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

Alzheimer's disease and related dementias (ADRD) ¹ and Parkinson's disease and related disorders (PDRD) ² have substantial genetic contributions, yet the role of rare damaging coding variants remains incompletely characterized at population scale ^3-6 . 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 diseases ⁷ . We confirmed rare variant burden in established ADRD genes ( <i>ABCA7, PSEN1, ADAM10, ATP8B4, GRN, SORL1, TREM2, SHARPIN</i> ) and PDRD genes ( <i>GBA1, LRRK2</i> ). We additionally identified novel associations in ADRD ( <i>IMPA2, PMM2, SYNE1, CHRNA4, FCGR1A</i> ) and PDRD ( <i>ANKRD27, CCL7, USP19, SKP1, KANSL3</i> ). The strongest signal was observed for <i>ANKRD27</i> , 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.