Population-scale burden analysis of rare damaging coding variants identifies novel risk genes for Alzheimer's disease and related dementias and Parkinson's disease and related disorders

Alzheimer's disease and related dementias (ADRD) and Parkinson's disease and related disorders (PDRD) have substantial genetic contributions, yet the role of rare damaging coding variants remains incompletely characterized at population scale. We performed gene-burden testing of loss-of-function and deleterious missense variants in biobanks and disease-focused sequencing cohorts, using calibrated proxy-phenotypes and diagnosed-case sensitivity analyses to increase power for late-onset disease. At study-wide significance, we confirmed rare-variant burden in established ADRD genes (TREM2, ABCA7, SORL1, PSEN1, GRN, ATP8B4, ABCA1, ADAM10) and PDRD genes (GBA1, LRRK2). We also identified a novel ADRD burden association at IMPA2, and novel PDRD associations at ANKRD27, and CCL7. The strongest signal was observed for ANKRD27, where damaging variants clustered within domains mediating interactions with Rab GTPases and retromer components. Our results demonstrate the value of population-scale sequencing to identify rare coding risk genes for neurodegenerative diseases.