Sex-specific genetic architecture of late-life memory performance

Title: Sex-specific genetic architecture of late-life memory performance
Author(s): Eissman, JM; Archer, DB; Mukherjee, S; Lee, ML; Choi, S; Scollard, P; Trittschuh, EH; Mez, JB; Bush, WS; Kunkle, BW; Naj, AC; Gifford, KA; Alzheimer's Disease Neuroimaging Initiative (ADNI) | Alzheimer's Disease Genetics Consortium (ADGC) | The Alzheimer's Disease Sequencing Project (ADSP); Cuccaro, ML; Cruchaga, C; Pericak-Vance, MA; Farrer, LA; Wang, L; Schellenberg, GD; Mayeux, RP; Haines, JL; Jefferson, AL; Kukull, WA; Keene, CD; Saykin, AJ; Thompson, PM; Martin, ER; Bennett, DA; Barnes, LL; Schneider, JA; Crane, PK; Hohman, TJ; Dumitrescu, L;
Year: 2024;  
Journal: Alzheimer's & Dementia: The Journal of the Alzheimer's Association;  
Volume: 20;  
Issue: 2;  
DOI: 10.1002/alz.13507
Abstract:

BACKGROUND: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer’s disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear.
METHODS: We conducted the largest sex-aware genetic study on late-life memory to date (Nmales  = 11,942; Nfemales  = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants.
RESULTS: We identified three sex-specific loci (rs67099044-CBLN2, rs719070-SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633-EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits.
DISCUSSION: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory.
HIGHLIGHTS: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits.