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PubMed · 39228715

Genome-wide association study of copy number variations in Parkinson's disease.

Zied Landoulsi·Ashwin Ashok Kumar Sreelatha·Nicole Kuznetsov·Claudia Schulte·Dheeraj Reddy Bobbili·Ludovica Montanucci·Costin Leu·Lisa-Marie Niestroj·Emadeldin Hassanin·Cloé Domenighetti·Pierre-Emmanuel Sugier·Milena Radivojkov-Blagojevic·Peter Lichtner·Berta Portugal·Connor Edsall·Jens Kru Ger·Dena G Hernandez·Cornelis Blauwendraat·George D Mellick·Alexander Zimprich·Walter Pirker·Manuela Tan·Ekaterina Rogaeva·Anthony Lang·Sulev Koks·Pille Taba·Suzanne Lesage·Alexis Brice·Jean-Christophe Corvol·Marie-Christine Chartier-Harlin·Eugenie Mutez·Kathrin Brockmann·Angela B Deutschländer·Georges M Hadjigeorgiou·Efthimos Dardiotis·Leonidas Stefanis·Athina Maria Simitsi·Enza Maria Valente·Simona Petrucci·Letizia Straniero·Anna Zecchinelli·Gianni Pezzoli·Laura Brighina·Carlo Ferrarese·Grazia Annesi·Andrea Quattrone·Monica Gagliardi·Lena F Burbulla·Hirotaka Matsuo·Akiyoshi Nakayama·Nobutaka Hattori·Kenya Nishioka·Sun Ju Chung·Yun Joong Kim·Lukas Pavelka·Pierre Kolber·Bart Pc van de Warrenburg·Bastiaan R Bloem·Andrew B Singleton·Dan Vitale·Mathias Toft·Lasse Pihlstrom·Leonor Correia Guedes·Joaquim J Ferreira·Soraya Bardien·Jonathan Carr·Eduardo Tolosa·Mario Ezquerra·Pau Pastor·Karin Wirdefeldt·Nancy L Pedersen·Caroline Ran·Andrea C Belin·Andreas Puschmann·Carl E Clarke·Karen E Morrison·Dimitri Krainc·Matt J Farrer·Dennis Lal·Global Parkinson Genetics Program (GP2)·Alexis Elbaz·Thomas Gasser·Rejko Krüger·Manu Sharma·Patrick May
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Abstract

OBJECTIVE: To investigate the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data and explore their role in sporadic PD. METHODS: We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings. RESULTS: The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results. INTERPRETATION: The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk.

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Zied Landoulsi, Ashwin Ashok Kumar Sreelatha, Nicole Kuznetsov, Claudia Schulte, Dheeraj Reddy Bobbili, Ludovica Montanucci, Costin Leu, Lisa-Marie Niestroj, Emadeldin Hassanin, Cloé Domenighetti, Pierre-Emmanuel Sugier, Milena Radivojkov-Blagojevic, Peter Lichtner, Berta Portugal, Connor Edsall, Jens Kru Ger, Dena G Hernandez, Cornelis Blauwendraat, George D Mellick, Alexander Zimprich, Walter Pirker, Manuela Tan, Ekaterina Rogaeva, Anthony Lang, Sulev Koks, Pille Taba, Suzanne Lesage, Alexis Brice, Jean-Christophe Corvol, Marie-Christine Chartier-Harlin, Eugenie Mutez, Kathrin Brockmann, Angela B Deutschländer, Georges M Hadjigeorgiou, Efthimos Dardiotis, Leonidas Stefanis, Athina Maria Simitsi, Enza Maria Valente, Simona Petrucci, Letizia Straniero, Anna Zecchinelli, Gianni Pezzoli, Laura Brighina, Carlo Ferrarese, Grazia Annesi, Andrea Quattrone, Monica Gagliardi, Lena F Burbulla, Hirotaka Matsuo, Akiyoshi Nakayama, Nobutaka Hattori, Kenya Nishioka, Sun Ju Chung, Yun Joong Kim, Lukas Pavelka, Pierre Kolber, Bart Pc van de Warrenburg, Bastiaan R Bloem, Andrew B Singleton, Dan Vitale, Mathias Toft, Lasse Pihlstrom, Leonor Correia Guedes, Joaquim J Ferreira, Soraya Bardien, Jonathan Carr, Eduardo Tolosa, Mario Ezquerra, Pau Pastor, Karin Wirdefeldt, Nancy L Pedersen, Caroline Ran, Andrea C Belin, Andreas Puschmann, Carl E Clarke, Karen E Morrison, Dimitri Krainc, Matt J Farrer, Dennis Lal, Global Parkinson Genetics Program (GP2), Alexis Elbaz, Thomas Gasser, Rejko Krüger, Manu Sharma, Patrick May. 2025-07-08. Genome-wide association study of copy number variations in Parkinson's disease.. https://doi.org/10.1101/2024.08.21.24311915

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BACKGROUND: Frailty is a major risk factor for influenza-related complications and can influence vaccine effectiveness. We aimed to assess the relative vaccine effectiveness (rVE) of high-dose (HD-IIV) versus standard-dose inactivated influenza vaccine (SD-IIV) in older adults aged 65 years or older according to frailty risk. METHODS: This study was a prespecified analysis of DANFLU-2, an open-label, individually randomised trial, conducted in Denmark during three consecutive influenza seasons (2022-23, 2023-24, and 2024-25). Adults aged 65 years or older were randomised (1:1) to the HD-IIV or SD-IIV group. The primary endpoint was hospitalisation for influenza or pneumonia. Frailty was defined according to the validated Hospital Frailty Risk Score (HFRS) based on ICD-10 codes within 10 years before randomisation. Participants were stratified into three HFRS categories, namely low (<5 points), intermediate (5-15 points), and high (>15 points) frailty risk. The rVE of HD-IIV versus SD-IIV against the primary endpoint was assessed across prespecified HFRS categories and treating HFRS as a continuous variable. Pearson's chi-square test was used to compare safety events across frailty risk groups and randomisation groups. FINDINGS: Among 332&#x2009;438 randomised participants (mean age 73&#xb7;7 years [SD 5&#xb7;8]; 161&#x2009;538 [48&#xb7;6%] were female), 276&#x2009;173 (83&#xb7;1%) had low frailty risk, 52&#x2009;395 (15&#xb7;8%) had intermediate frailty risk, and 3861 (1&#xb7;2%) had high frailty risk. The primary endpoint of hospitalisation for influenza or pneumonia occurred in 1424 (0&#xb7;5%) of 276&#x2009;173 participants with low frailty risk, 761 (1&#xb7;5%) of 52&#x2009;395 with intermediate frailty risk, and 163 (4&#xb7;2%) of 3861 with high frailty risk (relative risk [RR] for intermediate vs low frailty risk 2&#xb7;8 [95% CI 2&#xb7;6-3&#xb7;1]; RR for high vs low frailty risk 8&#xb7;2 [7&#xb7;0-9&#xb7;6]). HFRS as a continuous variable significantly modified the effect of HD-IIV versus SD-IIV against the primary endpoint with higher rVE estimates with increasing HFRS (pinteraction=0&#xb7;020). The rVE was 0&#xb7;2% (95% CI -10&#xb7;8 to 10&#xb7;2) among those with low frailty risk, 13&#xb7;1% (-0&#xb7;4 to 24&#xb7;8) among those with intermediate frailty risk, and 19&#xb7;9% (-10&#xb7;3 to 42&#xb7;1) among those with high frailty risk. No significant interaction was observed when HFRS was assessed according to the prespecified categorical frailty groups (pinteraction=0&#xb7;17). The proportion of participants with at least one serious adverse event increased across frailty risk groups (13&#x2009;366 [4&#xb7;8%] of 275&#x2009;795 for low frailty risk, 5475 [10&#xb7;5%] of 52&#x2009;315 for intermediate frailty risk, and 777 [20&#xb7;2%] of 3850 for high frailty risk; p<0&#xb7;0001), with similar proportions of serious adverse events in the HD-IIV and SD-IIV groups for each frailty risk group. INTERPRETATION: Among adults aged 65 years or older in Denmark, frailty risk might modify the effects of HD-IIV versus SD-IIV against hospitalisation for influenza or pneumonia, with higher rVE estimates with increasing frailty risk. These findings might support considering high-dose influenza vaccines for frail older adults. However, effect modification was not evident when frailty was assessed using prespecified categorical subgroups, and subgroup-specific estimates were imprecise, with 95% CIs crossing the null. These results should be considered exploratory, warranting further investigation. FUNDING: The DANFLU-2 trial was funded by Sanofi.

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