{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:05:58Z","timestamp":1790082358771,"version":"4.0.1"},"posted":{"date-parts":[[2026,3,4]]},"group-title":"Neurology","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Alzheimer\u2019s disease and related dementias (ADRD)\n                  <jats:sup>1<\/jats:sup>\n                  and Parkinson\u2019s disease and related disorders (PDRD)\n                  <jats:sup>2<\/jats:sup>\n                  have substantial genetic contributions, yet the role of rare damaging coding variants remains incompletely characterized at population scale\n                  <jats:sup>3\u20136<\/jats:sup>\n                  . We performed gene-burden testing of loss-of-function and deleterious missense variants in biobanks and disease-focused sequencing cohorts, using calibrated proxy-phenotypes and diagnosed-case sensitivity analyses to increase power for late-onset disease\n                  <jats:sup>7<\/jats:sup>\n                  . At study-wide significance, we confirmed rare-variant burden in established ADRD genes (\n                  <jats:italic>TREM2, ABCA7, SORL1, PSEN1, GRN, ATP8B4, ABCA1, ADAM10<\/jats:italic>\n                  ) and PDRD genes (\n                  <jats:italic>GBA1, LRRK2<\/jats:italic>\n                  ). We also identified a novel ADRD burden association at\n                  <jats:italic>IMPA2<\/jats:italic>\n                  , and novel PDRD associations at\n                  <jats:italic>ANKRD27<\/jats:italic>\n                  , and\n                  <jats:italic>CCL7<\/jats:italic>\n                  . The strongest signal was observed for\n                  <jats:italic>ANKRD27<\/jats:italic>\n                  , where damaging variants clustered within domains mediating interactions with Rab GTPases and retromer components. Our results demonstrate the value of population-scale sequencing to identify rare coding risk genes for neurodegenerative diseases.\n                <\/jats:p>","DOI":"10.64898\/2026.03.03.26347540","type":"posted-content","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T03:40:11Z","timestamp":1772682011000},"source":"Crossref","is-referenced-by-count":3,"title":["Population-scale burden analysis of rare damaging coding variants identifies novel risk genes for Alzheimer\u2019s disease and related dementias and Parkinson\u2019s disease and related disorders"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6649-8364","authenticated-orcid":false,"given":"Yann","family":"Le Guen","sequence":"first","affiliation":[{"name":"Quantitative Sciences Unit, Division of Computational Medicine, Department of Medicine Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Pe\u00f1a-Tauber","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Catoia Pulgrossi","sequence":"additional","affiliation":[{"name":"Quantitative Sciences Unit, Division of Computational Medicine, Department of Medicine Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyoung","family":"Park","sequence":"additional","affiliation":[{"name":"Quantitative Sciences Unit, Division of Computational Medicine, Department of Medicine Stanford University, Stanford, CA"},{"name":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holden","family":"Orias","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Greicius","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092205150748000_2026.03.03.26347540v4.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01024-z"},{"key":"2026092205150748000_2026.03.03.26347540v4.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30320-5"},{"key":"2026092205150748000_2026.03.03.26347540v4.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01208-7"},{"key":"2026092205150748000_2026.03.03.26347540v4.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-018-0112-7"},{"key":"2026092205150748000_2026.03.03.26347540v4.5","doi-asserted-by":"crossref","first-page":"4622","DOI":"10.1093\/brain\/awad214","article-title":"Large-scale rare variant burden testing in Parkinson\u2019s disease","volume":"146","year":"2023","journal-title":"Brain"},{"key":"2026092205150748000_2026.03.03.26347540v4.6","doi-asserted-by":"crossref","unstructured":"Fan, Y. , Hu, Z. , Yan, Q. , Wan, J. & Liu, J . Whole-exome sequencing and burden analysis identify six novel candidate risk genes and expand the genetic landscape of Parkinson\u2019s disease. Npj Park. Dis. 11, 347 (2025).","DOI":"10.1038\/s41531-025-01195-6"},{"key":"2026092205150748000_2026.03.03.26347540v4.7","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3766"},{"key":"2026092205150748000_2026.03.03.26347540v4.8","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26153"},{"key":"2026092205150748000_2026.03.03.26347540v4.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02089-w"},{"key":"2026092205150748000_2026.03.03.26347540v4.10","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.0268"},{"key":"2026092205150748000_2026.03.03.26347540v4.11","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1001\/jamaneurol.2022.1166","article-title":"Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease","volume":"79","year":"2022","journal-title":"JAMA Neurol"},{"key":"2026092205150748000_2026.03.03.26347540v4.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01584-8"},{"key":"2026092205150748000_2026.03.03.26347540v4.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-29108-8"},{"key":"2026092205150748000_2026.03.03.26347540v4.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01787-7"},{"key":"2026092205150748000_2026.03.03.26347540v4.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.06.009"},{"key":"2026092205150748000_2026.03.03.26347540v4.16","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/s41586-025-09272-9","article-title":"Whole-genome sequencing of 490,640 UK Biobank participants","volume":"645","year":"2025","journal-title":"Nature"},{"key":"2026092205150748000_2026.03.03.26347540v4.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06957-x"},{"key":"2026092205150748000_2026.03.03.26347540v4.18","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000194"},{"key":"2026092205150748000_2026.03.03.26347540v4.19","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1002\/mds.28549","article-title":"Accelerating Medicines Partnership: Parkinson\u2019s Disease. Genetic Resource","volume":"36","year":"2021","journal-title":". Mov. Disord. Off. J. Mov. Disord. Soc"},{"key":"2026092205150748000_2026.03.03.26347540v4.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"2026092205150748000_2026.03.03.26347540v4.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"2026092205150748000_2026.03.03.26347540v4.22","doi-asserted-by":"publisher","DOI":"10.1038\/S41588-021-00870-7"},{"key":"2026092205150748000_2026.03.03.26347540v4.23","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1590\/S1980-57642013DN70100010","article-title":"Evaluation of patients with behavioral and cognitive complaints: misdiagnosis in frontotemporal dementia and Alzheimer\u2019s disease","volume":"7","year":"2013","journal-title":"Dement. Neuropsychol"},{"key":"2026092205150748000_2026.03.03.26347540v4.24","doi-asserted-by":"publisher","DOI":"10.1101\/2025.03.14.24319455"},{"key":"2026092205150748000_2026.03.03.26347540v4.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(98)00209-2"},{"key":"2026092205150748000_2026.03.03.26347540v4.26","doi-asserted-by":"publisher","DOI":"10.1148\/radiology.187.2.8475286"},{"key":"2026092205150748000_2026.03.03.26347540v4.27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M604474200"},{"key":"2026092205150748000_2026.03.03.26347540v4.28","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/s41586-025-09335-x","article-title":"Lithium deficiency and the onset of Alzheimer\u2019s disease","volume":"645","year":"2025","journal-title":"Nature"},{"key":"2026092205150748000_2026.03.03.26347540v4.29","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp323"},{"key":"2026092205150748000_2026.03.03.26347540v4.30","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww079"},{"key":"2026092205150748000_2026.03.03.26347540v4.31","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1080\/21678421.2020.1813312","article-title":"Juvenile amyotrophic lateral sclerosis with complex phenotypes associated with novel SYNE1 mutations","volume":"22","year":"2021","journal-title":"Amyotroph. Lateral Scler. Front. Degener"},{"key":"2026092205150748000_2026.03.03.26347540v4.32","doi-asserted-by":"crossref","unstructured":"Foster, E. M. , Dangla-Valls, A. , Lovestone, S. , Ribe, E. M. & Buckley, N. J . Clusterin in Alzheimer\u2019s Disease: Mechanisms, Genetics, and Lessons From Other Pathologies. Front. Neurosci. 13, 164 (2019).","DOI":"10.3389\/fnins.2019.00164"},{"key":"2026092205150748000_2026.03.03.26347540v4.33","doi-asserted-by":"crossref","unstructured":"Shen, R. et al. Upregulation of RIN3 induces endosomal dysfunction in Alzheimer\u2019s disease. Transl. Neurodegener. 9, 26 (2020).","DOI":"10.1186\/s40035-020-00206-1"},{"key":"2026092205150748000_2026.03.03.26347540v4.34","doi-asserted-by":"crossref","unstructured":"Maaser-Hecker, A. K. et al. RIN3 mutations impairing binding of the Alzheimer\u2019s disease\u2013associated protein BIN1 lead to RAB5 hyperactivation and endosomal pathology. Sci. Adv. 12, eadx2127 (2026).","DOI":"10.1126\/sciadv.adx2127"},{"key":"2026092205150748000_2026.03.03.26347540v4.35","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-06-01992.2003"},{"key":"2026092205150748000_2026.03.03.26347540v4.36","doi-asserted-by":"crossref","first-page":"25424823251384245","DOI":"10.1177\/25424823251384245","article-title":"KIAA0319 modulates Alzheimer\u2019s disease risk through PMM2 regulation: Evidence from integrated pQTL-mediation and transcriptomic analyses","volume":"9","year":"2025","journal-title":"J. Alzheimers Dis. Rep"},{"key":"2026092205150748000_2026.03.03.26347540v4.37","doi-asserted-by":"crossref","unstructured":"Regan, P. , McClean, P. L. , Smyth, T. & Doherty, M . Early Stage Glycosylation Biomarkers in Alzheimer\u2019s Disease. Medicines 6, 92 (2019).","DOI":"10.3390\/medicines6030092"},{"key":"2026092205150748000_2026.03.03.26347540v4.38","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-4328(00)00215-1"},{"key":"2026092205150748000_2026.03.03.26347540v4.39","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy099"},{"key":"2026092205150748000_2026.03.03.26347540v4.40","doi-asserted-by":"crossref","first-page":"e2426339122","DOI":"10.1073\/pnas.2426339122","article-title":"Sp140L functions as a herpesvirus restriction factor suppressing viral transcription and activating interferon-stimulated genes","volume":"122","year":"2025","journal-title":"Proc. Natl. Acad. Sci"},{"key":"2026092205150748000_2026.03.03.26347540v4.41","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-021-02384-2"},{"key":"2026092205150748000_2026.03.03.26347540v4.42","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.brainresbull.2019.05.020","article-title":"Role of chemokines in Parkinson\u2019s disease","volume":"152","year":"2019","journal-title":"Brain Res. Bull"},{"key":"2026092205150748000_2026.03.03.26347540v4.43","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4000"},{"key":"2026092205150748000_2026.03.03.26347540v4.44","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12406"},{"key":"2026092205150748000_2026.03.03.26347540v4.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2014.04.010"},{"key":"2026092205150748000_2026.03.03.26347540v4.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2014.06.024"},{"key":"2026092205150748000_2026.03.03.26347540v4.47","doi-asserted-by":"crossref","unstructured":"Schorova, L. et al. USP19 deubiquitinase inactivation regulates \u03b1-synuclein ubiquitination and inhibits accumulation of Lewy body-like aggregates in mice. Npj Park. Dis. 9, 157 (2023).","DOI":"10.1038\/s41531-023-00601-1"},{"key":"2026092205150748000_2026.03.03.26347540v4.48","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.538934"},{"key":"2026092205150748000_2026.03.03.26347540v4.49","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.733410"},{"key":"2026092205150748000_2026.03.03.26347540v4.50","doi-asserted-by":"crossref","first-page":"4974","DOI":"10.1093\/brain\/awad246","article-title":"The non-specific lethal complex regulates genes and pathways genetically linked to Parkinson\u2019s disease","volume":"146","year":"2023","journal-title":"Brain J. Neurol"},{"key":"2026092205150748000_2026.03.03.26347540v4.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.09.052"},{"key":"2026092205150748000_2026.03.03.26347540v4.52","doi-asserted-by":"crossref","unstructured":"Boassa, D. , Nguyen, P. , Hu, J. , Ellisman, M. H. & Sosinsky, G. E . Pannexin2 oligomers localize in the membranes of endosomal vesicles in mammalian cells while Pannexin1 channels traffic to the plasma membrane. Front. Cell. Neurosci. 8, (2015).","DOI":"10.3389\/fncel.2014.00468"},{"key":"2026092205150748000_2026.03.03.26347540v4.53","doi-asserted-by":"publisher","DOI":"10.1038\/S41588-018-0311-9"},{"key":"2026092205150748000_2026.03.03.26347540v4.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.08.018"},{"key":"2026092205150748000_2026.03.03.26347540v4.55","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq559"},{"key":"2026092205150748000_2026.03.03.26347540v4.56","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt144"},{"key":"2026092205150748000_2026.03.03.26347540v4.57","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21896"},{"key":"2026092205150748000_2026.03.03.26347540v4.58","doi-asserted-by":"crossref","unstructured":"Le Guen, Y. et al. A novel age-informed approach for genetic association analysis in Alzheimer\u2019s disease. Alzheimers Res. Ther. 13, 72 (2021).","DOI":"10.1186\/s13195-021-00808-5"},{"key":"2026092205150748000_2026.03.03.26347540v4.59","doi-asserted-by":"crossref","unstructured":"McLaren, W. et al. The Ensembl Variant Effect Predictor. Genome Biol. 17, 122 (2016).","DOI":"10.1186\/s13059-016-0974-4"},{"key":"2026092205150748000_2026.03.03.26347540v4.60","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07050-7"},{"key":"2026092205150748000_2026.03.03.26347540v4.61","doi-asserted-by":"publisher","DOI":"10.1038\/sj.hdy.6800717"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.03.26347540","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:15:17Z","timestamp":1790079317000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.03.03.26347540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,4]]},"references-count":61,"URL":"https:\/\/doi.org\/10.64898\/2026.03.03.26347540","relation":{},"subject":[],"published":{"date-parts":[[2026,3,4]]},"subtype":"preprint"}}