BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging risk factor for cardiovascular diseases. Genetic IL (interleukin)-6 signaling deficiency reduced cardiovascular disease risk in CHIP carriers. However, the association between CHIP and incident abdominal aortic aneurysm (AAA) and whether IL-6 signaling inhibition attenuates AAA risk among individuals with CHIP remained unclear. METHODS: Participants without prevalent AAA from the UK Biobank were included. The associations of any CHIP (variant allele fraction, ≥2%), large CHIP (variant allele fraction, ≥10%), and gene-specific CHIP subtypes with incident AAA were investigated. The protection role of IL6R p.Asp358Ala, a genetic proxy for IL-6 deficiency, was tested after stratification by CHIP status. Furthermore, the interaction and joint effects of CHIP and genetic susceptibility on AAA risk were tested. RESULTS: This study included 425 211 participants. Any CHIP and large CHIP was identified in 13 768 (3.2%) and 8576 (2.0%) participants, respectively. CHIP was associated with an increased risk of incident AAA (hazard ratio [HR], 1.21 [95% CI, 1.01–1.44]; P =0.034), with large CHIP clones exhibiting greater effect size (HR, 1.35 [95% CI, 1.10–1.66]; P =0.0045). Driver gene-specific analyses revealed that ASXL1 -mediated CHIP exerted the strongest effect size on AAA risk (HR, 2.10 [95% CI, 1.54–2.88]; P <0.001). The presence of 2 IL6R p.Asp358Ala alleles attenuated the risk of AAA in large CHIP carriers (HR, 0.48 [95% CI, 0.23–0.99]; P =0.046). In the joint analysis, participants with CHIP and high genetic risk had a higher risk of developing AAA than those without CHIP and with low genetic risk (HR, 2.15 [95% CI, 1.63–2.85]; P <0.001). CONCLUSIONS: CHIP is associated with an increased risk of AAA. Genetic IL-6 signaling deficiency attenuates the risk of AAA in large CHIP carriers. CHIP may serve as an attractive target for the prevention and treatment of AAA.

Smoking is a widespread behavior, while the relationship between smoking and various diseases remains a topic of debate. We conducted analysis to further examine the identified associations and assess potential causal relationships. We utilized seven single nucleotide polymorphisms (SNPs) known to be linked to smoking extracting genotype data from the UK Biobank, a large-scale biomedical repository encompassing comprehensive health-related and genetic information of European descent. Phenome-wide association study (PheWAS) analysis was conducted to map the association of genetically predicted smoking status with 1,549 phenotypes. The associations identified in the PheWAS were then meticulously examined through two-sample Mendelian randomization (MR) analysis, utilizing data from the UK Biobank (n = 487,365) and the Sequencing Consortium of Alcohol and Nicotine Use (GSCAN) (n = 337,334). This approach allowed us to comprehensively characterize the links between smoking and disease patterns. The PheWAS analysis produced 34 phenotypes that demonstrated significant associations with smoking (P = 0.05/1460). Importantly, sickle cell anemia and type 2 diabetes exhibited the most significant SNPs (both 85.71% significant SNPs). Furthermore, the MR analyses provided compelling evidence supporting causal associations between smoking and the risk of following diseases: obstructive chronic bronchitis (IVW: Beta = 0.48, 95% confidence interval (CI) 0.36-0.61, P = 1.62×10⁻¹³), cancer of the bronchus (IVW: Beta = 0.92, 95% CI 0.68-1.17, P = 2.02×10⁻¹³⁾, peripheral vascular disease (IVW: Beta = 1.09, 95% CI 0.71-1.46, P = 1.63×10⁻⁸), emphysema (IVW: Beta = 1.63, 95% CI 0.90-2.36, P = 1.29×10⁻⁵), pneumococcal pneumonia (IVW: Beta = 0.30, 95% CI 0.11-0.49, P = 1.60×10⁻³), chronic airway obstruction (IVW: Beta = 0.83, 95% CI 0.30-1.36, P = 2.00×10⁻³) and type 2 diabetes (IVW: Beta = 0.53, 95% CI 0.16-0.90, P = 5.08×10⁻³). This study affirms causal relationships between smoking and obstructive chronic bronchitis, cancer of the bronchus, peripheral vascular disease, emphysema, pneumococcal pneumonia, chronic airway obstruction, type 2 diabetes, in the European population. These findings highlight the broad health impacts of smoking and support smoking cessation efforts.

The gut–brain axis is a key interface between neuropsychiatric and digestive disorders, however, the underlying shared genetic mechanisms and microbial mediators remain poorly understood. Utilizing genome-wide association study (GWAS) data from 18 neuropsychiatric and 24 digestive disorders, along with microbial quantitative trait loci (mbQTL) data encompassing 211 taxa (N = 18,340), we conducted a comprehensive analysis integrating linkage disequilibrium score regression, MAGMA gene-based pleiotropy mapping, and Mendelian randomization. We identified 12 significant genetic correlations between gut–brain disorder pairs, including attention-deficit/hyperactivity disorder (ADHD) and fatty liver disease. In total, 5339 pleiotropic genes were discovered, with MSH5 appearing in 28 disorder pairs. Pathway enrichment analysis implicated immune regulation and synaptic signaling as core biological processes. Novel causal relationships were also uncovered, such as ADHD increasing the risk of irritable bowel syndrome. Co-localization analysis validated three causal associations. Microbiota-focused analyses further demonstrated a protective role of Actinobacteria against stroke, resolving previous inconsistencies in the literature. Collectively, these findings highlight the dual role of the gut microbiota—as both modulator and contributor—and provide critical genetic insights that may guide the development of targeted interventions across the gut–brain axis.

Background Previous investigations have elucidated epidemiological associations linking smoking to neuropsychiatric and gastrointestinal diseases, yet the underlying causal relationships remain enigmatic. To shed light on this matter, we undertook a Mendelian randomisation(MR) study with the aim of gauging the potential causal association between smoking and the susceptibility to neuropsychiatric and gastrointestinal tract diseases. Methods We meticulously collected and preprocessed genome-wide association study (GWAS) data encompassing smoking (280,508 cases and 180,558 controls) as well as neuropsychiatric and gastrointestinal phenotypes (n = 6,681 to 87,3341). To investigate the genetic correlation between smoking and diseases, we employed linkage disequilibrium score regression. We further applied multi-trait analysis of GWAS to identify the shared risk single-nucleotide polymorphisms (SNPs) implicated in both smoking and diseases. Pleiotropic genes were annotated by enrichment analysis. Subsequently, bidirectional MR analysis was performed to infer causality. Results Our findings, supported by robust evidence derived from an expansive sample size, demonstrate that smoking exerts a causal influence on merely six of these diseases, while no disease was found to causally impact smoking. Intriguingly, we discovered 513 pleiotropic genes enriched in pathways such as the regulation of growth and synapses, suggesting a potential shared genetic basis between smoking and these diseases, leading to aberrant neural development. Remarkably, among the 42 diseases scrutinized, a significant genetic correlation was exclusively observed with gastroesophageal reflux disease (GRED). Furthermore, we identified risk SNPs shared by smoking and GRED. Conclusions This study revealed the shared genetic basis and causal effects connecting smoking to neuropsychiatric and gastrointestinal diseases, thereby providing novel etiological insights into the role of smoking in these diseases.