Shared genetic architecture between Alzheimer’s disease and psychiatric disorders revealed by multi-trait genome-wide analyses

Clarify the shared genetic architecture between Alzheimer’s disease (AD) and major psychiatric disorders. We integrated large GWAS summary datasets derived predominantly from individuals of European ancestry for AD and eight psychiatric disorders; estimated genome-wide genetic correlations with LDSC/HDL; mapped local genetic correlations with SUPERGNOVA; ran pairwise Multi-trait analysis of GWAS (MTAG (AD with ADHD, BIP, MDD, PTSD, SCZ)) followed by FUMA; performed cross-trait colocalization with HyPrColoc and trait–eQTL colocalization using GTEx v8 (49 tissues). HDL identified significant genome-wide correlations for five AD–psychiatric pairs, led by AD–MDD; LDSC was significant for AD–MDD. We mapped 18 locally correlated regions. MTAG yielded 33 AD-associated loci (118 SNPs), including 12 novel (e.g., RAB27B/rs12968702, PTCH1/rs3824488, EP300/rs12157997), and 336 psychiatric-trait signals across 265 loci. HyPrColoc detected 74 AD–psychiatric colocalized regions (40 with PP ≥ 0.8), with 13 driven by a single candidate causal variant. Trait–eQTL colocalization prioritized 25 genes in 122 associations; brain-tissue signals implicated P4HTM, GPX1, CCDC71, and—at an AD–SCZ locus—ADAM10. AD shares substantial pleiotropic architecture with psychiatric disorders, particularly MDD. Integrative multi-trait association, colocalization, and tissue-specific eQTL evidence highlights convergent mechanisms—exosome biology (RAB27B), astrocytic Ca²⁺ signaling (P4HTM), and non-amyloidogenic APP processing (ADAM10)—and nominates testable therapeutic targets.