Comparing the Relationships of Genetically Proxied PCSK9 Inhibition With Mood Disorders, Cognition, and Dementia Between Men and Women: A Drug-Target Mendelian Randomization Study

Abstract

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.

Keywords: Alzheimer disease; Mendelian randomization; PCSK9; cholesterol; cognition; dementia; depression; low‐density lipoprotein.

Figure 1. Overview of study methods and procedures.

All summary‐level genetic associations were derived from genome‐wide association studies (GWAS) of European ancestry. Additional information regarding the GWAS data (consortium, study cohort, and author information of the GWAS for the exposure and neuropsychiatric outcomes) are located in Table S1. We performed cis‐instrumentation of genetically predisposed PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition in several complementary data sets. First, single‐nucleotide polymorphisms (SNPs) ±100 kilobases of the PCSK9 gene locus were extracted from the Global Lipids Genetics Consortium (GLGC) 2021 meta‐analysis on circulating low‐density lipoprotein (LDL) cholesterol (LDL‐C) levels surpassing conventional genome‐wide significance (P<5×10⁻⁸). We also proxied PCSK9 inhibition using circulating levels of the PCSK9 protein and tissue‐specific gene expression of PCSK9 in the liver, whole blood, and brain (cortex). These PCSK9 SNPs were then extracted from selected neuropsychiatric end points spanning mood disorders, insomnia, dementia, and cognition from UK Biobank data that combined men and women, as well as male‐only and female‐only GWASs. Finally, we performed drug‐target Mendelian randomization to evaluate the neuropsychiatric impact of genetically predisposed PCSK9 inhibition across men and women (see Methods section). eQTL indicates expression quantitative trait loci; GTEx Genotype‐Tissue Expression; and LDLR, low‐density lipoprotein receptor.

Figure 2. Inverse variance–weighted Mendelian randomization results of genetically proxied PCSK9 (proprotein convertase subtilisin/kexin type 9) in circulating low‐density lipoprotein cholesterol (LDL‐C) and circulating protein levels on neuropsychiatric outcomes for men and women.

Estimates for the LDL‐C–lowering impact of PCSK9 inhibition are reported as odds ratios (ORs) corresponding to a change in the risk for the neuropsychiatric end point per 1‐SD reduction of genetically determined circulating LDL‐C levels (ie, the primary physiological response of pharmacologic PCSK9 inhibition). For the analyses using circulating PCSK9 protein levels, the ORs correspond to a change in genetically determined normalized circulating PCSK9 protein levels (ie, the primary physiological target of monoclonal PCSK9 inhibitors). Because fluid intelligence is a continuous variable, it was not included in the Forest plot but is discussed in the Results section. Full results, including combined‐sex results, are presented in Table S4 and Table S5.

Figure 3. Inverse variance–weighted and Wald ratio Mendelian randomization results of genetically proxied lowering of tissue‐specific PCSK9 (proprotein convertase subtilisin/kexin type 9) gene expression on neuropsychiatric outcomes for men and women.

Estimates are reported odds ratios (ORs) and 95% CIs corresponding to a change in the risk for the neuropsychiatric end point for a change in genetically determined liver, whole blood, and brain PCSK9 gene expression (measured in transcripts per million [TPM]). Full results, including the combined‐sex results, are presented in Table S9.