An APOE*4-Informed Genomic Atlas of the X Chromosome in Alzheimer's Disease
Cook, N.; Zeng, Y.; Yang, C.; Jiang, Z.; Wang, T.-C.; Le Guen, Y.; Cody, K.; Johnson, M.; Zhang, R.; Merritt, V. C.; Hauger, R. L.; The VA Million Veteran Program, ; FinnGen, ; Koran, M. E.; Mormino, E. C.; Gordon, B.; DeCasien, A.; Andrews, S. J.; Dumitrescu, L.; Archer, D. B.; Hohman, T. J.; Pottier, C.; Cruchaga, C.; Sherva, R.; Logue, M.; Napolioni, V.; Greicius, M. D.; Belloy, M. E.
Show abstract
The genetic contributions of the X chromosome to Alzheimers disease (AD) remain poorly understood yet are expected to importantly shape sex differences in AD. We therefore performed large-scale X-chromosome-wide association studies (N=1,240,451), evaluating differential risk due to sex, APOE*4, and escape from X-chromosome inactivation, finding most X-linked loci appear relevant to female-biased AD etiology. In evaluating genetic pleiotropy with hormonal, lipid, and brain imaging traits, we discovered X-linked AD loci converged on white matter traits, particularly in the anterior corona radiata and splenium of the corpus callosum. Through brain-centric functional genomics analyses, we then nominated candidate causal genes, including 5 that appeared highly robust. Notably, we found the escape gene RBBP7 decreases AD risk in APOE*4 carriers likely through higher expression in excitatory neurons to counter tau-related neurodegeneration. Altogether, we provide an atlas of sex and APOE*4-informed candidate X-linked AD risk loci, genes, and mechanisms that will guide future studies.
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