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

Alzheimers disease and related dementias (ADRD)1 and Parkinsons disease and related disorders (PDRD)2 have substantial genetic contributions, yet the role of rare damaging coding variants remains incompletely characterized at population scale3-6. We performed gene-based burden testing of rare loss-of-function and deleterious missense variants using whole-genome sequencing data from large population biobanks combined with disease-specific sequencing cohorts, leveraging proxy phenotypes to maximize statistical power for late-onset neurodegenerative diseases7. We confirmed rare variant burden in established ADRD genes (ABCA7, PSEN1, ADAM10, ATP8B4, GRN, SORL1, TREM2, SHARPIN) and PDRD genes (GBA1, LRRK2). We additionally identified novel associations in ADRD (IMPA2, PMM2, SYNE1, CHRNA4, FCGR1A) and PDRD (ANKRD27, CCL7, USP19, SKP1, KANSL3). 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 power of population-scale sequencing combined with proxy phenotypes to identify rare coding risk genes for neurodegenerative diseases.