Genome-wide association study provides insights into the genetic basis of Lewy body dementia.

Lewy body dementia (LBD) is the second most prevalent dementia, however most genetic risk remains uncharacterized. Here, we performed the largest LBD genome-wide association study (GWAS) meta-analysis including 4252 LBD cases and 189,290 controls. We confirmed four previously known risk loci APOE, GBA, BIN1, and SNCA-AS1, and highlighted a novel locus SYT16. We further integrated LBD GWAS with multi-omics datasets, and identified 85 LBD risk genes that were enriched in eight functional clusters including 51 statistically significant pathways (e.g., SYT16 was enriched in the phospholipid binding pathway). Drug-gene interaction analysis highlighted the potential clinical utility of these LBD risk genes, especially APOE, GBA, BIN1, SNCA, SYT16, and INO80E. Differential gene expression analysis further highlighted the significant dysregulation of these genes in LBD brain tissues (e.g., hippocampus) and brain cells (e.g., excitatory neurons). Using gene prioritization, we identified 20 candidate causal genes including five novel risk genes, one within the risk locus SYT16 and four outside known risk loci (INO80E, DOC2A, ASPHD1, and RITA1). Tissue and cell-type specific enrichment analyses showed significant enrichment in brain tissues (e.g., dorsolateral prefrontal cortex) and brain cells (e.g., astrocytes). Mendelian randomization analysis provided evidence for the causal effects of LBD on reduction in brain structures (e.g., hippocampus) and cognitive performance. Finally, genetic correlation analysis showed that LBD was significantly positively associated with Alzheimer's disease and Parkinson's disease. In summary, our findings provide insights into the genetic basis of LBD and identify novel targets for the molecular mechanisms underlying LBD.