[en] Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequence data from 2591 LBD cases and 4391 controls. We identified a significant risk locus within intron 1 of MAP3K15 (rs141773145, odds ratio = 2.42, 95% confidence interval = 1.65-3.56, p-value = 7.0 × 10(-6)) in female LBD cases conditioned for APOE ε4 dosage. The locus includes an enhancer region that regulates MAP3K15 expression in ganglionic eminence cells derived from primary cultured neurospheres. Rare variant burden testing showed differential enrichment of missense mutations in TEX13A in female LBD cases, that did not reach significance (p-value = 1.34 × 10(-4)). These findings support the sex-specific effects of genetic factors and a potential role of Alzheimer's-related risk for females with LBD.
Centre de recherche :
Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) LIH - Luxembourg Institute of Health
Disciplines :
Génétique & processus génétiques Neurologie
Auteur, co-auteur :
Bayram, Ece ; Department of Neurosciences, Parkinson and Other Movement Disorders Center, University of California San Diego, La Jolla, CA, USA.
Reho, Paolo; Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Litvan, Irene; Department of Neurosciences, Parkinson and Other Movement Disorders Center, University of California San Diego, La Jolla, CA, USA.
International LBD Genomics, Consortium
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Luxembourg Institute of Health > Transversal Translational Medicine ; Centre Hospitalier de Luxembourg > arkinson Research Clinic
MAY, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Ding, Jinhui; Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
Gibbs, J Raphael ; Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
Dalgard, Clifton L; Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. ; The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Traynor, Bryan J; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA. ; Neuromuscular Diseases Research Section, National Institute on Aging, Bethesda, MD, USA. ; Therapeutics Development Laboratory, National Center for Advancing Translational Sciences, Rockville, MD, USA.
Scholz, Sonja W ; Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. ; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
Chia, Ruth ; Neuromuscular Diseases Research Section, National Institute on Aging, Bethesda, MD, USA. ruth.chia@nih.gov.
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci.
1ZIANS003154/U.S. Department of Health & Human Services; NIH; National Institute of Neurological Disorders and Stroke (NINDS)/; K99AG073453/U.S. Department of Health & Human Services; National Institute on Aging (U.S. National Institute on Aging)/; 1ZIAAG000935/U.S. Department of Health & Human Services; National Institute on Aging (U.S. National Institute on Aging)/
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