Sex-Specific Genetic Drivers of Memory, Executive Functioning, and Language Performance in Older Adults
Eissman, J. M.; Regelson, A. N.; Walters, S.; Archer, D. B.; Durant, A.; Mukherjee, S.; Lee, M. L.; Choi, S.-E.; Scollard, P.; Trittschuh, E. H.; Mez, J.; Bush, W. S.; Kunkle, B. W.; Naj, A. C.; Gifford, K. A.; Bilgel, M.; Kuzma, A. B.; The Alzheimer's Disease Neuroimaging Initiative (ADNI)|, ; The Alzheimer's Disease Genetics Consortium (ADGC), ; The Alzheimer's Disease Sequencing Project (ADSP), ; Cuccaro, M. L.; Cruchaga, C.; Pericak-Vance, M. A.; Farrer, L. A.; Wang, L.-S.; Schellenberg, G. D.; Vardarajan, B. N.; Mayeux, R.; Haines, J. L.; Jefferson, A. L.; Kukull, W. A.; Keene, C. D.;
Show abstract
We previously identified sex-specific genetic loci associated with memory performance, a strong Alzheimers disease (AD) endophenotype. Here, we expand on this work by conducting sex-specific, cross-ancestral, genome-wide meta-analyses of three cognitive domains (memory, executive functioning, and language) in 33,918 older adults (57% female; 41% cognitively impaired; mean age=73 years) from 10 aging and AD cohorts. All three domains were comparably heritable across sexes. Genome-wide meta-analyses identified three novel loci: a female-specific language decline-associated locus, VRK2 (rs13387871), which is a published candidate for neuropsychiatric traits involving language ability; a male-specific memory decline-associated locus among cognitive impaired, DCHS2 (rs12501200), which is a published candidate gene for AD age-at-onset; and a sex-interaction with baseline executive functioning, AGA (rs1380012), among cognitive impaired. We additionally provide evidence for shared genetic architecture between lifetime estrogen exposure and AD-related cognitive decline. Overall, we identified sex-specific variants, genes, and pathways relating to three cognitive domains among older adults.
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