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Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease.

ABSTRACT: Parkinson's disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson's Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.

SUBMITTER: Skuladottir AT

PROVIDER: S-EPMC11327306 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease.

Skuladottir Astros Th AT Tragante Vinicius V Sveinbjornsson Gardar G Helgason Hannes H Sturluson Arni A Bjornsdottir Anna A Jonsson Palmi P Palmadottir Vala V Sveinsson Olafur A OA Jensson Brynjar O BO Gudjonsson Sigurjon A SA Ivarsdottir Erna V EV Gisladottir Rosa S RS Gunnarsson Arni F AF Walters G Bragi GB Jonsdottir Gudrun A GA Thorgeirsson Thorgeir E TE Bjornsdottir Gyda G Holm Hilma H Gudbjartsson Daniel F DF Sulem Patrick P Stefansson Hreinn H Stefansson Kari K

NPJ Parkinson's disease 20240815 1

Parkinson's disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson ...[more]

PMID: 39147844

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Project description:BACKGROUND:Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial. METHODS:To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants. RESULTS:BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02-36.57, P < 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99-59.66, P < 0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR = 1.81 95% CI = 1.00-3.30, P = 0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR = 1.42, 95% CI = 0.70-2.90, P = 0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR = 3.59, 95% CI = 1.43-9.01; P = 0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P = 0.0014) but not in BC (P = 0.0693) patients. CONCLUSIONS:To avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded.

Dataset Information

Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease.

Publications

Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease.

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