Abstract Introduction Sleep and circadian disturbances are highly prevalent in autism spectrum disorder (ASD), yet the mechanisms linking ASD risk genes to human sleep/circadian physiology remain unclear. Advances in single-cell expression quantitative trait loci (eQTL) datasets now enable testing of gene and cell-type-specific relationships with sleep traits. Methods We intersected the SPARK/ClinGen list of 162 ASD risk genes with cell-type–specific cis-eQTLs (N=983), yielding 111 genes with suitable instruments across seven brain cell types and 24 neuronal and glial sub-classes. These cis-eQTLs were used as expression proxies in a drug-target Mendelian randomization (DTMR) framework to estimate causal relationships with UK Biobank sleep traits (chronotype, sleep duration, ease of getting up, snoring; N≤413,343) under multiple-testing correction. To further prioritize ASD sleep–circadian genes, we triangulated DTMR findings with (i) postmortem human dorsolateral prefrontal cortex (dlPFC) time-series transcriptomics, and (ii) Drosophila RNAi circadian phenotyping. Results Across sleep outcomes, 12 ASD risk genes exhibited Bonferroni-significant, cell-type–specific relationships, primarily for chronotype (11 genes) and ease of getting up (5 genes). BCL11A showed concordant and opposite-direction chronotype associations across excitatory neurons, interneurons, and oligodendrocyte progenitors. RELN demonstrated robust chronotype associations across five neuronal and glial subclasses, strongest in interneurons. MEF2C displayed large chronotype relationships in homeostatic microglia and opposite-direction getting-up effects in activated microglia. Several Bonferroni- or FDR-significant genes (ACTB, EHMT1, DNMT3A, SETBP1, SHANK2, MAGEL2, IRF2BPL, CACNA1C, MEIS2) also displayed rhythmic or clock-regulated expression in dlPFC cell types, supporting conserved circadian roles. Further, Drosophila homologs of ASD genes such as NBEA, PHF3, PSMD12, and RERE produced canonical circadian phenotypes with complementary human MR associations. Although no ASD gene was implicated across all three systems, several showed convergent evidence across human genetics, brain circadian regulation, and Drosophila screening. Conclusion Integrating human genetic, transcriptomic, and cross-species functional evidence reveals that ASD risk genes exert cell-type–specific impact on human sleep and circadian traits, especially chronotype, highlighting conserved molecular pathways linking ASD genetics to sleep–circadian biology. Support (if any) SFARI, Eagles Autism Foundation, NINDS R35NS132223 (RA, GW, BL)

BACKGROUND:WNT signaling plays a key role in postnatal bone formation. Individuals with gain-of-function mutations in the WNT co-receptor LRP5 exhibit increased lower-body fat mass and potentially enhanced glucose metabolism, alongside high bone mass. However, the mechanisms by which LRP5 regulates fat distribution and its effects on systemic metabolism remain unclear. This study aims to explore the role of LRP5 in adipose tissue biology and its impact on metabolism. METHODS:Metabolic assessments and imaging were conducted on individuals with gain- and loss-of-function LRP5 mutations, along with age- and BMI-matched controls. Mendelian randomization analyses were used to investigate the relationship between bone, fat distribution, and systemic metabolism. Functional studies and RNA sequencing were performed on abdominal and gluteal adipose cells with LRP5 knockdown. RESULTS:Here we show that LRP5 promotes lower-body fat distribution and enhances systemic and adipocyte insulin sensitivity through cell-autonomous mechanisms, independent of its bone-related functions. LRP5 supports adipose progenitor cell function by activating WNT/β-catenin signaling and preserving valosin-containing protein (VCP)-mediated proteostasis. LRP5 expression in adipose progenitors declines with age, but gain-of-function LRP5 variants protect against age-related fat loss in the lower body. CONCLUSIONS:Our findings underscore the critical role of LRP5 in regulating lower-body fat distribution and insulin sensitivity, independent of its effects on bone. Pharmacological activation of LRP5 in adipose tissue may offer a promising strategy to prevent age-related fat redistribution and metabolic disorders.

ABSTRACT The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10-12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10-10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10-4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases. ARTICLE HIGHLIGHTS o This study investigates the impact of lipid-lowering therapies, specifically PCSK9 and HMGCR inhibition, on type 2 diabetes (T2D) risk across diverse populations using Mendelian randomization (MR) analyses. o We found no adverse effect of PCSK9 inhibition on T2D risk in EAS, SAS, HISP, or EUR populations, though weak evidence of increased risk was seen in AFR, which was not robust in sensitivity analyses. o HMGCR inhibition was associated with a slight increase in T2D risk, consistent with previous findings, but the cardiovascular benefits of statin therapy likely outweigh this risk.

Using 13C6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1H-13C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning β cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and β cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human β cells and increases basal insulin release. Lastly, cis-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in β cells to maintain appropriate insulin release.

HomeCirculation: Genomic and Precision MedicineVol. 17, No. 1Evaluating the Cardiovascular Impact of Genetically Proxied PCSK9 and HMGCR Inhibition in East Asian and European Populations: A Drug-Target Mendelian Randomization Study No AccessResearch ArticleRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessResearch ArticleRequest AccessFull TextEvaluating the Cardiovascular Impact of Genetically Proxied PCSK9 and HMGCR Inhibition in East Asian and European Populations: A Drug-Target Mendelian Randomization Study Daniel B. Rosoff, Andrew S. Bell, Lucas A. Mavromatis, Ali Hamandi, Lauren Park, Jeesun Jung, Josephin Wagner, Pal Pacher, David Ray, George Davey Smith and Falk W. Lohoff Daniel B. RosoffDaniel B. Rosoff https://orcid.org/0000-0002-5718-7668 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. NIH-Oxford-Cambridge Scholars Program, University of Oxford, United Kingdom (D.B.R.). Medical Research Council Integrative Epidemiology Unit, University of Bristol, United Kingdom (D.B.R., G.D.S.). , Andrew S. BellAndrew S. Bell https://orcid.org/0000-0003-2497-9420 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Lucas A. MavromatisLucas A. Mavromatis https://orcid.org/0000-0003-2921-4654 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Ali HamandiAli Hamandi Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Lauren ParkLauren Park https://orcid.org/0009-0003-6958-2539 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Jeesun JungJeesun Jung https://orcid.org/0000-0002-2668-5541 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Josephin WagnerJosephin Wagner https://orcid.org/0000-0002-8880-5721 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , Pal PacherPal Pacher https://orcid.org/0000-0001-7036-8108 Laboratory of Cardiovascular Physiology and Tissue Injury (P.P.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. , David RayDavid Ray https://orcid.org/0000-0002-4739-6773 Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, United Kingdom (D.R.). National Institute for Health and Care Research Oxford Biomedical Research Centre, John Radcliffe Hospital, United Kingdom (D.R.). , George Davey SmithGeorge Davey Smith https://orcid.org/0000-0002-1407-8314 Medical Research Council Integrative Epidemiology Unit, University of Bristol, United Kingdom (D.B.R., G.D.S.). and Falk W. LohoffFalk W. Lohoff Correspondence to: Falk W. Lohoff, MD, Section on Clinical Genomics and Experimental Therapeutics, Lasker Clinical Research Scholar, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Dr (10CRC/2-2352), Bethesda, MD 20892. Email E-mail Address: [email protected] https://orcid.org/0000-0002-0480-7755 Section on Clinical Genomics and Experimental Therapeutics (D.B.R., A.S.B., L.A.M., A.H., L.P., J.J., J.W., F.W.L.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Bethesda, MD. Originally published23 Jan 2024https://doi.org/10.1161/CIRCGEN.122.004224Circulation: Genomic and Precision Medicine. 2024;17FootnotesFor Sources of Funding and Disclosures, see page 62.Correspondence to: Falk W. Lohoff, MD, Section on Clinical Genomics and Experimental Therapeutics, Lasker Clinical Research Scholar, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Dr (10CRC/2-2352), Bethesda, MD 20892. Email falk.lohoff@nih.govREFERENCES1. Meadows TA, Bhatt DL, Cannon CP, Gersh BJ, Röther J, Goto S, Liau CS, Wilson PWF, Salette G, Smith SC, et al; REACH Registry Investigators. Ethnic differences in cardiovascular risks and mortality in atherothrombotic disease: insights from the Reduction of Atherothrombosis for Continued Health (REACH) registry.Mayo Clin Proc. 2011; 86:960–967. doi: 10.4065/mcp.2011.0010CrossrefMedlineGoogle Scholar2. Clark LT, Watkins L, Piña IL, Elmer M, Akinboboye O, Gorham M, Jamerson B, McCullough C, Pierre C, Polis AB, et al. Increasing diversity in clinical trials: overcoming critical barriers.Curr Probl Cardiol. 2019; 44:148–172. doi: 10.1016/j.cpcardiol.2018.11.002CrossrefMedlineGoogle Scholar3. Michos ED, Reddy TK, Gulati M, Brewer LC, Bond RM, Velarde GP, Bailey AL, Echols MR, Nasser SA, Bays HE, et al. Improving the enrollment of women and racially/ethnically diverse populations in cardiovascular clinical trials: an ASPC practice statement.Am J Prev Cardiol. 2021; 8:100250. doi: 10.1016/j.ajpc.2021.100250CrossrefMedlineGoogle Scholar4. Schmidt AF, Finan C, Gordillo-Marañón M, Asselbergs FW, Freitag DF, Patel RS, Tyl B, Chopade S, Faraway R, Zwierzyna M, et al. Genetic drug target validation using Mendelian randomisation.Nat Commun. 2020; 11:3255–3255. doi: 10.1038/s41467-020-16969-0CrossrefMedlineGoogle Scholar5. Da Dalt L, Castiglioni L, Baragetti A, Audano M, Svecla M, Bonacina F, Pedretti S, Uboldi P, Benzoni P, Giannetti F, et al. PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction.Eur Heart J. 2021; 42:3078–3090. doi: 10.1093/eurheartj/ehab431CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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Integrating proteomic and transcriptomic data with genetic architectures of problematic alcohol use and alcohol consumption behaviours can advance our understanding and help identify therapeutic targets. We conducted systematic screens using genome-wise association study data from ~3,500 cortical proteins (N = 722) and ~6,100 genes in 8 canonical brain cell types (N = 192) with 4 alcohol-related outcomes (N ≤ 537,349), identifying 217 cortical proteins and 255 cell-type genes associated with these behaviours, with 36 proteins and 37 cell-type genes being new. Although there was limited overlap between proteome and transcriptome targets, downstream neuroimaging revealed shared neurophysiological pathways. Colocalization with independent genome-wise association study data further prioritized 16 proteins, including CAB39L and NRBP1, and 12 cell-type genes, implicating mechanisms such as mTOR signalling. In addition, genes such as SAMHD1, VIPAS39, NUP160 and INO80E were identified as having favourable neuropsychiatric profiles. These findings provide insights into the genetic landscapes governing problematic alcohol use and alcohol consumption behaviours, highlighting promising therapeutic targets for future research. This study examines links between genetics and alcohol use, and identifies 217 proteins in the human cortex and 255 genes at single-cell resolution. Leveraging population genetics with proteomic and transcriptomic data opens new paths in addiction science.

Alcohol Use Disorder (AUD) is a persistent condition linked to neuroinflammation, neuronal oxidative stress, and neurodegenerative processes. While the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has demonstrated effectiveness in reducing liver inflammation associated with alcohol, its impact on the brain remains largely unexplored. This study aimed to assess the effects of alirocumab, a monoclonal antibody targeting PCSK9 to lower systemic low-density lipoprotein cholesterol (LDL-C), on central nervous system (CNS) pathology in a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for six weeks in 32 male rats subjected to a 35 % ethanol liquid diet or a control liquid diet (n = 8 per group). The study evaluated PCSK9 expression, LDL receptor (LDLR) expression, oxidative stress, and neuroinflammatory markers in brain tissues. Chronic ethanol exposure increased PCSK9 expression in the brain, while alirocumab treatment significantly upregulated neuronal LDLR and reduced oxidative stress in neurons and brain vasculature (3-NT, p22phox). Alirocumab also mitigated ethanol-induced microglia recruitment in the cortex and hippocampus (Iba1). Additionally, alirocumab decreased the expression of pro-inflammatory cytokines and chemokines (TNF, CCL2, CXCL3) in whole brain tissue and attenuated the upregulation of adhesion molecules in brain vasculature (ICAM1, VCAM1, eSelectin). This study presents novel evidence that alirocumab diminishes oxidative stress and modifies neuroimmune interactions in the brain elicited by chronic ethanol exposure. Further investigation is needed to elucidate the mechanisms by which PCSK9 signaling influences the brain in the context of chronic ethanol exposure

Importance Observational studies suggest that major psychiatric disorders and substance use behaviors reduce longevity, making it difficult to disentangle their relationships with aging-related outcomes. Objective To evaluate the associations between the genetic liabilities for major psychiatric disorders, substance use behaviors (smoking and alcohol consumption), and longevity. Design, Settings, and Participants This 2-sample mendelian randomization (MR) study assessed associations between psychiatric disorders, substance use behaviors, and longevity using single-variable and multivariable models. Multiomics analyses were performed elucidating transcriptomic underpinnings of the MR associations and identifying potential proteomic therapeutic targets. This study sourced summary-level genome-wide association study (GWAS) data, gene expression, and proteomic data from cohorts of European ancestry. Analyses were performed from May 2022 to November 2023. Exposures Genetic susceptibility for major depression (n = 500 199), bipolar disorder (n = 413 466), schizophrenia (n = 127 906), problematic alcohol use (n = 435 563), weekly alcohol consumption (n = 666 978), and lifetime smoking index (n = 462 690). Main Outcomes and Measures The main outcome encompassed aspects of health span, lifespan, and exceptional longevity. Additional outcomes were epigenetic age acceleration (EAA) clocks. Results Findings from multivariable MR models simultaneously assessing psychiatric disorders and substance use behaviorsm suggest a negative association between smoking and longevity in cohorts of European ancestry (n = 709 709; 431 503 [60.8%] female; β, −0.33; 95% CI, −0.38 to −0.28; P = 4.59 × 10 −34 ) and with increased EAA (n = 34 449; 18 017 [52.3%] female; eg, PhenoAge: β, 1.76; 95% CI, 0.72 to 2.79; P = 8.83 × 10 −4 ). Transcriptomic imputation and colocalization identified 249 genes associated with smoking, including 36 novel genes not captured by the original smoking GWAS. Enriched pathways included chromatin remodeling and telomere assembly and maintenance. The transcriptome-wide signature of smoking was inversely associated with longevity, and estimates of individual smoking-associated genes, eg, XRCC3 and PRMT6 , aligned with the smoking-longevity MR analyses, suggesting underlying transcriptomic mediators. Cis-instrument MR prioritized brain proteins associated with smoking behavior, including LY6H (β, 0.02; 95% CI, 0.01 to 0.03; P = 2.37 × 10 −6 ) and RIT2 (β, 0.02; 95% CI, 0.01 to 0.03; P = 1.05 × 10 −5 ), which had favorable adverse-effect profiles across 367 traits evaluated in phenome-wide MR. Conclusions The findings suggest that the genetic liability of smoking, but not of psychiatric disorders, is associated with longevity. Transcriptomic associations offer insights into smoking-related pathways, and identified proteomic targets may inform therapeutic development for smoking cessation strategies.

Abstract Human genetic and transgenic mouse studies have highlighted a potential liver-adipose tissue endocrine axis, involving activin C (Act-C) and/or Act-E and ALK7, influencing fat distribution and systemic metabolism. We investigated the bidirectional effects between circulating INHBC, which homodimerizes into Act-C, and adiposity traits, insulin resistance, inflammation, and cardiometabolic disease risk. Additionally, we examined if Act-C is an ALK7 ligand in human adipocytes. We used Mendelian randomization and in vitro studies in immortalized human abdominal and gluteal adipocytes. Circulating INHBC was causally linked to reduced lower-body fat, dyslipidaemia, and increased risks of coronary artery disease (CAD) and non-alcoholic fatty liver disease (NAFLD). Conversely, upper-body fat distribution, obesity, hypertriglyceridemia, subclinical inflammation, and type 2 diabetes positively impacted plasma INHBC levels. Mechanistically, an atherogenic lipid profile may partly explain the INHBC-CAD link, while inflammation and hypertriglyceridemia may partly explain how adiposity traits affect circulating INHBC. Phenome-wide Mendelian randomization showed weak causal relationships between higher plasma INHBC and impaired kidney function and higher gout risk. In human adipocytes, recombinant Act-C activated SMAD2/3 signaling via ALK7 and suppressed lipolysis. In summary, INHBC influences systemic metabolism by activating ALK7 in adipose tissue and may serve as a drug target for atherogenic dyslipidemia, CAD, and NAFLD. Article Highlights · We explored the bidirectional relationships between circulating INHBC and cardiometabolic traits and diseases, and investigated whether activin C, an INHBC homodimer, acts as an ALK7 ligand in human adipocytes. · Elevated circulating INHBC was linked to dyslipidemia, increased coronary artery disease and non-alcoholic fatty liver disease risk. Conversely, upper-body obesity, hypertriglyceridemia, inflammation, and diabetes increased circulating INHBC, potentially creating a vicious cycle. Activin C activated ALK7 signaling in adipocytes and suppressed lipolysis. · INHBC is a novel hepatokine influencing systemic metabolism and a potential drug target for cardiometabolic diseases.

ObjectiveObservational studies have reported bidirectional associations between metabolic syndrome (MetS) traits and short leukocyte telomere length (LTL), a TL marker in somatic tissues and a proposed risk factor for age-related degenerative diseases. However, in Mendelian randomization studies, longer LTL has been paradoxically associated with higher MetS risk. This study investigated the hypothesis that shorter LTL might be a consequence of metabolic dysfunction. MethodsThis study undertook univariable and multivariable Mendelian randomization. As instrumental variables for MetS traits, all of the genome-wide significant independent signals identified in genome-wide association studies for anthropometric, glycemic, lipid, and blood pressure traits conducted in European individuals were used. Summary-level data for LTL were obtained from a genome-wide association study conducted in the UK Biobank. ResultsHigher BMI was associated with shorter LTL (& beta; = -0.039, 95% CI: -0.058 to -0.020, p = 5 x 10(-5)) equivalent to 1.70 years of age-related LTL change. In contrast, higher low-density lipoprotein cholesterol was associated with longer LTL (& beta; = 0.022, 95% CI: 0.007 to 0.037, p = 0.003) equivalent to 0.96 years of age-related LTL change. Mechanistically, increased low-grade systemic inflammation, as measured by circulating C-reactive protein, and lower circulating linoleic acid levels might link higher BMI to shorter LTL. ConclusionsOverweight and obesity might promote the development of aging-related degenerative diseases by accelerating telomere shortening.

The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings; however, aging-related endpoints have been primarily assessed individually. Using data from these traits and multivariate genome-wide association study methods, we modeled their underlying genetic factor (‘mvAge’). mvAge (effective n = ~1.9 million participants of European ancestry) identified 52 independent variants in 38 genomic loci. Twenty variants were novel (not reported in input genome-wide association studies). Transcriptomic imputation identified age-relevant genes, including VEGFA and PHB1 . Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on mvAge ( P value = 8.41 × 10 −5 ). Similarly, genetically proxied thiazolidinediones ( P value = 3.50 × 10 −10 ), proprotein convertase subtilisin/kexin 9 inhibition ( P value = 1.62 × 10 −6 ), angiopoietin-like protein 4, beta blockers and calcium channel blockers also had beneficial Mendelian randomization estimates. Extending the drug-target Mendelian randomization framework to 3,947 protein-coding genes prioritized 122 targets. Together, these findings will inform future studies aimed at improving healthy aging.

Biological aging is accompanied by increasing morbidity, mortality, and healthcare costs; however, its molecular mechanisms are poorly understood. Here, we use multi-omic methods to integrate genomic, transcriptomic, and metabolomic data and identify biological associations with four measures of epigenetic age acceleration and a human longevity phenotype comprising healthspan, lifespan, and exceptional longevity (multivariate longevity). Using transcriptomic imputation, fine-mapping, and conditional analysis, we identify 22 high confidence associations with epigenetic age acceleration and seven with multivariate longevity. FLOT1, KPNA4, and TMX2 are novel, high confidence genes associated with epigenetic age acceleration. In parallel, cis-instrument Mendelian randomization of the druggable genome associates TPMT and NHLRC1 with epigenetic aging, supporting transcriptomic imputation findings. Metabolomics Mendelian randomization identifies a negative effect of non-high-density lipoprotein cholesterol and associated lipoproteins on multivariate longevity, but not epigenetic age acceleration. Finally, cell-type enrichment analysis implicates immune cells and precursors in epigenetic age acceleration and, more modestly, multivariate longevity. Follow-up Mendelian randomization of immune cell traits suggests lymphocyte subpopulations and lymphocytic surface molecules affect multivariate longevity and epigenetic age acceleration. Our results highlight druggable targets and biological pathways involved in aging and facilitate multi-omic comparisons of epigenetic clocks and human longevity.

Stroke is the second leading cause of death globally, and recent clinical trials have found that pharmacological proprotein convertase subtilisin kexin 9 (PCSK9) inhibition (PCSK9i) reduces stroke risk. However, the impact of long-term PCSK9 protein inhibition on stroke risk and the complex interplay of PCSK9 with various lipids remains unknown. Our goal was to leverage data on PCSK9 protein levels using drug-target Mendelian randomization (MR) and multivariable MR (MVMR) to investigate the impact of genetically-lowered PCSK9 protein levels on stroke risk. We created genetic instruments using PCSK9 variants associated with plasma PCSK9 concentration (Nprimary=35,559; Nreplication=10,186); low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG; N=1,320,016); apolipoprotein B (ApoB; N=439,125); lipoprotein a (Lp[a]; N=361,194); stroke (Ncases=40,585); ischemic stroke (IS; Ncases=34,217); and stroke subtypes (Ncases≤7,193). We performed drug-target MR investigating relationships between plasma PCSK9 and stroke phenotypes as well as MVMR assessing PCSK9 inhibition on stroke risk while controlling for five major lipid subfractions (LDL-C, HDL-C, TG, ApoB, and Lp[a]). We identified a strong protective association between genetically-lowered PCSK9 protein levels and stroke (odds ratio (OR)=0·86, 95% CI [0·83-0·88], P=1.74 × 10^-28), ischemic stroke (OR=0·88, 95% CI [0·85-0·90], P=1·70 × 10^-18), cardioembolic stroke (OR=0·84, 95% CI [0·76-0·93], P=0·001), and large artery ischemic stroke (OR=0·74, 95% CI [0·68-0·80], P=1·28 × 10^-14). We replicated these findings with complementary MR methods and two genetic instruments from independent data. MVMR analysis accounting for five lipid subfractions suggested that genetically proxied circulating PCSK9 inhibition was protective both for ischemic stroke (OR=0·89, 95% CI [0·82-0·97], P=0·008) and cardioembolic stroke (OR=0·83, 95% CI [0·69-1·00], P=0·04) supplementary to its established effect on lowering lipid levels, while PCSK9 inhibition was protective against large artery atherosclerosis entirely through its lipid pathways. MR estimates were generally consistent across complementary MR methods and tests for heterogeneity and pleiotropy were null, strengthening causal inference. Our data provide new evidence that plasma PCSK9 protein levels inversely associate with stroke risk, resolving discrepancies between randomized clinical trials and previous genomic studies. MVMR suggested pleiotropic relationships of PCSK9 on stroke risk beyond its effects on lipid fractions, underlining that future studies are needed to investigate the protective effect of PCSK9i beyond LDL-C-related pathways. Broadly, our study should reassure clinicians that anti-PCSK9 therapies reduce stroke.

Alcohol use disorder (AUD) is a common neuropsychiatric disorder that is a leading cause of morbidity and mortality worldwide; however, only a few pharmacological treatment options are currently available. While protein biomarkers with causal genetic evidence are promising novel drug target candidates for AUD, systematic scans of brain proteins have not been performed.

Our understanding of the genetics that underlies healthy aging can be improved by integrating complementary traits related to chronological and biological aging. We present a multitrait genome-wide association study that reflects the genetics of a broad healthy aging factor and use genetics methods to investigate potential therapeutic relationships among various drug targets.