Whole exome sequencing analyses identified novel genes for Alzheimer's disease and related dementia

Abstract INTRODUCTION The heritability of Alzheimer's disease (AD) is estimated to be 58%–79%. However, known genes can only partially explain the heritability. METHODS Here, we conducted gene‐based exome‐wide association study (ExWAS) of rare variants and single‐variant ExWAS of common variants, utilizing data of 54,569 clinically diagnosed/proxy AD and related dementia (ADRD) and 295,421 controls from the UK Biobank. RESULTS Gene‐based ExWAS identified 11 genes predicting a higher ADRD risk, including five novel ones, namely FRMD8 , DDX1 , DNMT3L , MORC1 , and TGM2 , along with six previously reported ones, SORL1 , GRN , PSEN1 , ABCA7 , GBA , and ADAM10 . Single‐variant ExWAS identified two ADRD‐associated novel genes, SLCO1C1 and NDNF . The identified genes were predominantly enriched in amyloid‐β process pathways, microglia, and brain regions like hippocampus. The druggability evidence suggests that DDX1 , DNMT3L , TGM2 , SLCO1C1 , and NDNF could be effective drug targets. DISCUSSION Our study contributes to the current body of evidence on the genetic etiology of ADRD. Highlights Gene‐based analyses of rare variants identified five novel genes for Alzheimer's disease and related dementia (ADRD), including FRMD8 , DDX1 , DNMT3L , MORC1 , and TGM2 . Single‐variant analyses of common variants identified two novel genes for ADRD, including SLCO1C1 and NDNF . The identified genes were predominantly enriched in amyloid‐β process pathways, microglia, and brain regions like hippocampus. DDX1 , DNMT3L , TGM2 , SLCO1C1 , and NDNF could be effective drug targets.