{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T01:32:28Z","timestamp":1790991148722,"version":"4.1.0"},"posted":{"date-parts":[[2026,6,4]]},"group-title":"Neurology","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006095","name":"Southern and Eastern Norway Regional Health Authority","doi-asserted-by":"crossref","award":["2021034"],"award-info":[{"award-number":["2021034"]}],"id":[{"id":"10.13039\/501100006095","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03zj4c476","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/03arq3225","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010969","name":"Alzheimer Nederland","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100010969","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Young onset Parkinson\u2019s disease may be caused by biallelic mutations in\n                  <jats:italic>PRKN<\/jats:italic>\n                  or other autosomal recessive Parkinson\u2019s 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\u2019s disease in young onset patients, but the specific genetic architecture of non-monogenic young onset Parkinson\u2019s disease is not well characterized.\n                <\/jats:p>\n                <jats:p>We conducted a genome-wide association study of 1,528 Parkinson\u2019s disease patients with symptom onset between 18 and 40 years and 20,408 controls of European ancestry using data from The Global Parkinson\u2019s Genetic Program, the International Parkinson\u2019s 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.<\/jats:p>\n                <jats:p>\n                  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\n                  <jats:italic>SNCA<\/jats:italic>\n                  ,\n                  <jats:italic>GBA1,<\/jats:italic>\n                  and\n                  <jats:italic>HIP1R<\/jats:italic>\n                  ) and two loci not previously associated with Parkinson\u2019s disease (rs74950462,\n                  <jats:italic>P<\/jats:italic>\n                  = 1.24\u00d710\n                  <jats:sup>-8<\/jats:sup>\n                  and rs72848817,\n                  <jats:italic>P<\/jats:italic>\n                  = 4.89\u00d710\n                  <jats:sup>-8<\/jats:sup>\n                  ). Furthermore, we identified a significant signal at the\n                  <jats:italic>PRKN<\/jats:italic>\n                  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\n                  <jats:italic>SNCA<\/jats:italic>\n                  ,\n                  <jats:italic>PRKN,<\/jats:italic>\n                  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\u2019s disease participants versus healthy controls. This increased polygenic burden was driven in part by loci harbouring mitochondrial pathway genes.\n                <\/jats:p>\n                <jats:p>Our results indicate that previously unidentified common and low-frequency variants contribute specifically to the young onset subgroup of Parkinson\u2019s disease. Association signals detected uniquely with a recessive model suggest that genetic susceptibility to young onset Parkinson\u2019s 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\u2019s 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.<\/jats:p>","DOI":"10.64898\/2026.06.03.26354799","type":"posted-content","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T23:35:18Z","timestamp":1780616118000},"source":"Crossref","is-referenced-by-count":1,"title":["A genome-wide association study of young onset Parkinson\u2019s disease in European ancestry"],"prefix":"10.64898","author":[{"given":"Ingeborg Haugesag","family":"Lie","sequence":"first","affiliation":[{"name":"Department of Neurology, Oslo University Hospital, Oslo, Norway"},{"name":"Faculty of Medicine, University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna","family":"van Wetering","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miko","family":"Valori","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oslo University Hospital, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kajsa Atterling","family":"Brolin","sequence":"additional","affiliation":[{"name":"Global Parkinson\u2019s Genetics Program (GP2)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4054-7030","authenticated-orcid":false,"given":"Kathryn","family":"Step","sequence":"additional","affiliation":[{"name":"Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa"},{"name":"South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Schulte","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Iwaki","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Related Dementias, National Institute on Aging, Bethesda, MD, USA"},{"name":"Data Tecnica International, Washington, D.C., USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bandres-Ciga","sequence":"additional","affiliation":[{"name":"Global Parkinson\u2019s Genetics Program (GP2)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-8110","authenticated-orcid":false,"given":"Hampton","family":"Leonard","sequence":"additional","affiliation":[{"name":"Global Parkinson\u2019s Genetics Program (GP2)"},{"name":"Data Tecnica International, Washington, D.C., USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manu","family":"Sharma","sequence":"additional","affiliation":[{"name":"Institute for Clinical Epidemiology and Applied Biometry, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the International Parkinson\u2019s Disease Genomics Consortium the Global Parkinson\u2019s Genetics Program","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Singleton","sequence":"additional","affiliation":[{"name":"Global Parkinson\u2019s Genetics Program (GP2)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7635-8645","authenticated-orcid":false,"given":"Lasse","family":"Pihlstr\u00f8m","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oslo University Hospital, Oslo, Norway"},{"name":"Faculty of Medicine, University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060801051760000_2026.06.03.26354799v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-7568(24)00094-1"},{"key":"2026060801051760000_2026.06.03.26354799v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.10305"},{"key":"2026060801051760000_2026.06.03.26354799v1.3","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.41.2_part_1.168"},{"key":"2026060801051760000_2026.06.03.26354799v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/mds.870020201"},{"key":"2026060801051760000_2026.06.03.26354799v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/33416"},{"key":"2026060801051760000_2026.06.03.26354799v1.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.1077209"},{"key":"2026060801051760000_2026.06.03.26354799v1.7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1096284"},{"key":"2026060801051760000_2026.06.03.26354799v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.01.014"},{"key":"2026060801051760000_2026.06.03.26354799v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/S1353-8020(11)70004-9"},{"key":"2026060801051760000_2026.06.03.26354799v1.10","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25132"},{"key":"2026060801051760000_2026.06.03.26354799v1.11","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2008.063917"},{"issue":"1","key":"2026060801051760000_2026.06.03.26354799v1.12","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/s41531-024-00778-z","article-title":"Parkinson\u2019s families project: a UK-wide study of early onset and familial Parkinson\u2019s disease","volume":"10","year":"2024","journal-title":"NPJ Parkinsons Dis."},{"key":"2026060801051760000_2026.06.03.26354799v1.13","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2010.194"},{"issue":"9","key":"2026060801051760000_2026.06.03.26354799v1.14","doi-asserted-by":"crossref","first-page":"2828","DOI":"10.1093\/brain\/awz191","article-title":"Genetic analysis of Mendelian mutations in a large UK population-based Parkinson\u2019s disease study","volume":"142","year":"2019","journal-title":"Brain"},{"key":"2026060801051760000_2026.06.03.26354799v1.15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028787"},{"key":"2026060801051760000_2026.06.03.26354799v1.16","doi-asserted-by":"crossref","unstructured":"Step K , Hernandez CF , Khani M , et al. Genome-Wide Assessment Reveals Ancestral Differences in Homozygosity Patterns Potentially Linked to Parkinson\u2019s Disease Etiology. Mov Disord. 2026;","DOI":"10.1002\/mds.70182"},{"key":"2026060801051760000_2026.06.03.26354799v1.17","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.40.10.1529"},{"issue":"s1","key":"2026060801051760000_2026.06.03.26354799v1.18","doi-asserted-by":"crossref","first-page":"S29","DOI":"10.3233\/JPD-202135","article-title":"Young Onset Parkinson\u2019s Disease: A Modern and Tailored Approach","volume":"10","year":"2020","journal-title":"J Parkinsons Dis"},{"key":"2026060801051760000_2026.06.03.26354799v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30320-5"},{"key":"2026060801051760000_2026.06.03.26354799v1.20","unstructured":"Leonard HL . Novel Parkinson\u2019s Disease Genetic Risk Factors Within and Across European Populations. medRxiv. 2025;"},{"key":"2026060801051760000_2026.06.03.26354799v1.21","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26192"},{"key":"2026060801051760000_2026.06.03.26354799v1.22","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24335"},{"issue":"2","key":"2026060801051760000_2026.06.03.26354799v1.23","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1002\/mds.29676","article-title":"The Genetic Drivers of Juvenile, Young, and Early-Onset Parkinson\u2019s Disease in India","volume":"39","year":"2024","journal-title":"Mov Disord"},{"issue":"1","key":"2026060801051760000_2026.06.03.26354799v1.24","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3233\/JPD-191854","article-title":"Ten Years of the International Parkinson Disease Genomics Consortium: Progress and Next Steps","volume":"10","author":"The International Parkinson\u2019s Disease Genomics Consortium","year":"2020","journal-title":"J Parkinsons Dis"},{"key":"2026060801051760000_2026.06.03.26354799v1.25","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27659"},{"key":"2026060801051760000_2026.06.03.26354799v1.26","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28494"},{"issue":"1","key":"2026060801051760000_2026.06.03.26354799v1.27","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41531-023-00533-w","article-title":"Defining the causes of sporadic Parkinson\u2019s disease in the global Parkinson\u2019s genetics program (GP2)","volume":"9","year":"2023","journal-title":"NPJ Parkinsons Dis"},{"key":"2026060801051760000_2026.06.03.26354799v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/ng.642"},{"key":"2026060801051760000_2026.06.03.26354799v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.10.019"},{"key":"2026060801051760000_2026.06.03.26354799v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3679"},{"key":"2026060801051760000_2026.06.03.26354799v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3643"},{"key":"2026060801051760000_2026.06.03.26354799v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3656"},{"issue":"11","key":"2026060801051760000_2026.06.03.26354799v1.33","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1002\/mds.29902","article-title":"NeuroBooster Array: A Genome-Wide Genotyping Platform to Study Neurological Disorders Across Diverse Populations","volume":"39","year":"2024","journal-title":"Mov Disord"},{"key":"2026060801051760000_2026.06.03.26354799v1.34","doi-asserted-by":"crossref","unstructured":"Vitale D , Koretsky MJ , Kuznetsov N , et al. GenoTools: an open-source Python package for efficient genotype data quality control and analysis. G3 (Bethesda). 2025;15(1)","DOI":"10.1093\/g3journal\/jkae268"},{"key":"2026060801051760000_2026.06.03.26354799v1.35","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25274"},{"key":"2026060801051760000_2026.06.03.26354799v1.36","unstructured":"Blauwendraat C , Heibron K , Vallagra C , et al. Parkinson\u2019s disease age at onset genome-wide association study: Defining heritability, genetic loci, and \u03b1-synuclein mechanisms. Movement Disorders. 2019;"},{"key":"2026060801051760000_2026.06.03.26354799v1.37","doi-asserted-by":"crossref","unstructured":"Chang CC , Chow CC , Tellier LC , Vattikuti S , Purcell SM , Lee JJ . Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7.","DOI":"10.1186\/s13742-015-0047-8"},{"key":"2026060801051760000_2026.06.03.26354799v1.38","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq340"},{"key":"2026060801051760000_2026.06.03.26354799v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01261-5"},{"key":"2026060801051760000_2026.06.03.26354799v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2213"},{"key":"2026060801051760000_2026.06.03.26354799v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.02.002"},{"key":"2026060801051760000_2026.06.03.26354799v1.42","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.jocn.2024.05.015","article-title":"Global prevalence and incidence of Young Onset Parkinson\u2019s disease: A systematic review and meta-analysis","volume":"125","year":"2024","journal-title":"J Clin Neurosci"},{"key":"2026060801051760000_2026.06.03.26354799v1.43","doi-asserted-by":"crossref","unstructured":"Choi SW , O\u2019Reilly PF . PRSice-2: Polygenic Risk Score software for biobank-scale data. Gigascience. 2019;8(7)","DOI":"10.1093\/gigascience\/giz082"},{"key":"2026060801051760000_2026.06.03.26354799v1.44","doi-asserted-by":"crossref","unstructured":"Tunold JA , Tan MMX , Koga S , et al. Lysosomal polygenic risk is associated with the severity of neuropathology in Lewy body disease. Brain. 2023;","DOI":"10.1093\/brain\/awad183"},{"key":"2026060801051760000_2026.06.03.26354799v1.45","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4"},{"key":"2026060801051760000_2026.06.03.26354799v1.46","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1016"},{"key":"2026060801051760000_2026.06.03.26354799v1.47","doi-asserted-by":"publisher","DOI":"10.1186\/s40246-023-00451-1"},{"key":"2026060801051760000_2026.06.03.26354799v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"issue":"12","key":"2026060801051760000_2026.06.03.26354799v1.49","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1002\/mds.27864","article-title":"The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight","volume":"34","year":"2019","journal-title":"Mov Disord"},{"key":"2026060801051760000_2026.06.03.26354799v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30320-5"},{"key":"2026060801051760000_2026.06.03.26354799v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3043"},{"key":"2026060801051760000_2026.06.03.26354799v1.52","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq469"},{"key":"2026060801051760000_2026.06.03.26354799v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00785-3"},{"key":"2026060801051760000_2026.06.03.26354799v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-43458-2"},{"key":"2026060801051760000_2026.06.03.26354799v1.55","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34732-5"},{"key":"2026060801051760000_2026.06.03.26354799v1.56","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-017-0324-9"},{"key":"2026060801051760000_2026.06.03.26354799v1.57","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.14345"},{"key":"2026060801051760000_2026.06.03.26354799v1.58","doi-asserted-by":"publisher","DOI":"10.1186\/2040-2392-4-26"},{"key":"2026060801051760000_2026.06.03.26354799v1.59","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq430"},{"key":"2026060801051760000_2026.06.03.26354799v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2019.06.001"},{"key":"2026060801051760000_2026.06.03.26354799v1.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.11.011"},{"key":"2026060801051760000_2026.06.03.26354799v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3211"},{"issue":"7","key":"2026060801051760000_2026.06.03.26354799v1.63","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1002\/mdc3.13523","article-title":"Age Cutoff for Early-Onset Parkinson\u2019s Disease: Recommendations from the International Parkinson and Movement Disorder Society Task Force on Early Onset Parkinson\u2019s Disease","volume":"9","year":"2022","journal-title":"Mov Disord Clin Pract"},{"key":"2026060801051760000_2026.06.03.26354799v1.64","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410360417"},{"issue":"7","key":"2026060801051760000_2026.06.03.26354799v1.65","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1002\/ajmg.b.30758","article-title":"Genetic association between alpha-synuclein and idiopathic Parkinson\u2019s disease","volume":"147B","year":"2008","journal-title":"Am J Med Genet B Neuropsychiatr Genet"},{"key":"2026060801051760000_2026.06.03.26354799v1.66","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21157"},{"key":"2026060801051760000_2026.06.03.26354799v1.67","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21782"},{"key":"2026060801051760000_2026.06.03.26354799v1.68","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-008-0466-z"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.03.26354799","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T08:05:40Z","timestamp":1780905940000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.06.03.26354799"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":68,"URL":"https:\/\/doi.org\/10.64898\/2026.06.03.26354799","relation":{},"subject":[],"published":{"date-parts":[[2026,6,4]]},"subtype":"preprint"}}