You are here

Acta Neuropathol DOI:10.1007/s00401-018-1881-4

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

Publication TypeJournal Article
Year of Publication2018
AuthorsDeming, Y, Dumitrescu, L, Barnes, LL, Thambisetty, M, Kunkle, B, Gifford, KA, Bush, WS, Chibnik, LB, Mukherjee, S, De Jager, PL, Kukull, W, Huentelman, M, Crane, PK, Resnick, SM, C Keene, D, Montine, TJ, Schellenberg, GD, Haines, JL, Zetterberg, H, Blennow, K, Larson, EB, Johnson, SC, Albert, M, Moghekar, A, Del Aguila, JL, Fernandez, MVictoria, Budde, J, Hassenstab, J, Fagan, AM, Riemenschneider, M, Petersen, RC, Minthon, L, Chao, MJ, Van Deerlin, VM, Lee, VM-Y, Shaw, LM, Trojanowski, JQ, Peskind, ER, Li, G, Davis, LK, Sealock, JM, Cox, NJ, Goate, AM, Bennett, DA, Schneider, JA, Jefferson, AL, Cruchaga, C, Hohman, TJ
Corporate AuthorsAlzheimer’s Disease Neuroimaging Initiative (ADNI), Alzheimer Disease Genetics Consortium (ADGC)
JournalActa Neuropathol
Volume136
Issue6
Pages857-872
Date Published2018 Dec
ISSN1432-0533
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; β = 0.03, p = 3.97 × 10) 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  0.38). 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) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (p = 0.047; p = 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.

DOI10.1007/s00401-018-1881-4
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29967939?dopt=Abstract

Alternate JournalActa Neuropathol.
PubMed ID29967939
PubMed Central IDPMC6280657
Grant ListP30 AG013854 / AG / NIA NIH HHS / United States
P30 AG053760 / AG / NIA NIH HHS / United States
P50 AG016574 / / National Institute on Aging /
R01 AG037639 / AG / NIA NIH HHS / United States
U01 AG046152 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
P50 AG005146 / / National Institute on Aging /
RF1 AG015819 / AG / NIA NIH HHS / United States
R01 AG056534 / AG / NIA NIH HHS / United States
R01 AG048015 / / National Institutes of Health /
P50 AG005142 / AG / NIA NIH HHS / United States
R01 AG058501 / AG / NIA NIH HHS / United States
U01 AG058922 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
R01 AG044546 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
P01 AG017586 / AG / NIA NIH HHS / United States
U01 AG052411 / AG / NIA NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
RF1 AG053303 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
P30 AG035982 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
R01 NS085419 / NS / NINDS NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
R01 HL111516 / HL / NHLBI NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
RF1 AG058501 / AG / NIA NIH HHS / United States
U19 AG033655 / AG / NIA NIH HHS / United States
K25 AG055620 / AG / NIA NIH HHS / United States
R01 AG027161 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
RF1 AG051504 / AG / NIA NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
R01 AG021155 / AG / NIA NIH HHS / United States
U24 AG041689 / AG / NIA NIH HHS / United States
P50 AG016570 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
P30 AG010124 / / National Institute on Aging /
R21 AG059941 / AG / NIA NIH HHS / United States
P30 AG008017 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R03 AG050856 / AG / NIA NIH HHS / United States
R01 AG061796 / AG / NIA NIH HHS / United States
K01 AG049164 / / National Institutes of Health /
P50 AG025688 / AG / NIA NIH HHS / United States
R01 NS080820 / NS / NINDS NIH HHS / United States
T32MH014877 / / National Institute of Mental Health /
P50 AG005133 / AG / NIA NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
S10 OD023680 / OD / NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
K12 HD043483 / HD / NICHD NIH HHS / United States
U01 AG046139 / AG / NIA NIH HHS / United States
U01 HG004610 / HG / NHGRI NIH HHS / United States
K01 AG049164 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
R01 AG048015 / AG / NIA NIH HHS / United States
K24 AG046373 / AG / NIA NIH HHS / United States
Z99 AG999999 / NULL / Intramural NIH HHS / United States
R01 NS100980 / NS / NINDS NIH HHS / United States
P30 AG028383 / AG / NIA NIH HHS / United States
01GS08125 / / German Federal Ministry of Education and Research National Genome Research Network /
P50 AG033514 / AG / NIA NIH HHS / United States
R01 AG034962 / AG / NIA NIH HHS / United States
P30 AG010161 / / National Institute on Aging /
R01 AG015819 / AG / NIA NIH HHS / United States
IK2 BX001820 / BX / BLRD VA / United States
R01 AG035083 / AG / NIA NIH HHS / United States