Brain

Lysosomal dysfunction is central to Parkinsons disease pathogenesis, with GBA1 as the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid and ceramide metabolism have been proposed as contributors to Parkinsons disease, underscoring the need for comprehensive genetic analyses across these pathways. We analysed rare variants (minor allele frequency < 0.01) across 36 lysosomal genes (excluding GBA1) in 8,267 individuals with Parkins...

Parkinsons disease genetics remain under-characterized in East Asians. We recruited a Taiwanese case-control cohort (2,245 PD; 2,147 controls), genotyped on the Illumina NeuroBooster Array, and imputed 7.6 million variants using the Taiwan Biobank reference. Logistic-regression GWAS identified genome-wide significant signals at SNCA and MCCC1; we also observed suggestive associations at GCH1, PPARGC1A and GALNT13. Haplotype analyses delineated an East Asian SNCA risk haplotype and confirmed effe...

Objective-synucleinopathies are clinically and biologically heterogeneous disorders lacking reliable biomarkers to assist with early diagnosis, disease progression, patient stratification, and therapeutic targeting. Genetic variation is known to impact biomarker levels, influencing their utility and interpretation in research and clinical settings. We aimed to identify common genetic modulators of biomarker levels implicated in -synucleinopathy pathogenesis. MethodsGenome-wide association studi...

Leucine-rich repeat kinase 2 (LRRK2) variants are the most common cause of inherited Parkinsons disease (PD), and the hyperactivity of the LRRK2 variants represent a validated drug target for PD. The penetration of common LRRK2 variants is incomplete, underscoring the need for molecular biomarkers that predict disease onset and guide therapeutics development. Here, we analyzed large datasets of cerebrospinal fluid (CSF) and urinary proteomics from the Parkinsons Progression Markers Initiative (P...

Parkinsons disease (PD) exhibits substantial clinical and molecular heterogeneity, driven in part by mutations in SNCA, GBA1 and LRRK2 genes. Understanding how these genetic subtypes differ in progression and peripheral transcriptomic profiles may inform personalized prognostic and therapeutic strategies. In this study, we aim to compare disease progression trajectories and blood-based gene expression patterns among SNCA-positive (SNCA+), GBA-positive (GBA+) and LRRK2-positive (LRRK2+), and spor...

Parkinsons disease (PD) is a progressive movement disorder that affects over ten million individuals worldwide. While the involvement of genetically-driven cellular mechanisms in PD pathogenesis is well-established, there is increasing evidence that epigenetic dysregulation also plays a key role. We profiled genome-wide DNA methylation in isolated neuronal, oligodendrocyte and other glial nuclei populations from the prefrontal cortex of 71 PD and 56 control individuals. We identified seven sign...

Glycoprotein nonmetastatic melanoma B (GPNMB), encoded by the target gene (GPNMB) of a Parkinsons disease (PD) risk locus, acts as a secreted factor mediating inflammatory effects in the context of immunity and cancer. In a neurodegenerative disease context, GPNMB is critical to cellular uptake of pathological forms of alpha-synuclein (aSyn), the hallmark disease protein that misfolds and accumulates in PD. Here, we demonstrate that the non-membrane-anchored, extracellular domain of GPNMB, shed ...

The dynamic genetic regulation of gene expression during the progression of common neurodegenerative diseases (NDDs) remains poorly characterized, obscuring the genetic architecture of longitudinal clinical traits. Here, we present 2sGen-GPS, a two-stage genetic Granger temporal causality framework designed to integrate genetic variants, intermediate longitudinal molecular traits, and disease progression phenotypes. In the discovery stage, we utilized multivariate polynomial temporal genetic ass...

BackgroundParkinsons disease (PD) and schizophrenia (SZ), while clinically distinct, exhibit overlapping symptoms and neurobiological features. Emerging genetic evidence suggests a shared heritable component between the two disorders. In this study, we aim to identify novel genetic loci common to both PD and SZ and to further investigate the convergent molecular mechanisms that may underlie their shared pathophysiology. MethodsWe analyzed large-scale genome-wide association studies (GWAS) on SZ...

TDP-43 proteinopathy is a neuropathological hallmark of nearly all amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal dementia (FTD) cases. Nuclear loss of TDP-43 leads to widespread RNA misprocessing, such as the inclusion of cryptic exons that are no longer repressed by TDP-43. Notably, in-frame cryptic exons encode novel cryptic peptides that can be detected in biofluids, including that found in the HDGFL2 transcript. Here, we quantified HDGFL2 cryptic peptide and ne...

ANO6 (TMEM16F), a Ca2{square}-activated lipid scramblase and ion channel, has been implicated in -synuclein secretion and propagation, a hallmark of Parkinsons disease (PD). To evaluate whether genetic variation in ANO6 contributes to PD risk, we analyzed common and rare variants across large-scale datasets. Relying on genome-wide association study (GWAS) summary statistics from 63,555 PD cases, 17,700 proxy cases, and 1.7 million controls, we identified seven noncoding common variants within AN...

ObjectiveMotor decline is a hallmark of Parkinsons disease (PD) and biological aging. While epigenetic clocks measure systemic biological aging, their specific relationship with neuromotor function in the context of aging and neurodegeneration remains under-characterized. This study utilized data from the Parkinsons Progression Markers Initiative (PPMI) to examine the relationships between multiple DNA methylation-based epigenetic aging measures and motor impairment across distinct domains. Met...

Parkinsons disease and dementia with Lewy bodies are defined neuropathologically by the accumulation of -synuclein. Postmortem studies have led to theories that pathology propagates systematically along anatomical brain networks. Yet, existing staging systems present conflicting patterns of pathology distribution. Recent work suggests that these discrepancies may reflect heterogeneous "brain-first" and "body-first" subtypes, but prior studies are largely based on clinical cohorts that underrepre...

Genetic studies have advanced our understanding of Parkinsons 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...

Picks disease (PiD) is a rare cause of sporadic frontotemporal dementia, neuropathologically defined by the presence of Pick bodies consisting of aggregates of 3-repeat tau. Given the genetic aetiology of PiD remains unresolved, we assembled the Picks disease International Consortium (PIC) to identify susceptibility loci through a genome-wide association study (GWAS). A GWAS was conducted in 294 autopsy confirmed PiD cases and 1,055 controls. Lead variants were annotated using the Functional Map...

1Amyotrophic lateral sclerosis (ALS) is highly heritable, yet the vast majority of cases lack an identifiable genetic cause and clinical progression remains largely unpredictable. To connect noncoding and rare genetic variation to disease phenotypes in a relevant cell type, we generated a multi-omic quantitative trait locus (QTL) atlas from 594 induced-pluripotent-stem-cell-derived human motor neuron lines (522 ALS patients, 72 controls). By mapping cis-QTLs for chromatin accessibility, splicing...

Advances in transcriptomics have transformed our understanding of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, revealing disrupted gene expression profiles and highlighting the multi-system biology of ALS. Despite major advances, transcriptomic studies have only begun to capture the complexity and the molecular hierarchy of transcriptomic alterations in ALS. To resolve and characterize the transcriptome in ALS, we performed a comprehensive reanalysis of bulk RNA ...

BackgroundPrimary malignant brain tumors (PMBTs), including glioblastomas (GBM) and low-grade gliomas (LGGs), frequently cause seizures, which worsen patient morbidity and quality of life. Alcohol use disorder (AUD) is a known risk factor for seizures in the general population, but its role in PMBT-associated seizures remains poorly understood. ObjectiveTo evaluate the association between AUD and seizure prevalence in PMBT patients, and to examine whether this relationship varies by age, sex, r...

Alzheimers disease and related dementias (ADRD)1 and Parkinsons disease and related disorders (PDRD)2 have substantial genetic contributions, yet the role of rare damaging coding variants remains incompletely characterized at population scale3-6. We performed gene-based burden testing of rare loss-of-function and deleterious missense variants using whole-genome sequencing data from large population biobanks combined with disease-specific sequencing cohorts, leveraging proxy phenotypes to maximiz...

Parkinsons disease (PD) is a disabling neurodegenerative disorder with a substantial heritable component. Despite major advances in genome-wide association studies (GWAS), polygenic risk scores (PRS) show reduced predictive performance outside European populations, limiting equitable translation. Latin American populations represent a particularly difficult case because of their characteristic three-way admixture. We evaluated the cross-ancestry transferability of PD PRS in 1,872 PD cases and 1,...