{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:46:01Z","timestamp":1793295961254,"version":"4.5.0"},"reference-count":81,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">PCSK9 (proprotein convertase subtilisin\/kexin type 9) inhibitors are important therapeutic options for reducing cardiovascular disease risk; however, questions remain regarding potential differences in the neuropsychiatric impact of long\u2010term PCSK9 inhibition between men and women.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Using PCSK9 gene single\u2010nucleotide polymorphisms from European ancestry\u2013based genome\u2010wide association studies of low\u2010density lipoprotein cholesterol (N=1\u2009320\u2009016), circulating PCSK9 protein levels (N=10\u2009186), tissue\u2010specific PCSK9 gene expression, sex\u2010specific genome\u2010wide association studies of anxiety, depression, cognition, insomnia, and dementia (ranging from 54\u2009321 to 194\u2009174), we used drug\u2010target inverse variance\u2013weighted Mendelian randomization (MR) and complementary MR methods (MR Egger, weighted median, and weighted mode) to investigate potential neuropsychiatric consequences of genetically proxied PCSK9 inhibition in men and women. We failed to find evidence surpassing correction for multiple comparisons of relationships between genetically proxied PCSK9 inhibition and the risk for the 12 neuropsychiatric end points in either men or women. Drug\u2010target analyses were generally well\u2010powered to detect effect estimates at several hypothesized thresholds for both combined\u2010sex and sex\u2010specific end points, especially analyses using PCSK9 instruments derived from protein and expression quantitative trait loci. Further, MR estimates across complementary MR methods and additional models using genetic instruments derived from circulating PCSK9 protein levels and tissue\u2010specific\n              <jats:italic>PCSK9<\/jats:italic>\n              expression were in alignment, strengthening causal inference.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Genetically proxied PCSK9 inhibition showed a neutral neuropsychiatric side effect profile with no major sex\u2010specific differences. Given statistical power considerations, replication with larger samples, as well as data from other ancestral populations, are necessary. These findings may have important clinical implications for lipid\u2010lowering drug\u2010prescribing practices and side effect monitoring of approved and future PCSK9 therapies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.122.026122","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T10:31:22Z","timestamp":1666780282000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Comparing the Relationships of Genetically Proxied PCSK9 Inhibition With Mood Disorders, Cognition, and Dementia Between Men and Women: A Drug\u2010Target Mendelian Randomization Study"],"prefix":"10.1161","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2497-9420","authenticated-orcid":false,"given":"Andrew S.","family":"Bell","sequence":"first","affiliation":[{"name":"Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5718-7668","authenticated-orcid":false,"given":"Daniel B.","family":"Rosoff","sequence":"additional","affiliation":[{"name":"Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda MD"},{"name":"NIH\u2010Oxford\u2010Cambridge Scholars Program, Nuffield Department of Population Health University of Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2921-4654","authenticated-orcid":false,"given":"Lucas A.","family":"Mavromatis","sequence":"additional","affiliation":[{"name":"Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2668-5541","authenticated-orcid":false,"given":"Jeesun","family":"Jung","sequence":"additional","affiliation":[{"name":"Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8880-5721","authenticated-orcid":false,"given":"Josephin","family":"Wagner","sequence":"additional","affiliation":[{"name":"Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0480-7755","authenticated-orcid":false,"given":"Falk W.","family":"Lohoff","sequence":"additional","affiliation":[{"name":"Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.04.050"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pop.2005.09.002"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107331"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00488"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1987.00520160052014"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.822515"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000350"},{"key":"e_1_3_1_9_2","first-page":"S139","article-title":"Epidemiology and management of hyperlipidemia","volume":"23","author":"Karr S","year":"2017","unstructured":"Karr S. 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