{"doi":"10.1016/j.celrep.2025.115355","title":"Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease","abstract":"Despite its significant heritability, the genetic basis of Parkinson's disease (PD) remains incompletely understood. Here, in analyzing whole-genome sequence data from 3,809 PD cases and 247,101 controls in the UK Biobank, we discover that protein-truncating variants in ITSN1 confer a substantially increased risk of PD ( p = 6.1 × 10 −7 ; odds ratio [95% confidence interval] = 10.5 [5.2, 21.3]). We replicate this association in three independent datasets totaling 8,407 cases and 413,432 controls (combined p = 4.5 × 10 −12 ). Notably, ITSN1 haploinsufficiency has also been associated with autism spectrum disorder, suggesting variable penetrance/expressivity. In Drosophila , we find that loss of the ITSN1 ortholog Dap160 exacerbates α-synuclein-induced neuronal toxicity and motor deficits, and in vitro assays further suggest a physical interaction between ITSN1 and α-synuclein. These results firmly establish ITSN1 as a PD risk gene with an effect size exceeding previously established loci, implicate vesicular trafficking dysfunction in PD pathogenesis, and potentially open new avenues for therapeutic development.","journal":"Cell Reports","year":2025,"id":515718,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":987157,"name":"Chloe F. 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Calame","orcid":"0000-0001-6860-372X","position":16,"is_corresponding":false},{"id":576531,"name":"Hiba Saade","orcid":null,"position":17,"is_corresponding":false},{"id":308537,"name":"Laurie Robak","orcid":"0000-0001-8279-2504","position":18,"is_corresponding":false},{"id":1381095,"name":"Ben Hollis","orcid":null,"position":19,"is_corresponding":false},{"id":876195,"name":"Vishnu Anand Cuddapah","orcid":"0000-0002-4606-673X","position":20,"is_corresponding":false},{"id":24573,"name":"Huda Y. Zoghbi","orcid":"0000-0002-0700-3349","position":21,"is_corresponding":false},{"id":232932,"name":"Joshua M. 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