{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T13:04:32Z","timestamp":1777727072777,"version":"3.51.4"},"reference-count":29,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Int Med Res"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>The pleiotropic effects of lipid-lowering therapies on mental health remain incompletely understood. This study aimed to investigate the causal impact of genetically proxied inhibition of three major lipid-lowering drug targets, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), Niemann-Pick C1-like protein 1 (NPC1L1), and proprotein convertase subtilisin\/kexin type 9 (PCSK9), on a spectrum of psychiatric disorders using a drug\u2013target Mendelian randomization approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used genetic variants located within or near the HMGCR, NPC1L1, and PCSK9 gene regions that are associated with low-density lipoprotein cholesterol levels as proxies for pharmacological inhibition. Summary-level data were obtained from large-scale genome-wide association studies for seven psychiatric outcomes: anorexia nervosa, anxiety, bipolar disorder, major depressive disorder, neuroticism, obsessive compulsive disorder, and schizophrenia. The inverse-variance weighted method was employed as the primary Mendelian randomization approach, supplemented by multiple sensitivity analyses to assess robustness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Genetically proxied inhibition of HMGCR was associated with an increased risk of major depressive disorder (odds ratio\u2009=\u20091.16; 95% confidence interval: 1.07\u20131.25;\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20094.5e\u221204). In contrast, NPC1L1 inhibition was associated with a decreased risk of major depressive disorder (odds ratio\u2009=\u20090.88; 95% confidence interval: 0.84\u20130.92;\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20098.1e\u221208). PCSK9 inhibition was significantly associated with an increased risk of major depressive disorder (odds ratio\u2009=\u20091.16; 95% confidence interval: 1.06\u20131.26;\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20098.2e\u221204) and bipolar disorder (odds ratio\u2009=\u20091.28; 95% confidence interval: 1.19\u20131.38;\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20099.4e\u221212). No significant associations were observed between these targets and the remaining psychiatric outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides genetic evidence that lipid-lowering drug targets exert distinct effects on psychiatric disorders. These findings highlight the importance of further clinical and mechanistic studies, particularly given the widespread use of lipid-lowering therapies in aging populations who are vulnerable to mental health conditions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/03000605261416738","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T10:33:32Z","timestamp":1769855612000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Causal effects of lipid-lowering drug targets on psychiatric disorders: A drug\u2013target Mendelian randomization study"],"prefix":"10.1177","volume":"54","author":[{"given":"Yan","family":"Wang","sequence":"first","affiliation":[{"name":"Fengqiu County Traditional Chinese Medicine Hospital, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"Taian City 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