Using genetic analysis to understand the relationship of cognitive traits with peptic ulcer and Alzheimer’s disease

Abstract Cognitive decline is typical of Alzheimer’s disease (AD). While studies suggest links between the gut and the brain in the risk of AD, the relationship of gastrointestinal tract (GIT) disorders with cognition is poorly understood. Leveraging large-scale genome-wide association study summary statistics, we assess the relationship of ten cognition-related traits with peptic ulcer disease (PUD) and AD. Similar to AD, we demonstrate a highly significant negative genetic correlation between PUD and intelligence (rg = -0.33, P = 2.11 × 10− 11), cognitive performance (rg = -0.32, P = 9.00 × 10− 16), educational attainment (rg = -0.46, P = 5.50 × 10− 33) and other cognitive traits (rg = -0.27 – -0.47, P = 8.41 × 10− 4 – 5.75 × 10− 25). Mendelian randomisation analysis suggests a risk-decreasing causal influence of genetically predicted intelligence (Odds ratio, OR = 0.77, P = 3.92 × 10− 7), educational attainment (OR = 0.56, P = 6.68 × 10− 21), and cognitive performance (OR = 0.75, P = 2.11 × 10− 6) on PUD’s risk. Genes with nominal association (Pgene < 0.05), in gene-based analyses, were significantly enriched (Pbinomial−test = 1.18 × 10− 3 – 3.85 × 10− 4) across cognitive traits, PUD and AD—indicating evidence of gene-level genetic overlap. Combining gene-based association results, we identify many shared genes reaching genome-wide significance (PFisher’s−combined−analysis <2.68 × 10− 6) for cognitive traits, PUD and AD. These findings highlight the protective role of cognitive traits on the risk of PUD and AD, provide additional insights into the genetic relationship of AD with GIT disorders and identify new targets for further investigation.