Integrative Genetic, Proteogenomic, and Multi-omics Analyses Reveal Sex-Biased Causal Genes and Drug Targets in Alzheimer's Disease
Cook, N.; Yang, C.; Zeng, Y.; Sivasankaran, S. K.; Song, S.; Talozzi, L.; Western, D.; Yang, C.; Liu, Y.; Le Guen, Y.; Stewart, I.; Young, C.; FinnGen, ; Mormino, E. C.; Altmann, A.; He, Z.; Napolioni, V.; Wingo, A. P.; Wingo, T. S.; Cruchaga, C.; Sung, Y. J.; Greicius, M. D.; Belloy, M. E.
Show abstract
Sex differences are pervasive in Alzheimers disease, but the underlying drivers remain poorly understood. To address this, we performed sex-stratified genome-wide association studies of Alzheimers disease in [~]1,000,000 individuals, which we subsequently integrated with proteogenomics datasets from neurological tissues to identify candidate causal genes. We further prioritized genes through additional multi-omics approaches, including quantitative trait locus summary-based mendelian randomization and colocalization. Altogether, we prioritized 125 female-biased and 21 male-biased risk genes. Female-biased pathways included amyloid, neurite, stress, clearance, and immune processes, with genes enriched for microglia and astrocyte expression. Through computational drug repurposing analyses, a set of sex hormone related drugs, converging on Epidermal Growth Factor Receptor (EGFR), were uniquely prioritized in women. Finally, we identified Haptoglobin (HP) as a female-specific gene, leveraging long-read sequencing approaches to implicate a link to oxidative stress, APOE, and hemoglobin biology. Altogether, our findings provide a portal into sex-specific precision medicine for Alzheimers disease.
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