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Sex-specific genetic predictors of Alzheimer’s disease biomarkers

, ; , ; Deming, Yuetiva; Dumitrescu, Logan; Barnes, Lisa L.; Thambisetty, Madhav; Kunkle, Brian; Gifford, Katherine A.; Bush, William S. and Chibnik, Lori B., et al. (2018) In Acta Neuropathologica 136(6). p.857-872
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... (More)

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.

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keywords
Alzheimer disease, Amyloid, APOE, Cerebrospinal fluid biomarkers, Neuropathology, Sex difference, Tau
in
Acta Neuropathologica
volume
136
issue
6
pages
857 - 872
publisher
Springer
external identifiers
  • scopus:85049573303
ISSN
0001-6322
DOI
10.1007/s00401-018-1881-4
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English
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yes
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0e1db61b-2f80-42f2-b6d6-149f2040384f
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2018-07-23 13:16:07
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2019-03-19 03:57:37
@article{0e1db61b-2f80-42f2-b6d6-149f2040384f,
  abstract     = {<p>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<sup>−8</sup>; β = 0.03, p = 3.97 × 10<sup>−8</sup>) 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 &lt; 0.02) but not males (p &gt; 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<sup>−10</sup>) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (p<sub>female</sub> = 0.047; p<sub>male</sub> = 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.</p>},
  author       = {,  and ,  and Deming, Yuetiva and Dumitrescu, Logan and Barnes, Lisa L. and Thambisetty, Madhav and Kunkle, Brian and Gifford, Katherine A. and Bush, William S. and Chibnik, Lori B. and Mukherjee, Shubhabrata and de Jager, Philip L. and Kukull, Walter and Huentelman, Matt and Crane, Paul K. and Resnick, Susan M. and Keene, C. Dirk and Montine, Thomas J. and Schellenberg, Gerard and Haines, Jonathan L. and Zetterberg, Henrik and Blennow, Kaj and Larson, Eric B. and Johnson, Sterling C. and Albert, Marilyn and Moghekar, Abhay and Del Aguila, Jorge L. and Fernandez, Maria Victoria and Budde, John and Hassenstab, Jason and Fagan, Anne M. and Riemenschneider, Matthias and Petersen, Ronald C. and Minthon, Lennart and Chao, Michael J. and van Deerlin, Vivianna M. and Lee, Virginia M.Y. and Shaw, Leslie M. and Trojanowski, John Q. and Peskind, Elaine R. and Li, Gail and Davis, Lea K. and Sealock, Julia M. and Cox, Nancy J. and Weiner, Michael W. and Petersen, Ron and Aisen, Paul and Jack, Clifford and Jagust, William and Shaw, Leslie M. and Trojanowski, John and Beckett, Laurel},
  issn         = {0001-6322},
  keyword      = {Alzheimer disease,Amyloid,APOE,Cerebrospinal fluid biomarkers,Neuropathology,Sex difference,Tau},
  language     = {eng},
  month        = {07},
  number       = {6},
  pages        = {857--872},
  publisher    = {Springer},
  series       = {Acta Neuropathologica},
  title        = {Sex-specific genetic predictors of Alzheimer’s disease biomarkers},
  url          = {http://dx.doi.org/10.1007/s00401-018-1881-4},
  volume       = {136},
  year         = {2018},
}