Sex‐specific genetic architecture of multiple domains of cognition among older adults
Authors: Eissman Jaclyn M. , Walters Skylar , Mukherjee Shubhabrata , Lee Michael L. , Choi Seo‐Eun , Scollard Phoebe , Trittschuh Emily H. , Mez Jesse B. , Bush William S. , Kunkle Brian W. , Naj Adam C. , Gifford Katherine A. ,   Alzheimer’s Disease Neuroimaging Initiative,   The Alzheimer’s Disease Sequencing Project (ADSP),   Alzheimer’s Disease Genetics Consortium (ADGC), Cuccaro Michael L. , Cruchaga Carlos , Pericak‐Vance Margaret A , Farrer Lindsay A. , Wang Li‐San , Haines Jonathan L. , Jefferson Angela L. , Kukull Walter A. , Keene C Dirk , Saykin Andrew J. , Thompson Paul M , Martin Eden R. , Bennett David A. A , Barnes Lisa L. , Schneider Julie A , Albert Marilyn S. , Johnson Sterling C , Engelman Corinne D , Mayeux Richard , Vardarajan Badri N , Crane Paul K , Hohman Timothy J. , Dumitrescu Logan C 
Published: December 2023

Background

Genetic analyses of cognitive endophenotypes have led to discoveries of novel loci contributing to Alzheimer’s disease (AD) risk. Sex differences are present in cognitive trajectories in aging and AD, and these may vary across cognitive domain. However, genetic drivers that may contribute to sex differences in cognitive trajectories have yet to be explored. Thus, we sought to investigate the sex‐specific genetic architecture of cognition.

Method

We leveraged 10 cohorts of cognitive aging and AD to complete this sex‐aware genetic study (N = 31,800; mean age = 73 yrs.; 55% female). Harmonized cognitive scores for memory, executive functioning, and language were derived using confirmatory factor analysis models. We calculated change in cognitive scores over time using a mixed effects model, to facilitate analysis on cognitive decline. We performed GWAS of baseline score and of estimated rate of decline in each domain and in each cohort separately among non‐Hispanic white (NHW) individuals, adjusting for baseline age and genetic principal components. Then we meta‐analyzed the results.

Result

In addition to the well‐characterized APOE locus, we identified a genome‐wide significant chromosome 2 locus that was associated with language decline among NHW women (rs13387871: MAF = 0.20; βwomen = 2.97×10−3; Pwomen = 2.65×10−9), but not among male counterparts (βmen = ‐3.14×10−4, Pmen = 0.60). This locus contains multiple eQTLs for VRK2, a serine/threonine kinase that has been previously linked to neuropsychiatric disorders, including schizophrenia. Furthermore, the top variant in this locus (rs13387871) was nominally significant for memory decline (βwomen = 1.74×10−3, Pwomen = 0.01) and for executive functioning decline (βwomen = 7.58×10−4, Pwomen = 0.02) in meta‐analyses among NHW women.

Conclusion

Our genetic analysis suggests that there may be some genetic drivers of language performance that differ by sex, and that these drivers may be shared to an extent across domains. Our future sex‐aware meta‐analyses will also include 1) non‐Hispanic black (NHB) within ancestry (N = 4,200), 2) cross‐ancestry (NHW + NHB), 3) diagnosis‐stratified, and 4) analysis of X‐chromosome. Planned follow‐up analyses will include gene‐set analyses, heritability tests, and genetic correlation tests. Through our preliminary analysis, we identified a promising locus for further exploration, and this is the first of many steps in elucidating the sex‐specific genetic architecture of cognition across ancestry groups.