BACKGROUND:Lysosomal dysfunction is central to Parkinson's disease (PD) pathogenesis, with GBA1 representing the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid, and ceramide metabolism have been proposed as contributors to PD, highlighting the need for genetic analyses across these pathways. OBJECTIVES:The aim was to evaluate the contribution of rare variants across lysosomal genes to PD risk. METHODS:We analyzed rare variants (minor allele frequency ≤0.01) across 36 lysosomal genes in 8267 individuals with PD and 68,208 controls, including 793 early-onset PD (≤50 years) cases. Targeted sequencing was performed in four cohorts at McGill University (3456 cases and 2664 controls) and combined with whole-genome sequencing data from the United Kingdom (UK) Biobank (2848 cases, 62,451 controls) and the Accelerating Medicines Partnership-PD cohort (1963 cases, 3093 controls). Associations were tested using Sequence Kernel Association Test-Optimal across variant classes (rare variants, nonsynonymous, loss-of-function, and predicted damaging variants with combined annotation-dependent depletion score >20), followed by meta-analysis across cohorts. Domain-level analyses were performed for variants located within protein domains. False discovery rate (FDR) correction was applied. RESULTS:Meta-analysis identified a significant association between rare variants in ST3GAL3 and Parkinson's disease (Pfdr = 0.04). Domain-based analyses showed enrichment of nonsynonymous variants within the β-acetyl-hexosaminidase-like domain of HEXA (P = 8.0 × 10-4), although this signal did not survive correction (Pfdr = 0.154). In early-onset PD, domain-based analyses identified significant associations in NAGLU (Pfdr = 7.3 × 10-6) and ST3GAL5 (Pfdr = 0.03). CONCLUSIONS:Rare variants across multiple lysosomal pathways, particularly those related to sialylation, ganglioside metabolism, ceramide biology, and lysosomal proteolysis, may contribute to PD susceptibility beyond GBA1, highlighting pathways for future replication and investigation. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Extensive neuroimaging research in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) has identified brain atrophy as a disease phenotype. While it is also related to a complex genetic architecture, the transition from genetic risk factors to brain vulnerabilities remains unclear. Using a population-based approach, we examined the associations between epilepsy-related polygenic risk for HS (PRS-HS) and brain structure in healthy developing children, assessed their relation to brain network architecture, and evaluated its correspondence with case-control findings in TLE-HS diagnosed patients relative to healthy individuals. We used genome-wide genotyping and structural T1-weighted MRI of 3826 neurotypical children from the Adolescent Brain Cognitive Development (ABCD) study. Surface-based linear models related PRS-HS to cortical thickness measures, and subsequently contextualized findings with structural and functional network architecture based on epicentre mapping approaches. Imaging-genetic associations were then correlated to atrophy and disease epicentres in 785 patients with TLE-HS relative to 1512 healthy controls aggregated across multiple sites. Higher PRS-HS was associated with decreases in cortical thickness across temporo-parietal as well as fronto-central regions of neurotypical children. These imaging-genetic effects were anchored to the connectivity profiles of distinct functional and structural epicentres. Compared with disease-related alterations from a separate epilepsy cohort, regional and network correlates of PRS-HS strongly mirrored cortical atrophy and disease epicentres observed in patients with TLE-HS and were highly replicable across different studies. Findings were consistent when using statistical models controlling for spatial autocorrelations and robust to variations in analytic methods. Capitalizing on recent imaging-genetic initiatives, our study provides novel insights into the genetic underpinnings of structural alterations in TLE-HS, revealing common morphological and network pathways between genetic vulnerability and disease mechanisms. These signatures offer a foundation for early risk stratification and personalized interventions targeting genetic profiles in epilepsy.

BACKGROUND:Biallelic SPG7 mutations cause one of the most common forms of hereditary spastic paraplegia (HSP). Several reports have suggested that heterozygous SPG7 variants may also play a role in HSP, but also in amyotrophic lateral sclerosis (ALS). However, it remains controversial whether heterozygous SPG7 mutations are pathogenic on their own, or if other mechanisms are at play. We recently provided evidence for non-Mendelian inheritance in spastic paraplegia 7 (SPG7), as heterozygous carriers of SPG7 mutations often also carried mutations in other disease-related genes, including AFG3L2, more frequently than expected by chance. Given that SPG7 and AFG3L2 encode interacting subunits of the mitochondrial m-AAA protease complex, we hypothesized that combined heterozygous mutations in these genes may act synergistically to disrupt mitochondrial function and contribute to disease. In this study, we aimed to examine whether digenic heterozygous mutations in SPG7 and AFG3L2 can lead to a spectrum of neurodegenerative disorders. METHODS:We first analyzed genome and exome sequencing data of 6644 unrelated individuals including 4817 motor neuron disorder (MND) and ataxia patients and 1827 controls. We next analyzed an additional 18,748 exome data from rare disease cohorts to further examine the occurrence of variants in SPG7 and AFG3L2. RESULTS:Among the first 4817 MND and ataxia patients, we identified a total of 6 patients, 4 of whom were unrelated, who carried potentially pathogenic variants in both SPG7 and AFG3L2, in contrast to none in 1827 unrelated controls. Further analysis of the 18,748 additional patients with rare disease, as well as a comprehensive literature review, identified 6 more patients, 5 of whom were unrelated, who had digenic mutations in SPG7 and AFG3L2. In the two families we identified, digenic mutations in SPG7 and AFG3L2 perfectly segregated with the disease. The 12 patients reported here exhibited predominant signs of motor neuron and cerebellar involvement. CONCLUSIONS:Our findings demonstrate that digenic inheritance of concurrent heterozygous mutations in SPG7 and AFG3L2 may cause motor neuron and cerebellar disorders. Screening of the entire SPG7 and AFG3L2 genes in genetically undiagnosed cases of MND and spastic ataxia may help to increase the diagnostic yield.

Abstract Isolated/idiopathic rapid-eye movement (REM) sleep behavior disorder (iRBD) is, in most cases, an early form of α -synuclein-related neurodegenerative diseases, including Parkinson’s disease and dementia with Lewy bodies. Clinical reports suggest that iRBD is more common in individuals with Post-Traumatic Stress Disorder (PTSD) compared to those without PTSD. We conducted polygenic risk score (PRS), genetic correlation, and Mendelian randomization analyses to explore potential genetic and/or causal associations between PTSD and iRBD. Dopamine transporter imaging binding status was also examined in iRBD patients with ( N = 6) and without PTSD ( N = 32). While not supporting a causal relationship, genetic analyses revealed a significant association between PTSD and iRBD, consistent with the exploratory imaging substudy. These findings suggest that individuals genetically at risk for PTSD may also be at higher risk for iRBD. Further investigation of iRBD in individuals with PTSD may help inform potential neurodegenerative risk.

Importance Genome-wide association studies (GWAS) have identified numerous risk loci for Parkinson's disease, yet identifying causal genes and mechanisms remains challenging due to non-coding associations and complex linkage disequilibrium. Objective To prioritize candidate genes within Parkinson's disease GWAS loci using a machine learning approach and to validate these candidates through rare variant burden analysis at both the gene and functional domain levels. Design, Setting, and Participants This genetic association study prioritized genes within 147 GWAS loci using an XGBoost machine-learning model trained on 285 multi-omic features, including brain-specific eQTLs and single-cell expression. Prioritized candidates underwent gene- and domain-level rare variant burden analysis via optimal sequenced kernel association test (SKAT-O) across the Accelerating Medicines Partnership for Parkinson's Disease and UK Biobank cohorts (N case = 6,435, N proxy = 13,889, N control = 343,160). Main Outcomes and Measures The primary outcomes were gene prioritization scores and statistically significant associations of rare variants with Parkinson's disease risk. Analyses were performed at the gene- and domain-level. Results The model prioritized 406 genes with 48 features contributing to the prioritization. Meta-analysis of rare variants at the gene and domain levels replicated established associations ( GBA1 , LRRK2 ) and identified six novel potential risk genes ANKRD27 driven by p.Arg21Cys, UBXN2A , FAM171A1 , ERCC8 , BNC2 , and ADNP . Domain-level analysis uniquely uncovered a significant association in the zinc-finger domain of ADNP , which was masked in gene-level tests. Additionally, at cohort-level, one novel gene was nominated: LRRC45 driven by p.Met607ArgfsTer57. Conclusions and Relevance Integrating machine-learning prioritization with gene- and domain-level burden testing identified novel genes potentially involved in Parkinson's disease, with further validation needed to elucidate causality and mechanisms. ### Competing Interest Statement Z. G.-O. received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Inceptions Sciences (now Ventus), Neuron23, Handl Therapeutics, UCB, Capsida, Vanqua Bio, Congruence Therapeutics, Ono Therapeutics, Denali, Bial Biotech, Bial, EG427, Takeda, Jazz Pharmaceuticals, Simcere, Guidepoint, Lighthouse, and Deerfield. K.S. received consultancy fees from Acurex. ### Funding Statement This work was supported by grants from the Galen and Hilary Weston Foundation, the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), and the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) initiative. We also acknowledge contributions from the G-Can (GBA1-Canada) Initiative, an open-science collaboration dedicated to GBA1-associated neurodegeneration. G-Can is supported by the Galen and Hilary Weston Foundation, the Silverstein Foundation, and J. Sebastian van Berkom and Ghislaine Saucier. S.C.P. is supported by a Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship - Doctoral (CGS-D) award. Z.G.-O. holds a Fonds de recherche du Québec - Santé (FRQS) Chercheurs-boursiers award and is a William Dawson Scholar. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of McGill University gave ethical approval for this work (IRB Study Number 21-11-023). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The WGS cohort accessed and analysed in this study for the purposes of the burden analysis are accessible (conditional to institutional approval) at: AMP-PD Knowledge Platform (https://www.amp-pd.org) and the UK Biobank Research Analysis Platform. All information directly relevant to the study are included in the text and the supplementary files of this article, except for the full range of analysed variants, which have been made accessible online at the link: https://doi.org/10.5281/zenodo.18285356. All the scripts used in the machine learning prioritization and burden analyses are shared at the GitHub repository link: https://github.com/gan-orlab/ML\_and\_Burden_PD. [https://github.com/gan-orlab/ML\_and\_Burden_PD][1] [1]: https://github.com/gan-orlab/ML_and_Burden_PD

Background:Variants in GBA1 are important genetic risk factors for synucleinopathies, including Parkinson's disease (PD). While several GBA1 variants are established risk or severity modifiers, the role of the p.E427K variant remains unclear. Objective:To determine whether the GBA1 p.E427K variant is associated with risk of synucleinopathies. Methods:We performed a meta-analysis of case-control studies reporting the frequency of GBA1 p.E427K (p.E388K) in PD and related synucleinopathies. Data were obtained from published studies, open-access resources, and large cohorts, including in-house datasets. Odds ratios (ORs) were calculated for each cohort and pooled using a random-effects model. Results:Across 67,484 patients and 124,079 controls, GBA1 p.E427K was associated with increased disease risk (pooled OR = 1.87, 95% CI 1.28-2.72, P = 0.001). Enzymatic data showed reduced glucocerebrosidase activity in carriers. Conclusions:The GBA1 p.E427K variant is a risk factor for synucleinopathies and should be considered in genetic studies and clinical trials.

Abstract Background An X-linked levodopa-responsive parkinsonism-epilepsy syndrome has been associated with PGK1 , and the gene lies within the previously suspected PD locus PARK12 . Objective To examine the association of common and rare PGK1 variants with PD. Methods We analyzed common and rare variants from Accelerated Medicines Partnership - Parkinson’s Disease (AMP-PD) and UK Biobank (UKBB, total N=4,523 PD cases, 19,736 proxy cases, and 390,532 controls). To account for the X-linked location of PGK1 , we used sex-stratified, combined regression models and optimized sequence Kernel association (SKAT-O) tests, followed by meta-analysis using MetaSKAT. Results We found no association between common or rare PGK1 variants and PD in sex-stratified or combined analyses, including after cross-cohort meta-analysis. Conclusion Although we did not find evidence supporting an association between PGK1 and PD, very rare pathogenic PGK1 variants may still contribute to syndromic parkinsonism. Future research could explore larger datasets to further examine this potential association.

Abstract Background Variants in GBA1 are important genetic risk factors for synucleinopathies, including Parkinson's disease (PD). Although several GBA1 variants are established risk or severity modifiers, the role of the p.E427K variant remains unclear. Objective The aim was to determine whether the GBA1 p.E427K variant is associated with risk of synucleinopathies. Methods We performed a meta‐analysis of case–control studies reporting the frequency of GBA1 p.E427K (p.E388K) in PD and related synucleinopathies. Data were obtained from published studies, open‐access resources, and large cohorts, including in‐house datasets. Odds ratios (OR) were calculated for each cohort and pooled using a random‐effects model. Results Across 67,221 patients and 123,832 controls, GBA1 p.E427K was associated with increased disease risk (pooled OR = 1.94, 95% confidence interval 1.33–2.84, P = 0.0007). Enzymatic data showed reduced glucocerebrosidase activity in carriers. Conclusions The GBA1 p.E427K variant is a risk factor for synucleinopathies and should be considered in genetic studies and clinical trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

One of the most common genetic risk factors for Parkinson’s disease (PD) is 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 Parkinson’s 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 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.

LRRK2 variants are key genetic risk factors for Parkinson’s Disease (PD). We conducted a per-domain rare coding variant burden analysis, including 8,888 PD cases and 69,412 controls. In meta-analysis, the Kinase domain was strongly associated with PD (Exonic: PFDR = 1.61 × 10−22, Non-synonymous: PFDR = 1.54 × 10−23, CADD > 20: PFDR = 3.09 × 10−24). Excluding the p.G2019S variant nullified this effect. Nominal associations were found in the ANK and Roc-COR domains, with potentially protective variants, p.R793M and p.Q1353K.

Parkinson's disease (PD) is associated with various genetic risk factors and brain structural alterations. However, how these genetic factors influence brain anatomy and potentially contribute to disease risk remains unclear. Here, we aimed to characterize neuroanatomical correlates of PD genetic risk and differentiate between potential genetic factors that affect neurodevelopmental processes and those that contribute to later-life vulnerability toward PD Associations between polygenic risk scores of PD (PD-PRS) and structural and microstructural brain measures were examined using linear regression, and potentially causal relationships between brain structure and PD diagnosis were investigated through Mendelian randomization. Next, PD risk genes were stratified based on their functions into three distinct components of lysosomal, autophagy, and mitochondrial genes, and their pathway-specific neuroanatomical associations were assessed using linear regression. Finally, we investigated the developmental gene expression trajectories of each pathway using RNA-sequencing data spanning fetal stages through adulthood and compared them to the expression patterns of other PD risk genes. PD-PRS showed widespread positive associations with cortical SA, subcortical volumes, and white matter FA [Figure 1]. Mendelian randomization revealed increased cortical SA and larger subcortical volumes to have a potentially causal effect on PD development [Figure 2]. No significant associations were observed between lysosomal, autophagy, or mitochondrial pathway-specific PD-PRSs and brain structural measures. Developmental gene expression trajectory analyses revealed distinct patterns of expression for mitochondrial and autophagy pathway genes, showing significantly lower expression during fetal stages compared to other PD risk genes [Figure 3]. Our findings reveal a link between PD genetic risk and brain structure, indicative of greater size of grey matter and higher white matter integrity, potentially leading to increased risk of PD development. Additionally, the lower expression of mitochondrial and autophagy pathway genes during fetal stages as well as the non-significant associations between pathway-specific polygenic risk scores and neuroanatomical features suggest that these pathways may contribute to disease risk through mechanisms independent of early neurodevelopmental processes. These results provide new insights into how genetic risk factors might shape brain structure and contribute to PD susceptibility, highlighting the complex interplay between developmental and pathway-specific mechanisms in PD pathogenesis.

Genetic studies have advanced our understanding of Parkinson's disease (PD) pathogenesis, establishing a role for autophagy and lysosomal dysfunction. However, how genetic risk translates into neuronal vulnerability remains mostly unknown. Using recent genome-wide association studies and neuroimaging data from UK Biobank, we show that higher polygenic risk score of PD correlates with greater cortical surface area, white matter fractional anisotropy and subcortical volumes. Mendelian randomization supports a causal relation from increased brain size to PD, and cortical regions showing the greatest polygenic expansion in surface area show the greatest atrophy in PD. Lifespan gene expression and pathway-specific analyses identify autophagy-lysosomal and neurodevelopmental pathways as separate mechanisms of vulnerability. We show that a portion of PD susceptibility originates from neurodevelopmental processes that regulate neuronal proliferation. Genetically-determined increases in brain size confer vulnerability to PD in later life, supporting the existence of shared neurobiological pathways between brain development and neurodegeneration.

Objective:To explore potential genetic and/or causal associations between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder. Methods:We conducted polygenic risk score, genetic correlation, and Mendelian randomization analyses using the latest genome-wide association studies summary statistics and individual genotyping data. Next, a blinded observer examined dopamine transporter imaging binding status-a marker of neurodegeneration-in patients with isolated/idiopathic rapid-eye movement sleep behavior disorder, with (N = 6) and without Post-Traumatic Stress Disorder (N = 32). Results:Polygenic risk scores for Post-Traumatic Stress Disorder were associated with isolated/idiopathic rapid-eye-movement sleep behavior disorder, with each standard deviation increase linked to 14.7% higher odds (odds ratio = 1.15, 95% confidence interval: 1.04 to 1.26, p = 0.005). However, genetic correlation was weak, and Mendelian randomization did not support a potential causal relationship. The proportion of individuals with abnormal dopamine transporter imaging binding status was significantly higher in the Post-Traumatic Stress Disorder group compared to those without the disorder (p=0.01, X2 = 6.62). Interpretation:Polygenic risk scores analysis identified an association between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder, consistent with the result from the small exploratory substudy. The lack of strong genetic correlation or causation may reflect limited sample size. Further research with larger and more diverse cohorts is crucial to clarify the genetic, biological and physiological mechanisms underlying this association.

BackgroundFollowing stroke, a growth-promoting response resulting in heightened neuroplasticity occurs during the early subacute stages of recovery, a period during which the brain may be more responsive to therapeutical interventions. Given its central role in regulating neuroplastic processes and brain repair in animal models, brain-derived neurotrophic factor (BDNF) has been targeted as a potential biomarker for stroke recovery in humans, with interventions upregulating BDNF holding therapeutical potential. Cardiovascular exercise (CE) has been recommended for stroke rehabilitation, partly due to its potential to induce neural adaptations, including upregulation of BDNF.ObjectivesTo examine the effects of CE on BDNF in individuals at early subacute stages of recovery.MethodsSeventy-six participants within 3 months of first-ever ischemic stroke were randomly assigned to 8 weeks of either CE plus standard care or standard care alone. To measure the chronic and acute responses to exercise in serum BDNF levels, blood samples were collected before and immediately after a graded exercise test conducted at baseline, 4, and 8 weeks. The potential role of the BDNF Val66Met polymorphism in modulating the BDNF response was also explored. Data were analyzed following an intention-to-treat approach.ResultsDespite clinically important increases in cardiorespiratory fitness, CE did not induce significant chronic or acute changes in serum BDNF. Furthermore, the response to CE was not associated with changes in cardiorespiratory fitness and clinical outcomes or was modulated by Val66Met.ConclusionsThese findings indicate that CE has a limited capacity to upregulate circulating BDNF in subacute stages of stroke recovery.Trial Registration:Exercise and Genotype in Sub-acute Stroke: https://clinicaltrials.gov/study/NCT05076747.

Oxidative stress has been implicated in Parkinson disease (PD). Genes involved in PD, such as PRKN, PINK1, and PARK7, contribute to oxidative stress in dopaminergic neurons. The X-linked G6PD gene encodes glucose 6-phosphate dehydrogenase, an important regulator of oxidative stress. Recent studies suggested that alpha-synuclein aggregates may impair G6PD activity and contribute to dopaminergic neuron loss, and that G6PD mutations may independently increase the risk of PD. In this study, we aimed to examine the role of common and rare G6PD variants in PD across 6 cohorts, including 8,905 PD cases, 16,770 proxy cases, and 394,098 controls. These cohorts were analyzed after stratification by sex and then combined to account for the G6PD X-linked location. Using logistic regression, we did not identify significant associations for common variants in any of the cohorts. The optimized sequence Kernel association (SKAT-O) test was performed to assess the effect of rare variants (minor allele frequency <0.01) across six cohorts, followed by a meta-analysis using metaSKAT, also demonstrating lack of association. In conclusion, we did not find evidence for a role for G6PD in PD.

GBA1 variants and decreased glucocerebrosidase activity are implicated in Parkinson's disease (PD). We investigated the hypothesis that increased levels of glucosylceramide (GlcCer), a main substrate of glucocerebrosidase, are involved in PD pathogenesis. Using multiple genetic methods, we show that ATPase phospholipid transporting 10D (ATP10D), not GBA1, is the main regulator of plasma GlcCer levels, yet it is not involved in PD pathogenesis. Plasma GlcCer levels were associated with PD, but not in a causative manner, and are not predictive of disease status. These results argue against targeting GlcCer in GBA1-PD, and underscore the need to explore alternative mechanisms and biomarkers for PD. ANN NEUROL 2025;97:873-878.

REM sleep behavior disorder (RBD), is a prodromal synucleinopathy affecting a subset of Parkinson’s disease (PD) patients and associated with neuropsychiatric symptoms. This study compared the genetic profiles of 13,020 PD patients with probable RBD (PD + RBD) and 5403 without (PD-RBD) using genome-wide association study (GWAS). RBD was assessed by questionnaires or self-reporting. Potential genetic correlations between neuropsychiatric traits and PD + RBD were assessed using linkage disequilibrium score regression. The top variant in the SNCA locus was associated with PD + RBD (rs10005233-T, OR = 1.21, 95% CI = 1.16–1.27, p = 1.81e−15). PD risk variants in SNCA (rs5019538-G, OR = 0.85, 95% CI = 0.81–0.89, p = 2.46e−10; rs356182-G, OR = 0.89, 95% CI = 0.84–0.95, p = 0.0001) and LRRK2 loci (rs34637584, OR = 0.41, 95% CI = 0.28–0.61, p = 1.04e−5) were associated with reduced PD + RBD risk. A suggestive genetic correlation between attention deficit hyperactivity disorder and PD + RBD was observed but was not statistically significant after correction. These findings highlight genetic distinctions between PD + RBD and PD-RBD, offering insights into PD stratification and potential subtype-specific treatments.

Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is associated with a complex genetic architecture, but the translation from genetic risk factors to brain vulnerability remains unclear. Here, we examined associations between epilepsy-related polygenic risk scores for HS (PRS-HS) and brain structure in a large sample of neurotypical children, and correlated these signatures with case-control findings in in multicentric cohorts of patients with TLE-HS. Imaging-genetic analyses revealed PRS-related cortical thinning in temporo-parietal and fronto-central regions, strongly anchored to distinct functional and structural network epicentres. Compared to disease-related effects derived from epilepsy case-control cohorts, structural correlates of PRS-HS mirrored atrophy and epicentre patterns in patients with TLE-HS. By identifying a potential pathway between genetic vulnerability and disease mechanisms, our findings provide new insights into the genetic underpinnings of structural alterations in TLE-HS and highlight potential imaging-genetic biomarkers for early risk stratification and personalized interventions.

Two recent studies suggested that the APOE ε4 haplotype was associated with increased α-synuclein pathology in cell and mouse models. Genetic variants in the SNCA region have strong association with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and idiopathic REM sleep behaviour disorder (iRBD), while APOE is a genetic risk determinant for only DLB. To determine if genetic-level interactions between SNCA and APOE exists that can explain the protein-level association, we investigated the genotypic interaction of APOE and SNCA in cohorts of PD, DLB and iRBD. We analysed genome-wide association study (GWAS) data from 5229 PD patients and 5480 controls, 2610 DLB patients and 1920 controls, and 1055 iRBD patients and 3667 controls. We used logistic regression interaction models across all three cohorts independently between the (i) top GWAS signals of SNCA single nucleotide polymorphisms (SNPs) and APOE haplotypes and (ii) SNP×SNP and three-way SNP interaction across the entire coding region plus 200 kb flanking each gene. No significant interactions were found to be associated with any of the synucleinopathies after correction for multiple testing. Our results do not support a role for genetic interactions between APOE and SNCA across PD, DLB and iRBD. Since the tested genetic variants affect the expression and function of these proteins, it is likely that any interactions between them do not affect the risk of PD, DLB and iRBD.