Mendelian randomization reveals shared genetic landscape in autism spectrum disorder and Alzheimer's disease

Autism Spectrum Disorder (ASD) and Alzheimer's Disease (AD) represent the most common neurodevelopmental and neurodegenerative disorders, respectively. ASD and AD are considered disparate diseases given the differences in age at manifestation and disease phenotypes. However, AD may be related to ASD, as recent studies showed that adults with ASD are 2.5 times more likely to develop AD than age-matched controls without ASD. While some studies have implicated environmental factors in ASD-AD comorbidity, it is unknown whether genetics play a role in the increased risk of AD in ASD. Here, we hypothesized that the shared genetic factors are responsible for an increased risk of AD in ASD. To determine whether ASD and AD are genetically linked, we preformed genome-wide association studies (GWAS), revealing genomic loci across the human genome that are associated with ASD or AD. Subsequently, we performed Mendelian randomization (MR) analysis to evaluate the causal effect of ASD (exposure) on AD (outcome). Interestingly, MR analysis showed significant horizontal pleiotropy, suggesting the existence of shared genetic components between ASD and AD. In support, variant-to-gene mapping and gene ontology analysis showed that pathways involved in synaptic regulation were significantly enriched in both ASD- and AD-associated SNPs. Together, these data imply that shared genetic factors related to synaptic regulation may contribute to an increased risk of AD in individuals with ASD, providing insights into underlying disease mechanisms.