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Brain. 2019 Sep 1;142(9):2581-2589. doi: 10.1093/brain/awz206.

Sex differences in the genetic predictors of Alzheimer's pathology.

Author information

1
Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
2
Vanderbilt Genetics Institute, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
3
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
4
Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
5
John T MacDonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.
6
John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA.
7
Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
8
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
9
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
10
Department of Medicine, University of Washington, Seattle, WA, USA.
11
Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
12
Cell Circuits Program, Broad Institute, Cambridge MA, USA.
13
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
14
Department of Pathology, University of Washington, Seattle, WA, USA.
15
Department of Pathology, Stanford University, Stanford, CA, USA.
16
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
17
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
18
Ronald M Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
19
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
20
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
21
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
22
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
23
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
24
UK Dementia Research Institute at UCL, London, UK.
25
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
26
Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
27
Department of Neurology, the Johns Hopkins University School of Medicine, Baltimore, MD.

Abstract

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

KEYWORDS:

Alzheimer’s disease; beta-amyloid; genome-wide association study; neuropathology; tau

PMID:
31497858
DOI:
10.1093/brain/awz206

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