Dataset Information

Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers.

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.

SUBMITTER: Sugier PE

PROVIDER: S-EPMC10334300 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers.

Sugier Pierre-Emmanuel PE Lucotte Elise A EA Domenighetti Cloé C Law Matthew H MH Iles Mark M MM Brown Kevin K Amos Christopher C McKay James D JD Hung Rayjean J RJ Karimi Mojgan M Bacq-Daian Delphine D Boland-Augé Anne A Olaso Robert R Deleuze Jean-François JF Lesueur Fabienne F Ostroumova Evgenia E Kesminiene Ausrele A de Vathaire Florent F Guénel Pascal P Sreelatha Ashwin Ashok Kumar AAK Schulte Claudia C Grover Sandeep S May Patrick P Bobbili Dheeraj R DR Radivojkov-Blagojevic Milena M Lichtner Peter P Singleton Andrew B AB Hernandez Dena G DG Edsall Connor C Mellick George D GD Zimprich Alexander A Pirker Walter W Rogaeva Ekaterina E Lang Anthony E AE Koks Sulev S Taba Pille P Lesage Suzanne S Brice Alexis A Corvol Jean-Christophe JC Chartier-Harlin Marie-Christine MC Mutez Eugénie E Brockmann Kathrin K Deutschländer Angela B AB Hadjigeorgiou Georges M GM Dardiotis Efthimios E Stefanis Leonidas L Simitsi Athina Maria AM Valente Enza Maria EM Petrucci Simona S Straniero Letizia L Zecchinelli Anna A Pezzoli Gianni G Brighina Laura L Ferrarese Carlo C Annesi Grazia G Quattrone Andrea A Gagliardi Monica M Matsuo Hirotaka H Nakayama Akiyoshi A Hattori Nobutaka N Nishioka Kenya K Chung Sun Ju SJ Kim Yun Joong YJ Kolber Pierre P van de Warrenburg Bart P C BPC Bloem Bastiaan R BR Aasly Jan J Toft Mathias M Pihlstrøm Lasse L Guedes Leonor Correia LC Ferreira Joaquim J JJ Bardien Soraya S Carr Jonathan J Tolosa Eduardo E Ezquerra Mario M Pastor Pau P Diez-Fairen Monica M Wirdefeldt Karin K Pedersen Nancy N Ran Caroline C Belin Andrea C AC Puschmann Andreas A Rödström Emil Ygland EY Clarke Carl E CE Morrison Karen E KE Tan Manuela M Krainc Dimitri D Burbulla Lena F LF Farrer Matt J MJ Kruger Rejko R Gasser Thomas T Sharma Manu M Truong Thérèse T Elbaz Alexis A

Movement disorders : official journal of the Movement Disorder Society 20230214 4

<h4>Background</h4>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.<h4>Objective</h4>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.<h4>Methods</h4>We used individual data for participants of European ancestry from the Courage-PD (Comprehensive U ...[more]

PMID: 36788297

Similar Datasets

Project description:BackgroundGenome-wide association studies (GWAS) have indicated moderate genetic overlap between Alzheimer's disease (AD) and related dementias (ADRD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), neurodegenerative disorders traditionally considered etiologically distinct. However, the specific genetic variants and loci underlying this overlap remain almost entirely unknown.MethodsWe leveraged state-of-the-art GWAS for ADRD, PD, and ALS. For each pair of disorders, we examined each of the GWAS hits for one disorder and tested whether they were also significant for the other disorder, applying Bonferroni correction for the number of variants tested. This approach rigorously controls the family-wise error rate for both disorders, analogously to genome-wide significance.ResultsEleven loci with GWAS hits for one disorder were also associated with one or both of the other disorders: one with all three disorders (the MAPT/KANSL1 locus), five with ADRD and PD (near LCORL, CLU, SETD1A/KAT8, WWOX, and GRN), three with ADRD and ALS (near GPX3, HS3ST5/HDAC2/MARCKS, and TSPOAP1), and two with PD and ALS (near GAK/TMEM175 and NEK1). Two of these loci (LCORL and NEK1) were associated with an increased risk of one disorder but decreased risk of another. Colocalization analysis supported a shared causal variant between ADRD and PD at the CLU, WWOX, and LCORL loci, between ADRD and ALS at the TSPOAP1 locus, and between PD and ALS at the NEK1 and GAK/TMEM175 loci. To address the concern that ADRD is an imperfect proxy for AD and that the ADRD and PD GWAS have overlapping participants (nearly all of which are from the UK Biobank), we confirmed that all our ADRD associations had nearly identical odds ratios in an AD GWAS that excluded the UK Biobank, and all but one remained nominally significant (p < 0.05) for AD.ConclusionsIn one of the most comprehensive investigations to date of pleiotropy between neurodegenerative disorders, we identify eleven genetic risk loci shared among ADRD, PD, and ALS. These loci support lysosomal/autophagic dysfunction (GAK/TMEM175, GRN, KANSL1), neuroinflammation/immunity (TSPOAP1), oxidative stress (GPX3, KANSL1), and the DNA damage response (NEK1) as transdiagnostic processes underlying multiple neurodegenerative disorders.

Dataset Information

Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers.

Background

Objective

Methods

Results

Conclusions

Publications

Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers.

Similar Datasets

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