{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T07:00:33Z","timestamp":1792566033182,"version":"4.5.0"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T00:00:00Z","timestamp":1656028800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual\u2010level genetic data available.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership\u2013Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome\u2010wide association study meta\u2010analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene\u2010based analyses and functional enrichment analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A higher polygenic resilience score was associated with a lower risk for PD (\u03b2\u00a0=\u00a0\u22120.054, standard error [SE]\u00a0=\u00a00.022, <jats:italic>p<\/jats:italic>\u00a0=\u20090.013). Although no single locus reached genome\u2010wide significance, MAGMA gene\u2010based analyses nominated <jats:italic>TBCA<\/jats:italic> as a putative gene. Furthermore, we estimated the narrow\u2010sense heritability associated with resilience to PD (<jats:italic>h<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u20090.081, SE\u00a0=\u00a00.035, <jats:italic>p<\/jats:italic>\u00a0=\u20090.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high\u2010risk genetic burden from developing PD. ANN NEUROL 2022;92:270\u2013278<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26416","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T04:11:31Z","timestamp":1653279091000},"page":"270-278","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors"],"prefix":"10.1002","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5308-0874","authenticated-orcid":false,"given":"Hui","family":"Liu","sequence":"first","affiliation":[{"name":"Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research University of T\u00fcbingen and German Center of Neurodegenerative Diseases  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Dehestani","sequence":"additional","affiliation":[{"name":"Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research University of T\u00fcbingen and German Center of Neurodegenerative Diseases  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9358-8111","authenticated-orcid":false,"given":"Cornelis","family":"Blauwendraat","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, Molecular Genetics Section, National Institute on Aging National Institutes of Health  Bethesda MD USA"},{"name":"Center for Alzheimer's and Related Dementias National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary B.","family":"Makarious","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, Molecular Genetics Section, National Institute on Aging National Institutes of Health  Bethesda MD USA"},{"name":"Center for Alzheimer's and Related Dementias National Institutes of Health  Bethesda MD 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UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0253-4116","authenticated-orcid":false,"given":"Isabelle","family":"Foote","sequence":"additional","affiliation":[{"name":"Preventive Neurology Unit, Wolfson Institute of Population Health Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1260-5416","authenticated-orcid":false,"given":"Manu","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research University of T\u00fcbingen and German Center of Neurodegenerative Diseases  T\u00fcbingen Germany"},{"name":"Center for Genetic Epidemiology, Institute for Clinical Epidemiology and Functional Biometry University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"International Parkinson's Disease Genomics 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