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We employed two-sample Mendelian randomization (MR) integrating tissue-specific gene regulatory networks to identify causal genes and regulatory elements modulating PD risk. Two-sample MR analysis identified 79 putative causal genes for PD. A subset of the 79 causal genes was enriched within chr17q21.31 and chr16p11.2 cytobands that have been previously linked to neurodevelopmental disorders. Functional enrichment analysis of the 79 genes revealed autophagosome-lysosome fusion as a key process. Ten genes (<jats:italic>ELOVL7<\/jats:italic>, <jats:italic>HSD3B7<\/jats:italic>, <jats:italic>PLEKHM1<\/jats:italic>, <jats:italic>PRSS53<\/jats:italic>, <jats:italic>SNCA<\/jats:italic>, <jats:italic>STX1B<\/jats:italic>, <jats:italic>STX4<\/jats:italic>, <jats:italic>ZSWIM7<\/jats:italic>, <jats:italic>LINC02210<\/jats:italic>, and <jats:italic>RP11-1072 A3.3<\/jats:italic>) showed causal associations with tissue-specific expression patterns driving risk or protection for PD. Further investigation into their tissue-specific isoform expression profile revealed isoform-specific contributions to disease risk (or protection). These findings highlight the critical role of isoform-specific expression of causal genes in modulating PD risk, particularly relating to autophagosome-lysosome fusion. While our findings provide new insights into PD susceptibility, we acknowledge that the observed isoform-specific changes may, in part, reflect sample selection bias. Therefore, further experimental verification is needed to confirm the importance of incorporating tissue-specific gene isoform profiles in understanding PD causal mechanisms.<\/jats:p>","DOI":"10.1007\/s12035-025-05101-2","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T12:20:45Z","timestamp":1748866845000},"page":"12824-12838","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Inherited Genetic Variation in Parkinson\u2019s Disease: Convergence on Impaired Autophagosome-Lysosome Fusion Through the Altered Expression of mRNA Isoforms"],"prefix":"10.1007","volume":"62","author":[{"given":"Sreemol","family":"Gokuladhas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catriona","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antony A.","family":"Cooper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin M.","family":"O\u2019Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,2]]},"reference":[{"issue":"5321","key":"5101_CR1","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1126\/science.276.5321.2045","volume":"276","author":"MH Polymeropoulos","year":"1979","unstructured":"Polymeropoulos MH et al (1979) Mutation in the \u03b1-synuclein gene identified in families with Parkinson\u2019s disease. 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