Biology subjects

Gan-Or, Z.

Publications and source records attributed to Gan-Or, Z..

17 recordsLinked to original sources

bioRxiv2026

GBAviewer: a structural database of GBA1 variants in Parkinson's disease

Background: GBA1 variants are common risk factors for Parkinson's disease (PD), yet the structural consequences of most variants remain uncharacterized. No centralized resource currently integrates the growing number of GCase structures, compounds, and PD-associated variants. Objectives: To develop an interactive tool mapping GBA1-PD missense variants onto GCase structures, alongside interactors and therapeutic compounds. Methods: We built GBAviewer, an R/Shiny web server integrating GBA1-PD Browser variants with crystal structures, cryo-EM complexes, AlphaFold3 models, and AlphaMissense scores. We also modelled a putative GCase-Saposin C-glucosylceramide ternary complex using AlphaFold3. Results: GBAviewer maps variants in 3D across the GCase active site, LIMP-2 and SapC surfaces, chaperone pockets, and dimerization interface. Our ternary model corroborates SapC binding to the GCase active site entrance, where several variants of unknown significance cluster. Conclusions: GBAviewer is a freely accessible platform for structural analysis of GBA1 variants, supporting mechanistic studies and therapeutic development. Available at: https://g-can.shinyapps.io/GBAviewer/

neuroscience↗

bioRxiv2026

HippoGenes: A robust workflow for subregional transcriptomic profiling of the human hippocampus

The human hippocampus is a unique cortical structure central to brain function, plasticity, and disease. Unravelling its complex organization requires the integration of multiscale data, linking molecular features to mesoscale anatomy and macroscale functional patterns. Gene expression is a fundamental microscale phenotype, and its profiling can provide a reference description of how molecular features are distributed across the brain. Capitalizing on recent imaging-transcriptomic analyses, we introduce HippoGenes, a repository of fine-grained gene expression patterns across human hippocampal subregions. We leveraged spatial statistical models and hippocampal surface mapping to reconstruct dense transcriptomic maps from sparse post-mortem tissue samples of the Allen Human Brain Atlas, generating continuous expression estimates for thousands of genes aligned to a common surface-based coordinate system. We illustrate the utility of HippoGenes to (i) map medial-lateral and anterior-posterior transcriptomic gradients that align with subfield and tripartite subdivisions of the hippocampal formation, (ii) examine associations between gene expression and canonical microstructural and functional features of the hippocampus, and (iii) perform a molecular decoding of subregional alterations in neurological patients with hippocampal pathology. HippoGenes provides a framework for exploring the molecular organization of the hippocampus, opening avenues for multiscale integration in health and disease, and is openly available on https://hippogenes.readthedocs.io/.

neuroscience↗

bioRxiv2026

Bone Morphogenetic Protein Pathway Modulates Parkinson's Disease Genetic Risk and Promotes Motor Recovery

Progress toward disease-modifying Parkinsons disease (PD) therapies is hindered by limited understanding of pathogenic drivers and lack of therapies that restore the damaged dopaminergic (DA) neurons driving motor deficits. We investigated the role of the bone morphogenetic protein (BMP) pathway in PD using common and rare genetic variants across large-scale datasets. Single-variant analyses identified nominal associations with PD risk and onset age. A BMP polygenic risk score (PRS) was significantly associated with PD risk (OR = 1.21, empirical P = 1.0 x 10-), a result replicated in proxy-case analyses (OR = 1.14, empirical P = 1.0 x 10-) and remained significant after sensitivity testing. To test the results functional relevance, we genetically and pharmacologically inhibited BMP signaling in mice, which induced motor deficits and PD-like neuropathology. In a -synuclein preformed fibril (PFF) mouse model, BMP5 and BMP7 (BMP5/7) demonstrated neuroprotective effects when administered concurrently with -synuclein PFFs. Importantly, when delivered after PFFs-induced motor symptoms onset, BMP5/7 demonstrated neurorestorative effects, ameliorating both motor impairments and neuropathology. These findings provide first evidence that BMP signaling variations contribute to polygenic PD risk, identify a physiological role for this pathway in safeguarding against PD-related pathology, and demonstrate BMPs therapeutic potential for disease modification.

neuroscience↗

bioRxiv2025

LRRK2 Kinase Mediates Increased GCase Activity in Microglia in Response to Proinflammatory Stimuli

Variants in the LRRK2 and GBA1 genes are among the most common risk factors associated with Parkinsons disease (PD). Both patients carrying PD-associated variants in GBA1, encoding lysosomal enzyme glucocerebrosidase (GCase), and a subset of non-carrier patients have been shown to have reduced GCase enzymatic activity, suggesting that reduced GCase activity may be a feature of both genetic and a subset of sporadic PD. However, the effect of PD-associated variants in LRRK2, encoding a serine/threonine kinase, on GCase activity remains controversial, with conflicting results in various tissues and cell types. Moreover, rare patients carrying both GBA1 and LRRK2 risk alleles seem to have a more benign disease course than carriers of GBA1 variants alone, suggesting a complex interplay between these two genes in PD. Here we evaluate the effect of LRRK2 kinase activity on GCase activity in human induced pluripotent stem cell (iPSC)-derived microglia (iMGs), a PD-relevant brain cell type expressing high levels of LRRK2. Using CRISPR editing, isogenic control iPSC lines were generated to match PD patient-derived iPSC lines harbouring the LRRK2 p.G2019S, p.M1646T, or p.N551K-p.R1398H protective haplotype variants. Whereas iMGs harbouring the p.M1646T variant, and the protective haplotype, respectively increased and decreased phosphorylation of canonical LRRK2 substrate, Rab10, GCase protein levels and activity were not altered in any of the LRRK2 variant lines. Additionally, whereas pharmacological inhibition of LRRK2 kinase activity had no impact on GCase activity in iMGs under basal conditions, it attenuated the increase in GCase activity elicited in response to interferon {gamma} (IFN{gamma}) treatment. Moreover, GCase activity induced by IFN{gamma} was reduced in PD risk LRRK2 p.M1646T iMGs and increased in p.N551K-p.R1398H protective haplotype iMGs compared to their isogenic corrected controls, congruent with their respective effects on LRRK2 kinase activity and PD risk. Thus, our data suggests a role for LRRK2 kinase activity in regulation of GCase activity in response to neuroinflammation.

neuroscience↗

bioRxiv2025

Genomic structural equation modeling of impulsivity and risk-taking traits reveals three latent factors distinctly associated with brain structure and development

BackgroundImpulsivity is a multifaceted transdiagnostic trait that emerges in childhood. Research has identified genetic loci and brain systems associated with different facets of impulsivity and risk-taking. However, how these genetic underpinnings overlap across different facets, and how they are associated with brain development during childhood remain unknown. MethodsUsing genomic structural equation modeling on 17 impulsivity and risk-taking traits, we identified latent factors capturing overlapping genetic architecture. We then calculated polygenic scores for these factors using Adolescent Brain Cognitive Development Study data (N = 4,142) and examined their associations with brain structure, development, and behavior in children aged 9-14 years. Finally, we tested whether socioeconomic status modulated the associations between latent polygenic scores and brain structures. ResultsWe identified three distinct genetic latent factors, which we label lack of self-control, reward drive, and sensation seeking. In children, polygenic scores for the three factors showed associations with distinct brain patterns: lack of self-control associated with reduced prefrontal cortical thickness, reward drive with increased subcortical cellular density, and sensation seeking with increased cortical surface area and white matter integrity. Longitudinally, lack of self-control predicted slower white matter development. The association between polygenetic score for lack of self-control and white matter mean diffusivity was modulated by socioeconomic status. ConclusionsWe identified three genetically distinct dimensions of impulsivity and risk-taking with separable neurodevelopmental origins. These genetic predispositions manifested as distinct brain patterns as early as ages 9-10. Environmental experience modulated some of the genetic effects on brain development.

neuroscience↗

bioRxiv2024

Genome-wide association study of glucocerebrosidase activity modifiers.

One of the most common genetic risk factors for Parkinsons disease (PD) are variants in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GCase deficiency has been associated with an increased PD risk, but not all individuals with low GCase activity are carriers of GBA1 mutations, suggesting other factors may be acting as modifiers. We aimed to discover common variants associated with GCase activity, as well as replicate previously reported associations, by performing a genome-wide association study using two independent cohorts: a Columbia University cohort consisting of 697 PD cases and 347 controls and the Parkinsons Progression Markers Initiative (PPMI) cohort consisting of 357 PD cases and 163 controls. As expected, GBA1 variants have the strongest association with decreased activity, led by p.N370S (beta = -4.36, se = 0.32, p = 5.05e-43). We also identify a novel association in the GAA locus (encoding for acid alpha-glucosidase, beta = -0.96, se = 0.17, p = 5.23e-09) that may be the result of an interaction between GCase and acid alpha-glucosidase based on various interaction analyses. Lastly, we show that several PD-risk loci are potentially associated with GCase activity. Further research will be needed to replicate and validate our findings and to uncover the functional connection between acid alpha-glucosidase and GCase.

genetics↗

bioRxiv2023

The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons

Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinsons disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.

neuroscience↗

bioRxiv2023

MerTK mediates the immunologically silent uptake of alpha-synuclein fibrils by human microglia

MerTK is a receptor tyrosine kinase that mediates the immunologically silent phagocytic uptake of diverse types of cellular debris. Highly expressed on the surface of microglial cell, MerTK is of importance in brain development, homeostasis, plasticity, and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with aging and in neurodegenerative diseases has yet to be defined. The current study explored the function of MerTK in the microglial uptake of alpha-synuclein fibrils which play a causative role in the pathobiology of synucleinopathies. Using human primary and induced pluripotent stem cell-derived microglia, the MerTK- dependence of alpha-synuclein fibril internalization was investigated in vitro. Relevance of this pathway to synucleinopathies was assessed by analyzing MerTK expression in patient-derived cells and tissues. Pharmacological inhibition of MerTK and siRNA-mediated MERTK knockdown both caused a decreased rate of alpha-synuclein fibril internalization by human microglia. Consistent with the immunologically silent nature of MerTK-mediated phagocytosis, alpha-synuclein fibril internalization did not induce secretion of pro-inflammatory cytokines from microglia. In addition, burden analysis in two independent patient cohorts revealed a significant association between rare functionally deleterious MERTK variants and Parkinsons disease in one of the cohorts (p = 0.002). Accordingly, MERTK expression was significantly upregulated in nigral microglia from Parkinsons disease/Lewy body dementia patients compared to those from non-neurological control donors in a single-nuclei RNA-sequencing dataset (p = 5.08x10-21), and MerTK protein expression positively correlated with alpha-synuclein level in human cortex lysates (p = 0.0029). Taken together, our findings define a novel role for MerTK in mediating the uptake of alpha-synuclein aggregates by human microglia, with possible involvement in limiting alpha-synuclein spread in synucleinopathies such as Parkinsons disease.

cell biology↗

bioRxiv2020

Large-scale pathway-specific polygenic risk, transcriptomic community networks and functional inferences in Parkinson disease

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological pathways underlying PD using the largest currently available cohorts of genetic data and gene expression data from International Parkinsons Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership - Parkinsons disease initiative (AMP-PD), among other sources. We placed these insights into a cellular context. We applied large-scale pathway-specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk in a cohort of 457,110 individuals by focusing on a compilation of 2,199 publicly annotated gene sets representative of curated pathways, of which we nominate 46 pathways associated with PD risk. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data, including 4,331 individuals. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for adult dopaminergic neurons, serotonergic neurons, and radial glia. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of 1,612 PD patients, which revealed 54 connecting networks associated with PD. Our analyses highlight several promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

genetics↗

bioRxiv2019

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease and progressive supranuclear palsy converge on altered glial regulation

Parkinsons disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD, we fine-mapped the 17q21.31 locus in order to identify novel mechanisms conferring risk for the disease. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble -synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with -synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

neuroscience↗

bioRxiv2019

No genetic evidence for involvement of alcohol dehydrogenase genes in risk for Parkinson’s disease

Multiple genes have been implicated in Parkinsons disease (PD), including causal gene variants and risk variants typically identified using genome-wide association studies (GWAS). Variants in the alcohol dehydrogenase genes ADH1C and ADH1B are among the genes that have been associated with PD, suggesting that this family of genes may be important in PD. As part of the International Parkinsons Disease Genomics Consortiums (IPDGC) efforts to scrutinize previously reported risk factors for PD, we explored genetic variation in the alcohol dehydrogenase genes ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6, and ADH7 using imputed GWAS data from 15,097 cases and 17,337 healthy controls. Rare-variant association tests and single-variant score tests did not show any statistically significant association of alcohol dehydrogenase genetic variation with the risk for PD.

genetics↗

bioRxiv2019

Analysis of common and rare VPS13C variants in late onset Parkinson disease

ObjectiveWe aimed to study the role of coding VPS13C variants in a large cohort of late-onset PD (LOPD) patients.\n\nMethodsVPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 PD patients and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis.\n\nResultsNo bi-allelic carriers of rare VPS13C variants were found among patients and two carriers of compound heterozygous variants were found in two controls. There was no statistically significant burden of rare (MAF<1%) or very rare (MAF<0.1%) coding VPS13C variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V (OR=0.48, 95%CI=0.28-0.82, p=0.0052). This haplotype was not in linkage disequilibrium (LD) with the known genome-wide association study (GWAS) top hit.\n\nConclusionsOur results do not support a role for rare heterozygous or bi-allelic VPS13C variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD.

genetics↗

bioRxiv2019

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinsons disease

ObjectiveTo assess genetic modifiers of Parkinsons disease (PD) age at onset (AAO) penetrance in individuals carrying common and rare LRRK2 risk alleles\n\nMethodsWe analysed reported genetic modifier DNM3 rs2421947 in 724 LRRK2 p.G2019S heterozygotes using linear regression of AAO. We meta-analysed our data with previously published data (n=754). VAMP4 is in close proximity to DNM3 and is associated with PD. We analysed the effect of the rs11578699 VAMP4 variant on pG2019S penetrance in 786 LRRK2 p.G2019S heterozygotes. We also evaluated the impact of VAMP4 variants using AAO regression in 4882 patients with PD carrying a common LRRK2 risk variant (rs10878226).\n\nResultsThere was no evidence for linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699. Our linear regression AAO of 724 p.G2019S carriers showed no relationship between DNM3 rs2421947 and AAO (beta = -1.19, p = 0.55, n =708). Meta-analysis with previously published data did not indicate a significant effect on AAO (beta = -2.21, p = 0.083, n = 1304), but there was significant heterogeneity in the analyses of new and previously published data. VAMP4 rs11578699 was nominally associated with AAO in patients dichotomized by the common LRRK2 risk variant rs10878226 (beta=1.68, se=0.81 p=0.037).\n\nInterpretationAnalysis of DNM3 in previously unpublished data does not show an interaction between DNM3 and LRRK2 G2019S for AAO, however the inter-study heterogeneity may indicate ethnic-specific effects of DNM3 rs2421947. Analysis of sporadic PD patients stratified by the PD risk variant rs10878226 indicates a possible interaction between LRRK2 and VAMP4.

genetics↗

bioRxiv2019

The Parkinsons Disease Mendelian Randomization Research Portal

BackgroundMendelian randomization (MR) is a method for exploring observational associations to find evidence of causality.\n\nObjectiveTo apply MR between multiple risk factors/phenotypic traits (exposures) and Parkinsons disease (PD) in a large, unbiased manner, and to create a public resource for research.\n\nMethodsWe used two-sample MR in which the summary statistics relating to SNPs from genome wide association studies (GWASes) of 5,839 exposures curated on MR Base were used to assess causal relationships with PD. We selected the highest quality exposure GWASes for this report (n=401). For the disease outcome, summary statistics from the largest published PD GWAS were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted (IVW) method, followed by a range of sensitivity analyses. We used a false discovery rate (FDR) corrected p-value of <0.05 from the IVW analysis to prioritize traits of interest.\n\nResultsWe observed evidence for causal associations between twelve exposures and risk of PD. Of these, nine were causal effects related to increasing adiposity and decreasing risk of PD. The remaining top exposures that affected PD risk were tea drinking, time spent watching television and forced vital capacity, but the latter two appeared to be biased by violations of underlying MR assumptions.\n\nDiscussionWe present a new platform which offers MR analyses for a total of 5,839 GWASes versus the largest PD GWASes available (https://pdgenetics.shinyapps.io/pdgenetics/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD.

neuroscience↗

bioRxiv2018

The Landscape of Parkin Variants Reveals Pathogenic Mechanisms and Therapeutic Targets in PD

Mutations in Parkin (PARK2) are the most common genetic cause of early-onset Parkinsons disease (PD). Parkin encodes an E3 ubiquitin ligase implicated in the turnover of damaged mitochondria. Hundreds of Parkin missense variants have been reported in public databases, yet the role of most of them in PD remains unclear. We analyzed Parkin variants using clinical, experimental, and structural modeling approaches. For most variants, clinical evidence alone was insufficient to determine pathogenicity. Utilizing a cell model that allows measurement of Parkin-mediated mitophagy and Parkin stability, 51 variants were classified into five groups based on their effect on Parkin function. Most variants were like wildtype but, unexpectedly, several enhanced mitophagy. A minority destabilized Parkin or severely disrupted Parkin-mediated mitophagy, most of which were also determined as pathogenic based on clinical evidence alone. Structural simulation predicted discrete mechanisms explaining both increases and decreases in Parkin function. Interestingly, impaired mitophagy in several of the most common pathogenic Parkin variants could be rescued both by naturally-occurring (p.V224A) and structure-guided designer (p.W403A; p.F146A) hyperactive Parkin variants. These findings provide a coherent framework to classify Parkin variants based on pathogenicity and suggest that several pathogenic Parkin variants represent promising targets for genotype-specific drug design.

neuroscience↗

bioRxiv2018

Parkinson disease age of onset GWAS: defining heritability, genetic loci and a-synuclein mechanisms

Increasing evidence supports an extensive and complex genetic contribution to Parkinsons disease (PD). Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age of onset are largely unknown. Here we performed an age of onset GWAS based on 28,568 PD cases. We estimated that the heritability of PD age of onset due to common genetic variation was ~0.11, lower than the overall heritability of risk for PD (~0.27) likely in part because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni corrected significant effect at other known PD risk loci, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. In addition, we identified that GBA coding variant carriers had an earlier age of onset compared to non-carriers. Notably, SNCA, TMEM175, SCARB2, BAG3 and GBA have all been shown to either directly influence alpha-synuclein aggregation or are implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci such as GCH1, MAPT and RAB7L1/NUCKS1 (PARK16) did not show a significant effect on age of onset of PD. While for some loci, this may be a measure of power, this is clearly not the case for the MAPT locus; thus genetic variability at this locus influences whether but not when an individual develops disease. We believe this is an important mechanistic and therapeutic distinction. Furthermore, these data support a model in which alpha-synuclein and lysosomal mechanisms impact not only PD risk but also age of disease onset and highlights that therapies that target alpha-synuclein aggregation are more likely to be disease-modifying than therapies targeting other pathways.

genetics↗

bioRxiv2018

Genetic variability and potential effects on clinical trial outcomes: perspectives in Parkinson’s disease

BackgroundImproper randomization in clinical trials can result in the failure of the trial to meet its primary end-point. The last [~]10 years have revealed that common and rare genetic variants are an important disease factor and sometimes account for a substantial portion of disease risk variance. However, the burden of common genetic risk variants is not often considered in the randomization of clinical trials and can therefore lead to additional unwanted variance between trial arms. We simulated clinical trials to estimate false negative and false positive rates and investigated differences in single variants and mean genetic risk scores (GRS) between trial arms to investigate the potential effect of genetic variance on clinical trial outcomes at different sample sizes.\n\nMethodsSingle variant and genetic risk score analyses were conducted in a clinical trial simulation environment using data from 5851 Parkinsons Disease patients as well as two simulated virtual cohorts based on public data. The virtual cohorts included a GBA variant cohort and a two variant interaction cohort. Data was resampled at different sizes (n = 200-5000 for the Parkinsons Disease cohort) and (n = 50-800 and n = 50-2000 for virtual cohorts) for 1000 iterations and randomly assigned to the two arms of a trial. False negative and false positive rates were estimated using simulated clinical trials, and percent difference in genetic risk score and allele frequency was calculated to quantify disparity between arms.\n\nFindingsSignificant genetic differences between the two arms of a trial are found at all sample sizes. Approximately 90% of the iterations had at least one statistically significant difference in individual risk SNPs between each trial arm. Approximately 10% of iterations had a statistically significant difference between trial arms in polygenic risk score mean or variance. For significant iterations at sample size 200, the average percent difference for mean GRS between trial arms was 130.87%, decreasing to 29.87% as sample size reached 5000. In the GBA only simulations we see an average 18.86% difference in GRS scores between trial arms at n = 50, decreasing to 3.09% as sample size reaches 2000. Balancing patients by genotype reduced mean percent difference in GRS between arms to 36.71% for the main cohort and 2.00% for the GBA cohort at n = 200. When adding a drug effect to the simulations, we found that unbalanced genetics with an effect on the chosen measurable clinical outcome can result in high false negative rates among trials, especially at small sample sizes. At a sample size of n = 50 and a targeted drug effect of -0.5 points in UPDRS per year, we discovered 33.9% of trials resulted in false negatives.\n\nInterpretationsOur data support the hypothesis that within genetically unmatched clinical trials, particularly those below 1000 participants, heterogeneity could confound true therapeutic effects as expected. This is particularly important in the changing environment of drug approvals. Clinical trials should undergo pre-trial genetic adjustment or, at the minimum, post-trial adjustment and analysis for failed trials. Clinical trial arms should be balanced on genetic risk variants, as well as cumulative variant distributions represented by GRS, in order to ensure the maximum reduction in trial arm disparities. The reduction in variance after balancing allows smaller sample sizes to be utilized without risking the large disparities between trial arms witnessed in typical randomized trials. As the cost of genotyping will likely be far less than greatly increasing sample size, genetically balancing trial arms can lead to more cost-effective clinical trials as well as better outcomes.

genomics↗