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Background 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‐term PCSK9 inhibition between men and women. Methods and Results Using PCSK9 gene single‐nucleotide polymorphisms from European ancestry–based genome‐wide association studies of low‐density lipoprotein cholesterol (N=1 320 016), circulating PCSK9 protein levels (N=10 186), tissue‐specific PCSK9 gene expression, sex‐specific genome‐wide association studies of anxiety, depression, cognition, insomnia, and dementia (ranging from 54 321 to 194 174), we used drug‐target inverse variance–weighted 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‐target analyses were generally well‐powered to detect effect estimates at several hypothesized thresholds for both combined‐sex and sex‐specific 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‐specific PCSK9 expression were in alignment, strengthening causal inference. Conclusions Genetically proxied PCSK9 inhibition showed a neutral neuropsychiatric side effect profile with no major sex‐specific 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‐lowering drug‐prescribing practices and side effect monitoring of approved and future PCSK9 therapies.

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