Sex‐stratified GWAS meta‐analyses reveal novel sex‐specific association with CSF biomarkers of Alzheimer's Disease [Abstract]

Wang, Ting‐Chen, Timsina, Jigyasha, Jiang, Chenyang, McCartney, Daniel L, Tao, Feifei, Anastasi, Federica, Genius, Patricia, Rodríguez‐Fernández, Blanca, Navarro, Arcadi, Puerta, Raquel, van der Lee, Sven J, Marioni, Riccardo E, Bertram, Lars, Michael, Nagle W., Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199, Vilor‐Tejedor, Natalia, Bradley, Joseph, Ali, Muhammad, Wang, Ciyang, Liu, Menghan, Ruiz, Agustin, Fernandez, Maria Victoria, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Budde, John P., Tijms, Betty, Castillo, Atahualpa, Blennow, Kaj, Zetterberg, Henrik, Lleo, Alberto, Lee, Virginia M. M.‐Y., Heslegrave, Amanda J, Pastor, Pau, Peskind, Elaine R., Saykin, Andrew J., Morris, John C., Schindler, Suzanne E., Holtzman, David M., Riemenschneider, Matthias, Albert, Marilyn S. S., Van Deerlin, Vivianna M, Shaw, Leslie M., Sung, Yun Ju Ju, Hohman, Timothy J., Cruchaga, Carlos and Dumitrescu, Logan 2025. Sex‐stratified GWAS meta‐analyses reveal novel sex‐specific association with CSF biomarkers of Alzheimer's Disease [Abstract]. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 21 , e102560. 10.1002/alz70855_102560

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Abstract

Background: Cerebrospinal fluid (CSF) biomarkers, including amyloid‐β 42 (Aβ42), have emerged as essential endophenotypes in genome‐wide association studies (GWAS) of Alzheimer's disease (AD), advancing our understanding of AD biological processes beyond traditional case‐control studies. Using the largest sample size to date (N = 18,491), we aim to elucidate sex‐specific associations with AD pathology by performing sex‐stratified GWAS of three well‐established CSF endophenotypes, Aβ42, Tau, and phosphorylated tau (pTau181). Method: We conducted meta‐analyses of sex‐stratified GWAS for each CSF biomarker, leveraging 22 US and European cohorts with available raw CSF and genotype data (N = 6,785; 51.84% male; age=68), along with summary statistics from six external cohorts (N = 11,706; 45.27% male; age=69). Consistent quality control was applied prior to genetic analyses, including z‐score standardization on raw CSF biomarker values in internal cohorts. The GWAS adjusted for age, ten principal components of genetic ancestry, and cohort‐array combination as applicable. We defined a sex‐specific effect as a variant association that reached genome‐wide significance in one sex and had non‐overlapping 95% confidence intervals of the effect estimates between sexes. Result: We identified seven genome‐wide significant loci, including four previously reported loci and three novel female‐specific associations, including one for Aβ42 (rs372578, p(Females)=1.86E‐08, b(F)=‐0.09, p(Males)=0.78), Figure 1), one for Tau (rs1582763, p(F)=5.56E‐09, b(F)=‐0.09, p(M)=0.05, Figure 2), and one for pTau181 (rs6434518, p(F)=2.95E‐08, b(F)= 0.17, p(M)=0.80, Figure 3). The lead Aβ42 variant, rs372578, is an eQTL for BMP6 (p = 8.00E‐04, http://www.braineac.org), which encodes a TGF‐beta ligand involved in iron homeostasis and bone/fat development. Increased expression of BMP6 is linked to hippocampal neurogenesis defects in AD patients and APP‐transgenic mice. The lead Tau variant, rs1582763, is in the MS4 locus, an established genetic risk factor for AD with some evidence of female‐specificity, and has been linked to soluble TREM2 level regulation in CSF. Finally, the top pTau181 variant, rs6434518, is an eQTL for immune response genes STAT4, STAT1 (p = 2.40E‐02), and MYO1B (p = 2.60E‐02) involved in lipid metabolism and proteostasis. Conclusion: Our results highlight significant female‐specific genetic associations across CSF biomarkers, underscoring the importance of sex‐specific genetic analyses in deepening understanding of AD genetic architecture.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Wiley
ISSN:	1552-5260
Date of First Compliant Deposit:	9 January 2026
Last Modified:	09 Jan 2026 16:15
URI:	https://orca.cardiff.ac.uk/id/eprint/183770

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