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To leverage expression imputation models (i.e., base models) trained with multiple reference panels, regression methods, and tissues, we develop a Stacked Regression based TWAS (SR-TWAS) tool which can obtain optimal linear combinations of base models for a given validation transcriptomic dataset. Both simulation and real studies showed that SR-TWAS improved power, due to increased effective training sample sizes and borrowed strength across multiple regression methods and tissues. Leveraging base models across multiple reference panels, tissues, and regression methods, our real application studies identified 6 independent significant risk genes for Alzheimer\u2019s disease (AD) dementia for supplementary motor area tissue and 9 independent significant risk genes for Parkinson\u2019s disease (PD) for substantia nigra tissue. Relevant biological interpretations were found for these significant risk genes.<\/jats:p>","DOI":"10.1101\/2023.06.20.23291605","type":"posted-content","created":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T15:50:15Z","timestamp":1687881015000},"source":"Crossref","is-referenced-by-count":0,"title":["SR-TWAS: Leveraging Multiple Reference Panels to Improve TWAS Power by Ensemble Machine Learning"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6836-4496","authenticated-orcid":false,"given":"Randy L.","family":"Parrish","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6426-2742","authenticated-orcid":false,"given":"Aron S.","family":"Buchman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Tasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanling","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denis","family":"Avey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jishu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":false,"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9647-9738","authenticated-orcid":false,"given":"Michael P.","family":"Epstein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4191-4138","authenticated-orcid":false,"given":"Jingjing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024051603550550000_2023.06.20.23291605v4.1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22288"},{"key":"2024051603550550000_2023.06.20.23291605v4.2","doi-asserted-by":"publisher","DOI":"10.1101\/2020.04.23.043653"},{"key":"2024051603550550000_2023.06.20.23291605v4.3","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/s41598-020-58510-9","article-title":"A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration","volume":"10","year":"2020","journal-title":"Scientific Reports"},{"key":"2024051603550550000_2023.06.20.23291605v4.4","doi-asserted-by":"crossref","unstructured":"Wu, C. et al. 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