Sex-specific genetic predictors of Alzheimer’s disease biomarkers
Open accessAbstract
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 (p female = 0.047; p male = 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.
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Several additional loci, including APOE, have been identified as exhibiting sex-specific association with AD endophenotypes.
“Several additional loci, including APOE [264], have been identified as exhibiting sex-specific association with AD endophenotypes”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [265]
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- Authors
- (ADNI), A. D. N. I., Deming, Y., The Alzheimer Disease Genetics Consortium (ADGC), Dumitrescu, L., Barnes, L. L., Thambisetty, M., Kunkle, B., Gifford, K. A., Bush, W. S., Chibnik, L. B., Mukherjee, S., De Jager, P. L., Kukull, W., Huentelman, M., Crane, P. K., Resnick, S. M., Keene, C. D., Montine, T. J., Schellenberg, G. D., Haines, J. L., Zetterberg, H., Blennow, K., Larson, E. B., Johnson, S. C., Albert, M., Moghekar, A., del Aguila, J. L., Fernandez, M. V., Budde, J., Hassenstab, J., Fagan, A. M., Riemenschneider, M., Petersen, R. C., Minthon, L., Chao, M. J., Van Deerlin, V. M., Lee, V. M.-Y., Shaw, L. M., Trojanowski, J. Q., Peskind, E. R., Li, G., Davis, L. K., Sealock, J. M., Cox, N. J., Goate, A. M., Bennett, D. A., Schneider, J. A., Jefferson, A. L., Cruchaga, C., & Hohman, T. J.
- Affiliations
- Vanderbilt University (US)
- Rush University Medical Center (US)
- National Institutes of Health (US)
- Harvard University (US)
- Brigham and Women's Hospital (US)
- University of Washington (US)
- Translational Genomics Research Institute (US)
- Stanford Medicine (US)
- Case Western Reserve University (US)
- Sahlgrenska University Hospital (SE)
- University of Wisconsin–Madison (US)
- Johns Hopkins University (US)
- Washington University in St. Louis (US)
- Mayo Clinic (US)
- Lund University (SE)
- University of Pennsylvania (US)
- Corresponding author
- Hohman, Timothy J.
- ORCID
- Deming, Yuetiva
- Dumitrescu, Logan
- Barnes, Lisa L.
- Thambisetty, Madhav
- Kunkle, Brian
- Gifford, Katherine A.
- Bush, William S.
- Chibnik, Lori B.
- Mukherjee, Shubhabrata
- Kukull, Walter
- Crane, Paul K.
- Resnick, Susan M.
- Keene, C. Dirk
- Montine, Thomas J.
- Schellenberg, Gerard D.
- Haines, Jonathan L.
- Zetterberg, Henrik
- Blennow, Kaj
- Larson, Eric B.
- Johnson, Sterling C.
- Albert, Marilyn
- Moghekar, Abhay
- Budde, John
- Hassenstab, Jason
- Fagan, Anne M.
- Petersen, Ronald C.
- Lee, Virginia M.-Y.
- Shaw, Leslie M.
- Trojanowski, John Q.
- Peskind, Elaine R.
- Davis, Lea K.
- Sealock, Julia M.
- Cox, Nancy J.
- Goate, Alison M.
- Bennett, David A.
- Schneider, Julie A.
- Jefferson, Angela L.
- Cruchaga, Carlos
- Hohman, Timothy J.
- Venue
- Acta Neuropathologica
- Published
- 2018-07-02
- Volume
- 136
- Issue
- 6
- Pages
- 857-872
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC6280657
- OpenAlex
- W2811424297
- Cited by
- 110
- References
- 51
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 13 · 2023: 19 · 2022: 8 · 2021: 18 · 2020: 13 · 2019: 12 · 2018: 5
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institute of Mental Health (T32MH014877)
- National Institutes of Health (R01 AG048015, K01 AG049164)
- German Federal Ministry of Education and Research National Genome Research Network (01GS08125)
- National Institute on Aging (P50 AG005146, P50 AG016574, P30 AG010161, P30 AG010124)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, sex differences, amyloid-beta 42, tau protein, cerebrospinal fluid biomarkers, endophenotypes, sex interaction, SERPINB1, SERPINB9, prefrontal cortex gene expression, amyloid plaques, neurofibrillary tangles, Religious Orders Study, Rush Memory and Aging Project
- MeSH terms
- Aged, 80 and over, Alzheimer Disease, Amyloidosis, Apolipoproteins E, Brain, Female, Genotype, Humans, Male, Muscle Proteins, Mutation, Peptide Fragments, Sex Factors, Transcription Factors, Biomarkers, Serpins, Amyloid beta-Peptides, tau Proteins, Genome-Wide Association Study, Claudins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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