Role of the X Chromosome in Alzheimer Disease Genetics,JAMA Neurology

当前位置： X-MOL 学术 › JAMA Neurol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Role of the X Chromosome in Alzheimer Disease Genetics
JAMA Neurology ( IF 20.4 ) Pub Date : 2024-09-09 , DOI: 10.1001/jamaneurol.2024.2843
Michael E Belloy _{1,

2,

3} , Yann Le Guen _{1,

4} , Ilaria Stewart ₁ , Kennedy Williams ₁ , Joachim Herz ₅ , Richard Sherva ₆ , Rui Zhang ₇ , Victoria Merritt _{8,

9} , Matthew S Panizzon _{9,

10} , Richard L Hauger _{8,

9,

10} , J Michael Gaziano _{11,

12} , Mark Logue _{6,

7,

13,

14} , Valerio Napolioni ₁₅ , Michael D Greicius ₁

Affiliation

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California.
NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, Missouri.
Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, California.
Center for Translational Neurodegeneration Research, Department of Molecular Genetics University of Texas Southwestern Medical Center at Dallas, Dallas.
Biomedical Genetics, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts.
National Center for PTSD, Behavioral Sciences Division, VA Boston Healthcare System, Boston, Massachusetts.
Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, San Diego, California.
Department of Psychiatry, University of California San Diego, La Jolla.
Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla.
Million Veteran Program (MVP) Coordinating Center, VA Boston Healthcare System, Boston, Massachusetts.
Division of Aging, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts.
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.

ImportanceThe X chromosome has remained enigmatic in Alzheimer disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD.ObjectivesTo perform the first large-scale X chromosome–wide association study (XWAS) of AD.Design, Setting, and ParticipantsThis was a meta-analysis of genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the US Alzheimer’s Disease Genetics Consortium, the Alzheimer’s Disease Sequencing Project, the UK Biobank, the Finnish health registry, and the US Million Veterans Program. Risk of AD was evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024. Genetic data available from high-density single-nucleotide variant microarrays and whole-genome sequencing and summary statistics for multitissue expression and protein quantitative trait loci available from published studies were included, enabling follow-up genetic colocalization analyses. A total of 1 629 863 eligible participants were selected from referred and volunteer samples, 477 596 of whom were excluded for analysis exclusion criteria. The number of participants who declined to participate in original studies was not available.Main Outcome and MeasuresRisk of AD, reported as odds ratios (ORs) with 95% CIs. Associations were considered at X chromosome–wide (P &lt; 1 × 10−5) and genome-wide (P &lt; 5 × 10−8) significance. Primary analyses are nonstratified, while secondary analyses evaluate sex-stratified effects.ResultsAnalyses included 1 152 284 participants of non-Hispanic White, European ancestry (664 403 [57.7%] female and 487 881 [42.3%] male), including 138 558 individuals with AD. Six independent genetic loci passed X chromosome–wide significance, with 4 showing support for links between the genetic signal for AD and expression of nearby genes in brain and nonbrain tissues. One of these 4 loci passed conservative genome-wide significance, with its lead variant centered on an intron of SLC9A7 (OR, 1.03; 95% CI, 1.02-1.04) and colocalization analyses prioritizing both the SLC9A7 and nearby CHST7 genes. Of these 6 loci, 4 displayed evidence for escape from X chromosome inactivation with regard to AD risk.Conclusion and RelevanceThis large-scale XWAS of AD identified the novel SLC9A7 locus. SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid β accumulation. Overall, this study advances our knowledge of AD genetics and may provide novel biological drug targets. The results further provide initial insights into elucidating the role of the X chromosome in sex-based differences in AD.

更新日期：2024-09-09

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南