Gut microbiome alterations are sex-dependently associated with brain abnormalities in a mouse model of Neurofibromatosis type I.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition that affects approximately 2% of the global population []. While primarily characterized by challenges in social communication and repetitive behaviors, ASD is often associated with various medical, neurological, and psychiatric comorbidities that impact the quality of life and longevity of affected individuals [–]. The etiology of ASD is multifaceted and involves complex interactions between genetic and environmental factors. With an estimated heritability of approximately 80% [, ], recent genome-wide association studies (GWAS) and sequencing efforts have revealed the mixed genetic nature of ASD, with both rare and common genetic variants contributing to risk [–]. Emerging evidence suggests that individuals with ASD have a significantly higher prevalence of various physical health comorbidities, which affect multiple systems and represent an important health burden []. In particular, individuals with ASD are at an elevated risk for cardiometabolic comorbidities, with studies reporting higher incidences of metabolic syndrome and other conditions such as obesity, type 2 diabetes mellitus (T2D), hypercholesterolemia, dyslipidemia (with risk increases of between 1.41 and 2.7-fold), as well cardiovascular traits, such as hypertension and cardiovascular disease (with incremental risks of 2.2-fold) in ASD populations compared to neurotypical peers [–]. While cardiovascular disease is traditionally classified as a cardiovascular trait due to its direct impact on the heart and blood vessels, it is closely linked to metabolic risk factors, which contribute to the progression of atherosclerosis [, ]. In contrast, blood pressure-related traits are more influenced by vascular resistance, kidney function, and autonomic regulation, highlighting distinct biological pathways []. This heightened risk appears to be multifactorial, with contributions from lifestyle factors such as diet and physical activity [, ], medication use [, ], and genetic predisposition. Specific loci, such as the 16p11.2 deletion and duplication, have been associated with obesity and other cardiometabolic conditions in ASD [, ]. Interestingly, other neuropsychiatric conditions, such as schizophrenia, also exhibit substantial genetic overlap with cardiometabolic traits, despite low genetic correlation (e.g., ranging from approximately 0.40 for total cholesterol to –0.17 for BMI) []. However, the extent to which genetic factors contribute to the co-occurrence of ASD and cardiometabolic diseases remains underexplored []. In the current study, we leverage large-scale GWAS datasets to explore the common genetic architecture and shared genetic variants between ASD and various cardiometabolic traits, including metabolic and cardiovascular phenotypes. By elucidating the complex relationship between these conditions, our research aims to identify the molecular mechanisms linking ASD and cardiometabolic health to gain a more comprehensive understanding of their relationship and contribute towards the identification of potential new targets for intervention.