Pastor, Pau

AbstractBackgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.ResultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells.ConclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract Background Levodopa‐induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2 . Objectives Our goal was to investigate the effects of genetic variants on risk and time to LID. Methods We performed a genome‐wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. Results We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21–2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09–1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (OR fourth_quartile = 1.27; 95% CI, 1.03–1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HR third_quartile = 1.38; 95% CI, 1.07–1.79; P = 0.0128; HR fourth_quartile = 1.38; 95% CI = 1.06–1.78; P = 0.0147). Conclusions This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Abstract Brain metabolism perturbation can contribute to traits and diseases. We conducted the first large-scale CSF and brain genome-wide association studies, which identified 219 independent associations (59.8% novel) for 144 CSF metabolites and 36 independent associations (55.6% novel) for 34 brain metabolites. Most of the novel signals (97.7% and 70.0% in CSF and brain) were tissue specific. We also integrated MWAS-FUSION approaches with Mendelian Randomization and colocalization to identify causal metabolites for 27 brain and human wellness phenotypes and identified eight metabolites to be causal for eight traits (11 relationships). Low mannose level was causal to bipolar disorder and as dietary supplement it may provide therapeutic benefits. Low galactosylglycerol level was found causal to Parkinson’s Disease (PD). Our study expanded the knowledge of MQTL in central nervous system, provided insights into human wellness, and successfully demonstrates the utility of combined statistical approaches to inform interventions.

Abstract Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome‐wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage‐PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta‐Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross‐phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (G corr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (G corr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). Conclusions We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

AbstractBackgroundTwo studies that examined the interaction between HLA‐DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions.ObjectiveTo perform a large‐scale independent replication of the HLA‐DRB1 × smoking interaction.MethodsWe genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA‐DRB1.ResultsAt the amino acid level, a valine at position 11 (V11) in HLA‐DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59–0.93, PInteraction = 0.028). In silico predictions of the influence of V11 and smoking‐induced modifications of α‐synuclein on binding affinity showed findings consistent with this interaction pattern.ConclusionsDespite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Abstract Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two‐sample Mendelian randomization (MR). Methods We genotyped a well‐established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage‐PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P ‐difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.