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Acta Neuropathol. 2018 Dec;136(6):857-872. doi: 10.1007/s00401-018-1881-4. Epub 2018 Jul 2.

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Collaborators (195)

Weiner MW, Petersen R, Aisen P, Jack C, Jagust W, Shaw LM, Trojanowski J, Beckett L, Toga A, Saykin A, Morris JC, Montine T, Green R, Abner E, Adams P, Albert M, Albin R, Apostolova L, Arnold S, Asthana S, Atwood C, Baldwin C, Barber R, Barnes L, Barral S, Beach T, Becker J, Beecham G, Beekly D, Bennett D, Bigio E, Bird T, Blacker D, Boeve B, Bowen J, Boxer A, Burke J, Burns J, Buxbaum J, Cairns N, Cantwell L, Cao C, Carlson C, Carlsson C, Carney R, Carrasquillo M, Chui H, Crane P, Cribbs D, Crocco E, Cruchaga C, De Jager P, DeCarli C, Dick M, Dickson D, Doody R, Duara R, Ertekin-Taner N, Evans D, Faber K, Fairchild T, Fallon K, Fardo D, Farlow M, Farrer L, Ferris S, Foroud T, Frosch M, Galasko D, Gearing M, Geschwind D, Ghetti B, Gilbert J, Goate A, Graff-Radford N, Green R, Growdon J, Haines J, Hakonarson H, Hamilton R, Hamilton-Nelson K, Hardy J, Harrell L, Honig L, Huebinger R, Huentelman M, Hulette C, Hyman B, Jarvik G, Jin LW, Jun G, Ilyas Kamboh M, Karydas A, Katz M, Kauwe J, Kaye J, Dirk Keene C, Kim R, Kowall N, Kramer J, Kukull W, Kunkle B, Kuzma A, LaFerla F, Lah J, Larson E, Leverenz J, Levey A, Li G, Lieberman A, Lipton R, Lopez O, Lunetta K, Lyketsos C, Malamon J, Marson D, Martin E, Martiniuk F, Mash D, Masliah E, Mayeux R, McCormick W, McCurry S, McDavid A, McDonough S, McKee A, Mesulam M, Miller B, Miller C, Miller J, Montine T, Morris J, Mukherjee S, Myers A, Naj A, O'Bryant S, Olichney J, Parisi J, Paulson H, Pericak-Vance M, Peskind E, Petersen R, Pierce A, Poon W, Potter H, Qu L, Quinn J, Raj A, Raskind M, Reiman E, Reisberg B, Reisch J, Reitz C, Ringman J, Roberson E, Rogaeva E, Rosen H, Rosenberg R, Royall D, Sager M, Sano M, Saykin A, Schellenberg G, Schneider J, Schneider L, Seeley W, Smith A, Sonnen J, Spina S, George-Hyslop PS, Stern R, Swerdlow R, Tanzi R, Trojanowski J, Troncoso J, Tsuang D, Valladares O, Van Deerlin V, Van Eldik L, Vardarajan B, Vinters H, Vonsattel JP, Wang LS, Weintraub S, Welsh-Bohmer K, Wilhelmsen K, Williamson J, Wingo T, Woltjer R, Wright C, Wu CK, Younkin S, Yu CE, Yu L, Zhao Y.

Author information

1
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
2
Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, 1207 17th Avenue S, Nashville, TN, 37212, USA.
3
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
4
Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
5
Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
6
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
7
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
8
Department of Medicine, University of Washington, Seattle, WA, USA.
9
Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA.
10
Cell Circuits Program, Broad Institute, Cambridge, MA, USA.
11
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
12
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
13
Department of Pathology, University of Washington, Seattle, WA, USA.
14
Department of Pathology, Stanford University, Stanford, CA, USA.
15
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
16
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
17
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
18
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
19
UK Dementia Research Institute at UCL, London, UK.
20
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
21
Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
22
Geriatric Research Education and Clinical Center of the Wm. S. Middleton Memorial VA Hospital, Madison, WI, USA.
23
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
24
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
25
Clinic of Psychiatry and Psychotherapy, Saarland University, Homburg/Saar, Germany.
26
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
27
Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
28
Ronald M Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
29
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
30
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
31
Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
32
Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
33
Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, 1207 17th Avenue S, Nashville, TN, 37212, USA. Timothy.J.Hohman@Vanderbilt.edu.

Abstract

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

KEYWORDS:

APOE; Alzheimer disease; Amyloid; Cerebrospinal fluid biomarkers; Neuropathology; Sex difference; Tau

PMID:
29967939
PMCID:
PMC6280657
[Available on 2019-12-01]
DOI:
10.1007/s00401-018-1881-4

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