Matching heterogeneous cohorts by projected principal components reveals two novel Alzheimer's disease-associated...

Alzheimer's disease (AD) is the most common form of dementia. Studies have suggested prevalence is greater in individuals self-identifying as Hispanic. Population-specific results enable personalized and equitable interventions. Ethnicity as a stratifier co-occurs with genomic inflation due to heterogeneity.

We conducted genome-wide association studies (GWAS) and meta-analyses among subjects from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella whole genome sequencing (WGS) dataset who self-identified as Hispanic and All of Us (AoU) sub-cohorts matched to that cohort, using projected genetically-derived principal components.

We identified a common variant in PIEZO2 on chromosome 18 protective for AD in ADSP subjects, with a p-value just beyond genome-wide significance (p =  $5.4\times {10}^{-8}$ ). Meta-analyses with genetically-matched AoU participants yielded three (two novel) genome-wide significant AD-associated loci based on rare lead variants: rs374043832 (RGS6/PSEN1), rs192423465 (ASPSCR1), and rs935208076 (GDAP2), which were nominally significant in AoU sub-cohorts.

We demonstrate a way to match subjects between large biobanks and small disease-specific cohorts, enabling novel findings.