Sex-specific genetic predictors of Alzheimer’s disease biomarkers
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-stratifi...
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Published in | Acta neuropathologica Vol. 136; no. 6; pp. 857 - 872 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Berlin/Heidelberg
Springer Berlin Heidelberg
01.12.2018
Springer Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | 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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Y.D. and L.D. contributed equally to this work: analyzed data, prepared figures and tables, and wrote the manuscript. L.L.B., M.T., B.K., K.A.G., W.S.B., L.B.C., S.M., P.L.DJ., W.K., M.H., P.K.C., S.M.R., C.D.K., T.J.M., G.D.S., J.L.H., E.B.L., S.C.J., M.A., A.M., A.L.J., L.K.D., J.M. S., and N.J.C. contributed to the interpretation of data and critical revision of the manuscript for important intellectual content. J.L.dA., M.V.F., and J.B. prepared genetic data: performed imputation, cleaning, and calculated principal components. Also contributed to critical revision of the manuscript for important intellectual content. J.H., A.M.F., M.R., R.C.P., L.M., V.M.VD., V.M-Y.L., L.M.S., J.Q.T., E.R.P., G.L., L.K.D., H.Z., ADNI, ADGC, A.M.G., D.A.B., J.A.S. provided data, contributed to analysis and/or interpretation of data, and contributed to critical revision of the manuscript for important intellectual content. C.C. and T.J.H. contributed equally to this work: conceived and planned the study, analyzed data, prepared the manuscript, and supervised the project. All authors reviewed and approved the final manuscript. Author contributions |
ISSN: | 0001-6322 1432-0533 1432-0533 |
DOI: | 10.1007/s00401-018-1881-4 |