Citations 2
An APOE *4-Informed Genomic Atlas of the X Chromosome in Alzheimer’s Disease
Cook, Noah , Zeng, Youjie , Yang, Chenyu , Jiang, Zhiwen , Wang, Ting‐Chen , Guen, Yann Le , Cody, Karly Alex , Johnson, Matthew, Zhang, Rui, Merritt, Victoria C. , Hauger, Richard L. , Program, the VA Million Veteran, FinnGen, Koran, Mary Ellen, Mormino, Elizabeth C. , Gordon, Brian , DeCasien, Alex, Andrews, Shea J. , Logue, Mark, Greicius, Michael D. , Le Guen, Yann , Cody, Karly A , Koran, Mary Ellen , Gordon, Brian A , Andrews, Shea , Dumitrescu, Logan , Archer, Derek , Seto, Mabel , Pottier, Cyril , Cruchaga, Carlos , Sherva, Richard , Logue, Mark W. , Napolioni, Valerio , Belloy, Michael E , Cook, Noah , Zeng, Youjie , Yang, Chenyu , Zhang, Rui, Merritt, Victoria C. , Hauger, Richard L. , Koran, Mary Ellen I. , Mormino, Elizabeth C. , DeCasien, Alex R. , Dumitrescu, Logan , Archer, Derek B. , Hohman, Timothy J. , Belloy, Michaël E.
No container title available | May 6, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract The genetic contributions of the X chromosome to Alzheimer’s 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.
Chromosome X-wide association study in multiple system atrophy identifies sex-differential risk loci
Ray, Anindita , Chia, Ruth , Rasheed, Memoona, Ece, Bayram, Jinhui, Ding, Walton, Ronald L., Diez-Fairen, Monica, Álvarez, Ignacio Morales, Fanciulli, Alessandra , Seppi, Mag Klaus, Duerr, Susanne, Leys, Fabian , Krismer, Florian , Sidoroff, Victoria , Pirker, Walter , Rascol, Olivier, Foubert-Samier, Alexandra, Meissner, Wassilios G, Tison, François , Barone, Paolo, Russillo, Maria Claudia, Marín-Lahoz, Juan, Kulisevsky, J, Torres, Soraya, Mir, Pablo, Periñán, María Teresa, Proukakis, C., Goh, Yee Yen, Parkkinen, Laura, Hu, Michele T, Saxon, Jennifer A. , Rollinson, Sara , Garland, Emily M. , Litvan, Irene, Alcalay, Roy N, Kwei, Kimberly , Lubbe, Steven, Mao, Qinwen, Flanagan, Margaret E, Castellani, Rudolph J, Ndayisaba, Alain , Calvo, Andrea, Canosa, Antonio, Bohannan, Ryan C., Norcliffe-Kaufmann, Lucy, Palma, Jose-Alberto, Dawson, Ted M, Albert, Marilyn S, Pletniková, Olga , Troncoso, Juan C, Lage, Carmen , Sánchez-Juan, Pascual, Serrano, Geidy E, Beach, Thomas G, Morris, Huw R, Clarimon, Jordi, Jaunmuktane, Zane, Révész, Tamás, Warner, Tom, Hardy, John A, Ryten, Mina, Ferrucci, Luigi, Topol, Eric, Torkamani, Ali, DeCasien, Alex R, Chiò, Adriano, Low, Philip, Wszolek, Zbigniew K, Dickson, Dennis W., Traynor, Bryan J, Gibbs, J Raphael, Dalgard, Clifton L, Ross, Owen A, Houlden, Henry, Scholz, Sonja W., Hardy, John , Dickson, Dennis W. , Ross, Owen A. , Houlden, Henry , Scholz, Sonja W. , Chia, Ruth , Proukakis, Christos , Dickson, Dennis W , Dalgard, Clifton L , Ross, Owen A , Houlden, Henry , Scholz, Sonja W , Hardy, John , Reynolds, Regina H. , Díez-Fairén, Mónica , Fanciulli, Alessandra , Stefanova, Nadia , Seppi, Klaus , Krismer, Florian, Zimprich, Alexander , Rascol, Olivier , Foubert‐Samier, Alexandra , Meissner, Wassilios G. , Tison, François , Traon, Anne Pavy‐Le , Pellecchia, Maria Teresa , Marín‐Lahoz, Juan , Kulisevsky, Jaime , Mir, Pablo , Chelban, Viorica , Wu, Lesley , Kobylecki, Christopher , Biaggioni, Italo , Litvan, Irene , Rubio, Ileana, Lubbe, Steven , Flanagan, Margaret E , Castellani, Rudolph J. , Khurana, Vikram , Mora, Gabriele , Floris, Gianluca , Moore, Anni K. , Norcliffe‐Kaufmann, Lucy , Palma, Jose-Alberto , Kaufmann, Horacio , Dawson, Ted M , Rosenthal, Liana S. , Pantelyat, Alexander , Troncoso, Juan C. , Infante, Jon , Serrano, Geidy E. , Beach, Thomas G. , Pástor, Pau , Albani, Diego , Clarimón, Jordi , Jaunmuktane, Zane , Frontzek, Karl , Warner, Thomas T. , Ferrucci, Luigi , Topol, Eric J. , Torkamani, Ali , DeCasien, Alex R. , Chiò, Adriano , Singer, Wolfgang , Cheshire, William P. , Wszołek, Zbigniew K. , Traynor, Bryan J. , Gibbs, J. Raphael
Brain | February 12, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.