{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:11:30Z","timestamp":1768565490073,"version":"3.49.0"},"posted":{"date-parts":[[2024,2,24]]},"group-title":"Genetic and Genomic Medicine","reference-count":42,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,2,24]],"date-time":"2024-02-24T00:00:00Z","timestamp":1708732800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,2,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Recently, a novel African ancestry specific Parkinson\u2019s disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (\n                  <jats:italic>GBA1<\/jats:italic>\n                  ). This variant (rs3115534-G) is carried by \u223c50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups, but is almost absent in European and Asian ancestry populations.\n                  <jats:italic>GBA1<\/jats:italic>\n                  is a gene of high clinical and therapeutic interest. Damaging bi-allelic protein-coding variants cause Gaucher disease and mono-allelic variants confer risk for PD and Dementia with Lewy Bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the novel African ancestry specific\n                  <jats:italic>GBA1<\/jats:italic>\n                  risk variant is a non-coding variant, suggesting a different mechanism of action. Using full length RNA transcript sequencing, we identified intron 8 expression in risk variant carriers (G) but not in non-variant carriers (T). Antibodies targeting the N-terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting the disease mechanism is RNA-based. CRISPR editing of the reported index variant (rs3115534) revealed that this is the responsible sequence alteration driving production of these intron 8 containing transcripts. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and therefore has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity we identified a dose-dependent reduction in risk variant carriers (G). Overall, we report the functional effect of a\n                  <jats:italic>GBA1<\/jats:italic>\n                  non-coding risk variant, which acts by interfering with the splicing of functional\n                  <jats:italic>GBA1<\/jats:italic>\n                  transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a novel therapeutic target in an underserved and underrepresented population.\n                <\/jats:p>","DOI":"10.1101\/2024.02.20.24302827","type":"posted-content","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T12:52:21Z","timestamp":1734094341000},"source":"Crossref","is-referenced-by-count":1,"title":["African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5812-1898","authenticated-orcid":false,"given":"Pilar \u00c1lvarez","family":"Jerez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8944-5716","authenticated-orcid":false,"given":"Peter A.","family":"Wild Crea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel 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