title: Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease.
abstract: Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, 75108 Uppsala, Sweden; Science for Life Laboratory, Uppsala University, 75123 Uppsala, Sweden. Electronic address: jan.dumanski@igp.uu.se.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Dumanski
authors.affiliation: University Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases, 59000 Lille, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, 75108 Uppsala, Sweden; Science for Life Laboratory, Uppsala University, 75123 Uppsala, Sweden.
authors.forename: Chiara
authors.initials: C
authors.lastname: Rasi
authors.affiliation: Department of Public Health and Caring Sciences, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Vilmantas
authors.initials: V
authors.lastname: Giedraitis
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, 75108 Uppsala, Sweden; Science for Life Laboratory, Uppsala University, 75123 Uppsala, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Davies
authors.affiliation: University Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases, 59000 Lille, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Grenier-Boley
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.affiliation: CNR-MAJ, Inserm, U1079, Rouen University Hospital, Rouen 76031 France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.affiliation: Inserm, U708, Victor Segalen University, Bordeaux 33076, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Dufouil
authors.affiliation: Université de Lille, CNR-MAJ, Inserm 1171, Distalz, Lille 59000, France; CHU, Lille 59000, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Pasquier
authors.affiliation: University Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases, 59000 Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.affiliation: Department of Public Health and Caring Sciences, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lannfelt
authors.affiliation: Department of Public Health and Caring Sciences, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.affiliation: Department of Public Health and Caring Sciences, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Kilander
authors.affiliation: Department of Medical Sciences, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, 75108 Uppsala, Sweden; Science for Life Laboratory, Uppsala University, 75123 Uppsala, Sweden. Electronic address: lars.forsberg@igp.uu.se.
authors.forename: Lars A
authors.initials: LA
authors.lastname: Forsberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D041322:Chromosomes, Human, Y / Q000235:genetics*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors