TY - JOUR
T1 - Sex-specific genetic predictors of Alzheimer’s disease biomarkers
AU - Deming, Yuetiva
AU - Dumitrescu, Logan
AU - Barnes, Lisa L.
AU - Thambisetty, Madhav
AU - Kunkle, Brian
AU - Gifford, Katherine A.
AU - Bush, William S.
AU - Chibnik, Lori B.
AU - Mukherjee, Shubhabrata
AU - De Jager, Philip L.
AU - Kukull, Walter
AU - Huentelman, Matt
AU - Crane, Paul K.
AU - Resnick, Susan M.
AU - Keene, C. Dirk
AU - Montine, Thomas J.
AU - Schellenberg, Gerard D.
AU - Haines, Jonathan L.
AU - Zetterberg, Henrik
AU - Blennow, Kaj
AU - Larson, Eric B.
AU - Johnson, Sterling C.
AU - Albert, Marilyn
AU - Moghekar, Abhay
AU - del Aguila, Jorge L.
AU - Fernandez, Maria Victoria
AU - Budde, John
AU - Hassenstab, Jason
AU - Fagan, Anne M.
AU - Riemenschneider, Matthias
AU - Petersen, Ronald C.
AU - Minthon, Lennart
AU - Chao, Michael J.
AU - Van Deerlin, Vivianna M.
AU - Lee, Virginia M.Y.
AU - Shaw, Leslie M.
AU - Trojanowski, John Q.
AU - Peskind, Elaine R.
AU - Li, Gail
AU - Davis, Lea K.
AU - Sealock, Julia M.
AU - Cox, Nancy J.
AU - Weiner, Michael W.
AU - Aisen, Paul
AU - Jack, Clifford
AU - Jagust, William
AU - Beckett, Laurel
AU - Abner, Erin
AU - Fardo, David
AU - Van Eldik, Linda
N1 - Publisher Copyright:
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
KW - APOE
KW - Alzheimer disease
KW - Amyloid
KW - Cerebrospinal fluid biomarkers
KW - Neuropathology
KW - Sex difference
KW - Tau
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U2 - 10.1007/s00401-018-1881-4
DO - 10.1007/s00401-018-1881-4
M3 - Article
C2 - 29967939
AN - SCOPUS:85049573303
SN - 0001-6322
VL - 136
SP - 857
EP - 872
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 6
ER -