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However, the impact of rare variants on traits is often neglected, and traditional MR assumptions can be violated by correlated horizontal pleiotropy (CHP) and uncorrelated horizontal pleiotropy (UHP). To address these issues, we propose a multivariable MR approach, an extension of the standard MR framework: MVMR incorporating Rare variants Accounting for multiple Risk factors and shared horizontal plEiotropy (RARE). In the simulation studies, we demonstrate that RARE effectively detects the causal effects of exposures on outcome with accounting for the impact of rare variants on causal inference. Additionally, we apply RARE to study the effects of high density lipoprotein and low density lipoprotein on type 2 diabetes and coronary atherosclerosis, respectively, thereby illustrating its robustness and effectiveness in real data analysis.<\/jats:p>","DOI":"10.1093\/bib\/bbaf214","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T06:26:42Z","timestamp":1747290402000},"source":"Crossref","is-referenced-by-count":1,"title":["Accounting for the impact of rare variants on causal inference with RARE: a novel multivariable Mendelian randomization method"],"prefix":"10.1093","volume":"26","author":[{"given":"Yu","family":"Cheng","sequence":"first","affiliation":[{"name":"Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University , #639 Longmian Ave, Jiangning District, Nanjing 211100, Jiangsu,","place":["China"]},{"name":"Department of Bioinformatics and Computational Biology, The University of Texas, M.D. Anderson 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