as PD risk genes in genome-wide association studies (upregulated: Brd2, Clk1, Siglec1; down-regulated: Memo1, Arhgap18, Fyn, and Pgrn/Grn). We validated progranulin (PGRN) as a lysosomal PD-associated protein that is downregulated by αSynAgg in microglia in-vivo and is expressed by microglia in post-mortem PD brain, congruent with our in vitro findings.Conclusion: Together, proteomics approach both reveals novel molecular insights into αSyn-mediated neuroinflammation in PD and other synucleinopathies.

A systems biology approach towards the identification of candidate therapeutic genes and potential biomarkers for Parkinson's disease.

Parkinson’s disease (PD) is an irreversible and incurable multigenic neurodegenerative disorder. It involves progressive loss of mid brain dopaminergic neurons in the substantia nigra pars compacta (SN). We compared brain gene expression profiles with those from the peripheral blood cells of a separate sample of PD patients to identify disease-associated genes. Here, we demonstrate the use of gene expression profiling of brain and blood for detecting valid targets and identifying early PD biomarkers. Implementing this systematic approach, we discovered putative PD risk genes in brain, delineated biological processes and molecular functions that may be particularly disrupted in PD and also identified several putative PD biomarkers in blood. 20 of the differentially expressed genes in SN were also found to be differentially expressed in the blood. Further application of this methodology to other brain regions and neurological disorders should facilitate the discovery of highly reliable and reproducible candidate risk genes and biomarkers for PD. The identification of valid peripheral biomarkers for PD may ultimately facilitate early identification, intervention, and prevention efforts as well.

Family-based association study on functional α-synuclein polymorphisms in attention-deficit/hyperactivity disorder.

Studies have strongly suggested a disturbed regulation of dopaminergic neurotransmission in attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD). A genetic and phenotypic overlap between both disorders is discussed. A well-studied risk gene for PD is the gene coding for α-synuclein (SNCA). α-Synuclein, a protein located primarily in the presynaptic vesicles, has been suggested to play a role in the modulation of dopamine transporter (DAT) function. DAT is the target of psychostimulants for the treatment of ADHD and plays a key role in regulating the dopamine concentrations in the synaptic cleft. In our sample consisting of German families with children affected by ADHD, we tested for association of allelic variants of two functionally relevant polymorphisms of the α-synuclein gene (NACP-Rep1: 156 families, 232 children; rs356219: 195 families, 284 children) with ADHD. Transmission disequilibrium test analysis revealed no over-transmission for NACP-Rep1 (OR 1, pnom = 1 padj = 1) and rs356219 (OR 1.28; pnom = 0288) in affected siblings. However, a subanalysis on trios with index children showed a nominal association of rs356219 with ADHD (OR 1.43, pnom = 0.020), which survived Bonferroni correction (padj = 0.039); again, no association for NACP-Rep1 (OR 0.8, p = 0.317, padj = 0.634) was found. In conclusion, we found in our pilot study a trend for an association of the rs356219 genotype in SNCA that may affect α-synuclein function and contribute to the aetiology of ADHD. In light of the small sample size of our study, the link between PD and ADHD through dopamine-related neurobiology warrants further investigations. Future studies on SNCA in large ADHD samples should focus on specified symptoms and traits, e.g. attentional capacities or emotional dysregulation.

In silico drug screening by using genome-wide association study data repurposed dabrafenib, an anti-melanoma drug, for Parkinson's disease.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss. At present, there are no drugs that stop the progression of PD. As with other multifactorial genetic disorders, genome-wide association studies (GWASs) found multiple risk loci for PD, although their clinical significance remains uncertain. Here, we report the identification of candidate drugs for PD by a method using GWAS data and in silico databases. We identified 57 Food and Drug Administration-approved drug families as candidate neuroprotective drugs for PD. Among them, dabrafenib, which is known as a B-Raf kinase inhibitor and is approved for the treatment of malignant melanoma, showed remarkable cytoprotective effects in neurotoxin-treated SH-SY5Y cells and mice. Dabrafenib was found to inhibit apoptosis, and to enhance the phosphorylation of extracellular signal-regulated kinase (ERK), and inhibit the phosphorylation of c-Jun NH2-terminal kinase. Dabrafenib targets B-Raf, and we confirmed a protein–protein interaction between B-Raf and Rit2, which is coded by RIT2, a PD risk gene in Asians and Caucasians. In RIT2-knockout cells, the phosphorylation of ERK was reduced, and dabrafenib treatment improved the ERK phosphorylation. These data indicated that dabrafenib exerts protective effects against neurotoxicity associated with PD. By using animal model, we confirmed the effectiveness of this in silico screening method. Furthermore, our results suggest that this in silico drug screening system is useful in not only neurodegenerative diseases but also other common diseases such as diabetes mellitus and hypertension.

Chapter 14 - Genetics of Parkinson disease

An understanding of the genetic etiology of Parkinson disease (PD) has become imperative for the modern-day neurologist. Although genetic forms cause only a minority of PD, the disease mechanisms they elucidate advance the understanding of idiopathic cases. Moreover, recently identified susceptibility variants contribute to complex-etiology PD and broaden the contribution of genetics beyond familial and early-onset cases. Dominantly inherited monogenic forms mimic idiopathic PD and are caused by mutations or copy number variations of SNCA, LRRK2, and VPS35. On the other hand, early-onset forms are associated with PARKIN, PINK1, and DJ1 mutations, nominating mitochondrial dysfunction and oxidative stress as another important molecular pathway in the causation of the disease, in addition to alpha-synuclein accumulation. Common variants in GBA are consistently identified by association studies and may be considered to be a major risk gene for PD, with markedly reduced penetrance. Other genes have been proposed to be associated with PD; however, these only cause very rare forms, if at all. Current guidelines recommend testing for LRRK2 variants in familial PD or in specific populations (ancestry), and for the recessive genes in early-onset PD. However, gene panels have made testing for multiple forms of genetic PD a viable approach.

Psychotropic drug effects on gene transcriptomics relevant to Parkinson's disease

Psychotropic drugs are widely prescribed in Parkinson's disease (PD) without regard to their pathobiological effects, and these drugs affect the transcription of a large number of genes. Effects of these drugs on PD risk gene transcription were therefore surveyed. Results summarize a comprehensive survey of psychotropic effects on messenger ribonucleic acid (mRNA) expression evident in published data for 70 genes linked to PD risk. Psychotropic drugs can meaningfully affect PD risk gene mRNA transcription, including antipsychotics (upregulate dopamine receptors D2 and D3 (DRD2, DRD3); downregulate low-density lipoprotein receptor-related protein 8 (LRP8), ubiquitin carboxyl-terminal esterase L1 (UCHL1, also known as PARK5)), haloperidol (upregulates DRD3, parkin (PRKN, also known as PARK2), DRD2; downregulates brain-derived neurotrophic factor (BDNF)), risperidone (upregulates monoamine oxidase B (MAOB), DRD2), olanzapine (upregulates transmembrane protein 163 (TMEM163), BDNF, glutathione S-transferase mu 1 (GSTM1), MAOB, DRD2, solute carrier organic anion transporter family, member 3A1 (SLCO3A1)), aripiprazole (upregulates DRD2), quetiapine, paliperidone, lurasidone, carbamazepine, and many antidepressants (upregulate BDNF), lithium and bupropion (downregulate BDNF), amitriptyline (upregulates DRD3, DRD2), imipramine (upregulates BDNF, DRD3, DRD2), desipramine (upregulates BDNF, DRD3), and fluoxetine (upregulates acid beta-glucosidase (GBA), coiled-coil domain containing 62 (CCDC62), BDNF, DRD3, UCHL1, unc-13 homolog B (UNC13B), and perhaps huntingtin interacting protein 1 related (HIP1R); downregulates microtubule-associated protein tau (MAPT), methylcrotonoyl-coenzyme A carboxylase I (MCCC1), GSTM1, 28kDa calbindin 1 (CALB1)). Fluoxetine effects on BDNF and UCHL1 in GEO Profiles were statistically robust. This report provides an initial summary and framework to understand the potential impact of psychotropic drugs on PD-relevant genes. Antipsychotics and serotoninergic antidepressants may potentially attenuate PD risk, and lithium and bupropion may augment risk, through MAPT, GBA, CCDC62, HIP1R, BDNF, and DRD2 transcription, with MAPT, GBA, and CCDC62 being strongly associated with PD risk in recent meta-analyses. Limitations of these findings and a research agenda to better relate them to the nigrostriatum and PD are discussed.

A Genome‐Wide Linkage Screen in the Amish with Parkinson Disease Points to Chromosome 6

Parkinson disease (PD) is a common complex neurodegenerative disorder with an underlying genetic etiology that has been difficult to dissect. Although some PD risk genes have been discovered, most of the underlying genetic etiology remains unknown. To further elucidate the genetic component, we have undertaken a genome-wide linkage screen in an isolated founder population of Amish living in the Midwestern United States. We performed tests for linkage and for association using a marker set of nearly 6000 single-nucleotide polymorphisms. Parametric multipoint linkage analysis generated a logarithm of the odds of linkage (LOD) score of 2.44 on chromosome 6 in the SYNE1 gene, approximately 8 Mbp from the PARK2 gene. In a different region on chromosome 6 (∼67 Mbp from PARK2) an association was found for rs4302647 (p < 4.0 × 10(-6) ), which is not within 300 kb of any gene. While the association exceeds Bonferroni correction, it may yet represent a false positive due to the small sample size and the low minor allele frequency. The minor allele frequency in affecteds is 0.07 compared to 0.01 in unaffecteds. Taken together, these results support involvement of loci on chromosome 6 in the genetic etiology of PD.