Hampton L. Leonard

Summary: Background: Parkinson disease (PD) is a genetically complex neurodegenerative disorder, but most genetic discoveries have been derived from populations of European ancestry, limiting the understanding of ancestry-specific genetic risk. Methods: This GWAS included 5,825 East Asian participants (3,043 patients with PD and 2,782 controls). We then combined these results with data from two additional East Asian cohorts through meta-analysis, resulting in a total of 74,716 participants (15,603 patients with PD and 59,113 controls). To our knowledge, this represents the largest genetic study of PD in East Asian populations to date. Findings: We identified two novel loci that were associated with PD in East Asian cohorts and reached genome-wide significance in the cross-ancestry meta-analysis (> 1.9 million subjects): TLE4 (lead variant rs10780320, P _{meta_combined} = 2.853×10 ⁻ 10) and HLA-V/HLA-G (lead variant rs11751333, P _{meta_combined} = 1.031×10-9). Integration of brain eQTL data identified an East Asian– specific intergenic variant at the LRRK2 locus (rs1388594) was significantly associated with LRRK2 expression in the basal ganglia. This association was replicated across 3 independent East Asian cohorts (P _{gp2_EAS} = 8.71 × 10 ⁻⁴ , P _{sg_EAS} = 1.13 × 10 ⁻⁵ , PTPMI_EAS = 4.86 × 10 ⁻⁴ ) and reached genome-wide significance in the East Asian meta-analysis (P _{meta_EAS} = 5.85 × 10 ⁻¹⁰ ; OR = 1.10, 95% CI: 1.07– 1.13). The variant was not associated with PD in populations of European ancestry (P = 0.08). Interpretation: These findings improve our understanding of the genetics of PD across different ancestry groups and highlight the need to include people from different backgrounds in genetic studies to identify ancestry-specific risk variants.

Expanded short tandem repeats contribute to a broad spectrum of neurodegenerative diseases, yet their roles in Parkinson’s disease (PD) and parkinsonism remain incompletely characterized, especially across diverse ancestries. We analyzed short-read whole-genome (WGS) and clinical exome sequencing (CES) data from 38,365 individuals (28,861 WGS; 9,504 CES), encompassing 23,242 patients with PD, 4,729 patients with atypical parkinsonism and 10,394 healthy controls from 11 genetic ancestries. To determine carrier frequencies and characterize repeat structures across diverse ancestries, we genotyped 12 established pathogenic loci where normal, intermediate, and pathogenic alleles can be reliably differentiated using short-read sequencing data. Additionally, we conducted threshold-based associations to determine the minimum threshold associated with increased PD risk in 15,995 individuals (8,591 PD, 7,404 controls) of European ancestry. Pathogenic repeat expansions were detected in 62 patients (56 PD and 6 atypical parkinsonism) and 5 controls across seven loci ( AR , ATXN1 , ATXN2 , ATXN3 , CACNA1A , HTT and THAP11 ), spanning seven ancestries. Among these, ATXN2 expansions were the most frequently observed in PD and were present in African, East Asian, European and Middle Eastern ancestries. Additionally, intermediate ATXN2 repeat expansions exhibited a strong, length-dependent association with PD risk in the European population, with individuals with ≥32 repeats having a more than four-fold increased risk (odds ratio 4.25, 95% confidence interval 1.80-12.05). Overall, >92% of expanded alleles harbor CAA interruptions within the CAG tract. Pathogenic expansions at other loci, such as ATXN3 and THAP11 , showed more ancestry-specific distributions. Clinically, individuals with pathogenic ATXN2 and ATXN3 expansions most often presented with typical PD features but frequently showed earlier disease onset and a strong family history of PD. This large-scale, multi-ancestry study comprehensively maps the genetic landscape of pathogenic and intermediate repeat expansions in PD. Our findings confirm a length- and structure-dependent risk association for ATXN2 with PD in the European population and highlight the pleiotropic effects of repeat expansions across the parkinsonian spectrum.

Young onset Parkinson’s disease may be caused by biallelic mutations in PRKN or other autosomal recessive Parkinson’s disease genes, but the majority of patients do not carry known monogenic variants. Previous studies have found an increased cumulative burden of common genetic risk variants for Parkinson’s disease in young onset patients, but the specific genetic architecture of non-monogenic young onset Parkinson’s disease is not well characterized. We conducted a genome-wide association study of 1,528 Parkinson’s disease patients with symptom onset between 18 and 40 years and 20,408 controls of European ancestry using data from The Global Parkinson’s Genetic Program, the International Parkinson’s Disease Genomics Consortium, and the NeuroGenetics Research Consortium. We performed meta-analyses of additive and recessive regression models and investigated associations between age at onset groups and different polygenic risk scores. An additive model meta-analysis identified six independent loci passing a genome-wide significance threshold, including three loci identified in previous genome-wide association studies (near SNCA , GBA1, and HIP1R ) and two loci not previously associated with Parkinson’s disease (rs74950462, P = 1.24×10 ^-8 and rs72848817, P = 4.89×10 ^-8 ). Furthermore, we identified a significant signal at the PRKN locus, prompting a follow-up analysis employing a recessive model. The recessive genome-wide association meta-analysis identified nine loci passing a genome-wide significance threshold, including SNCA , PRKN, and seven novel variants. Patients with onset between 18 and 40 years had significantly higher polygenic risk scores than later onset patients when the score was modelled specifically on genome-wide association statistics from independent young onset Parkinson’s disease participants versus healthy controls. This increased polygenic burden was driven in part by loci harbouring mitochondrial pathway genes. Our results indicate that previously unidentified common and low-frequency variants contribute specifically to the young onset subgroup of Parkinson’s disease. Association signals detected uniquely with a recessive model suggest that genetic susceptibility to young onset Parkinson’s disease may be partially driven by homozygous variation, in line with previous reports of increased runs of homozygosity in this particular group of patients and may be consistent with a loss of function mechanism. The findings support the notion of young onset Parkinson’s disease as a partly distinct subphenotype and highlight the mitochondrial pathway. These results may have implications for future precision medicine but should be interpreted with caution pending independent replication.

Known pathogenic variants (PVs) in Parkinson disease (PD) contribute to disease development but have yet to be fully explored by arrays on a large scale. This study evaluated genotyping success of the NeuroBooster array (NBA) and determined the frequencies of PVs across ancestries. We analyzed the presence and allele frequency of PVs in 28,710 PD cases, 9,614 other neurodegenerative disorder cases, and 15,821 controls across 11 ancestries within the Global Parkinson's Genetics Program (GP2) data set. Cluster plots were used to assess the quality of PVs genotyped on NBA. Genes previously predicted to have high or very high confidence of causing PD tend to have more PVs and are present across ancestry groups. Of 34 known PD gene PVs assessed, 25 were typed by NBA and classified as “good” (n = 12), “medium” (n = 4), or “bad” (n = 9) quality variants. Our results confirm the likelihood that established PD genes are pathogenic and highlight the importance of ancestrally diverse research in PD. We also show the usefulness of the NBA as a reliable tool for the genotyping of rare variants of PD.

In the Global Parkinson’s Genetics Program (GP2) we aim to advance precision medicine by integrating large-scale clinico-genetic data from diverse populations worldwide. We investigated potentially trial-eligible carriers of pathogenic and high-risk GBA1 and LRRK2 variants and conducted a global precision-medicine survey across GP2 sites. Among 65,509 individuals with Parkinson’s disease, we identified 9,019 (13.8%) potentially trial-eligible genetic variant carriers, including 6,789 GBA1 , 2,084 LRRK2 , and 146 dual GBA1-LRRK2 carriers. Individuals were distributed across multiple global regions, many of which currently lack active gene-targeted trials, highlighting a global disparity between relevant variant carriers and the availability of disease modifying treatment trials. GP2’s unified framework supports equitable recruitment for gene-targeted therapeutic studies and helps address critical gaps in Parkinson’s disease genetics and future therapeutic development.

SORL1, the gene encoding the SORLA protein, has arisen as a potential therapeutic target for Alzheimer’s disease (AD). Studies suggest that restoring SORLA function or its trafficking pathways, particularly the SORLA–retromer recycling system, may offer a promising strategy to slow or halt AD progression. While both rare and common SORL1 variants have been associated with increased AD risk, recent evidence suggests a potential involvement of SORL1 in other neurodegenerative conditions. This study assessed the contribution of SORL1 genetic variation to the risk of AD, related dementias (RD), and Parkinson’s disease (PD) using data from six large-scale biobanks, comprising 15,043 AD, 9,943 RD, and 42,763 PD cases, along with 111,969 controls across 11 ancestries. We identified 53 potentially disease-related SORL1 variants (CADD score > 20, MAC ≥ 2, annotated as protein-altering or splicing, and with the mutated allele present only in cases), including 41 novel and 12 previously reported variants. Three were found across multiple ancestries. Overall, 13 variants were found in AD-related cohorts, 5 in RD cohorts, and 35 in PD cohorts. Association analysis identified 10 nominally significant variants associated with AD and 5 with PD. The replication of multiple SORL1 variants across neurodegenerative diseases and ancestrally diverse populations underscores its potential broad genetic contribution to neurodegeneration and reinforces its relevance across distinct clinical phenotypes. Gene-based burden analysis did not reveal any significant cumulative effect of SORL1 variants in the populations tested. A family-based analysis identified a rare predicted-damaging variant in two East Asian families (11:121478242:G:A, p.R176Q) and two variants in two families of European ancestry (11:121514222:A:C, p.N371T; 11:121545392:G:A, p.V672M) that show some evidence of segregation in PD families. Although these variants were slightly more frequent in unrelated PD cases vs. controls, none of them showed statistically significant enrichment in PD, likely due to their very low frequency. Overall, our results extend the understanding of SORL1 beyond AD, suggesting a broader role in neurodegeneration and emphasizing the need for diverse population studies when evaluating genetic risk.

ANO6 (TMEM16F) , a Ca ² □-activated lipid scramblase and ion channel, has been implicated in α-synuclein secretion and propagation, a hallmark of Parkinson’s 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 ANO6 that reached genome-wide significance, but these signals were driven by linkage disequilibrium (LD) with the nearby LRRK2 p.G2019S variant. We further tested rare variant burden in 4,879 PD cases and 65,279 controls. Rare variant burden analysis showed significant enrichment only when all rare variants were aggregated (meta-analysis P _FDR = 0.02), with no signal detected in functional categories. Overall, human genetic data does not support an important role for ANO6 in PD.

Motivation: Copy Number Variations (CNVs) play pivotal roles in complex disease etiology, often requiring large sample sizes to analyze disease associations. While genotyping arrays offer a cost-effective approach for CNV detection using Log R Ratio (LRR) and B Allele Frequency (BAF) signals, existing independent array-based callers suffer from high false positive rates and noise susceptibility, burdening manual validation. Results: We present CNV-Finder, a deep learning pipeline employing Long Short-Term Memory (LSTM) networks for large-scale CNV identification within user-defined genomic regions. Trained on expert-annotated samples from the Global Parkinson’s Genetics Program across four neurodegenerative disease-associated genes (PRKN, LINGO2, MAPT, SNCA), CNV-Finder integrates human feedback to iteratively improve performance. In benchmarking across 105 936 samples spanning 11 ancestries and nearly 150 cohorts, the model achieved 91% and 89% visual confirmation rates for PRKN deletions and duplications at high-confidence thresholds. In two validation cohorts, CNV-Finder nominated 83% fewer candidates than a popular Hidden Markov Model-based caller while maintaining higher confirmation rates. Validation through MLPA, short-read, and long-read sequencing demonstrated robust performance, generalizing to diverse signatures including homozygous deletions and SNCA triplications absent from training. Our findings highlight human expertise’s value in complex loci like 17q21.31. Availability and implementation: CNV-Finder is freely available at https://github.com/nvk23/CNV-Finder.

Introduction: Parkinson’s disease (PD) affects females and males differently, with differences in prevalence, clinical phenotypes, and therapeutic response, suggesting that biological sex may influence the underlying molecular mechanisms of PD. The extent to which genetic factors may contribute to these differences remains largely unknown. Objective: To investigate sex-specific autosomal genetic factors associated with PD risk. Methods: We performed a sex-stratified autosomal GWAS meta-analysis leveraging data from the Global Parkinson’s Genetics Program, the International Parkinson’s Disease Genomics Consortium, the UK Biobank, and the Fox Insight Genetics Study, including a total of 226,196 individuals from different European populations: 18,145 female PD cases, 95,558 female controls, 28,747 male PD cases, and 83,746 male controls. Results: We observed a high genetic correlation between the male and female PD meta-analyses (rg = 0.909, SE = 0.0403; p = 8.03E-113), and the heritability estimates were comparable between sexes (∼10% in males and ∼11% in females) and similar to estimates from prior sex-combined analyses. Our sex-stratified GWAS identified 57 genome-wide significant association signals, including five novel risk loci, three of which reached genome-wide significance in males only ( RBM8A, ANKRD23, and CNTN4 ) and two in females only ( RERE and ARL6IP6 ). Of the remaining previously identified GWAS loci regions, several showed differences in effect magnitude between sexes, with the GALC, RERE, ARL6IP6, and RBM8A loci demonstrating statistically significant sex-specific effects. Conclusions: Overall, PD genetic architecture appears broadly similar between females and males, but the identification of five novel loci and significant differences at select regions highlights the value of sex-stratified analyses for uncovering additional genetic contributors to PD risk beyond those detected in combined analyses.

Background: DNAJC13 was initially linked to autosomal dominant (AD) Parkinson’s disease (PD) in a European Mennonite family carrying the p.N855S variant. However, imperfect segregation and conflicting reports of pathogenicity raised uncertainty of DNAJC13 ’s role in the disease. Objectives: Explore the association between common and rare variants in DNAJC13 and Parkinson’s disease. Methods: We leveraged the largest available PD genetics data from the Accelerating Medicines Partnership - Parkinson Disease (AMP-PD) and the diverse ancestry available through the Global Parkinson’s Genetics Program (GP2), consisting of 2,471 patients and 3,098 controls, and 44,186 patients and 27,066 controls, respectively, to perform burden tests and association tests for rare and common variants, respectively. Results: Burden analysis showed no association between rare variants in DNAJC13 and PD. However, association analysis within common non-synonymous variants nominated 5 variants within DNAJC13 . Nevertheless, these associations require further validation since the analyses are still underpowered. Discussion: Our analysis did not find further evidence supporting DNAJC13 involvement in PD. However, studies of even larger cohorts and AD-PD families may bring definite answers about DNAJC13’s role in PD.