Sex-specific genetic predictors of Alzheimer’s disease biomarkers

Alzheimer’S Disease Neuroimaging Initiative (Adni), The Alzheimer Disease Genetics Consortium (Adgc)

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 × 10−8; 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.

Original languageEnglish
Pages (from-to)857-872
Number of pages16
JournalActa Neuropathologica
Volume136
Issue number6
DOIs
StatePublished - 1 Dec 2018

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Alzheimer Disease
Biomarkers
Genome-Wide Association Study
Amyloid
Endophenotypes
Cerebrospinal Fluid
Amyloidosis
Prefrontal Cortex
Sex Characteristics
Autopsy
Gene Expression
Pathology

Keywords

  • APOE
  • Alzheimer disease
  • Amyloid
  • Cerebrospinal fluid biomarkers
  • Neuropathology
  • Sex difference
  • Tau

Cite this

Alzheimer’S Disease Neuroimaging Initiative (Adni), & The Alzheimer Disease Genetics Consortium (Adgc) (2018). Sex-specific genetic predictors of Alzheimer’s disease biomarkers. Acta Neuropathologica, 136(6), 857-872. https://doi.org/10.1007/s00401-018-1881-4
Alzheimer’S Disease Neuroimaging Initiative (Adni) ; The Alzheimer Disease Genetics Consortium (Adgc). / Sex-specific genetic predictors of Alzheimer’s disease biomarkers. In: Acta Neuropathologica. 2018 ; Vol. 136, No. 6. pp. 857-872.
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Alzheimer’S Disease Neuroimaging Initiative (Adni) & The Alzheimer Disease Genetics Consortium (Adgc) 2018, 'Sex-specific genetic predictors of Alzheimer’s disease biomarkers', Acta Neuropathologica, vol. 136, no. 6, pp. 857-872. https://doi.org/10.1007/s00401-018-1881-4

Sex-specific genetic predictors of Alzheimer’s disease biomarkers. / Alzheimer’S Disease Neuroimaging Initiative (Adni); The Alzheimer Disease Genetics Consortium (Adgc).

In: Acta Neuropathologica, Vol. 136, No. 6, 01.12.2018, p. 857-872.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sex-specific genetic predictors of Alzheimer’s disease biomarkers

AU - Alzheimer’S Disease Neuroimaging Initiative (Adni)

AU - The Alzheimer Disease Genetics Consortium (Adgc)

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 - Barber, Robert Clinton

AU - Fairchild, Thomas J.

AU - O'Bryant, Sidney

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

VL - 136

SP - 857

EP - 872

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 6

ER -

Alzheimer’S Disease Neuroimaging Initiative (Adni), The Alzheimer Disease Genetics Consortium (Adgc). Sex-specific genetic predictors of Alzheimer’s disease biomarkers. Acta Neuropathologica. 2018 Dec 1;136(6):857-872. https://doi.org/10.1007/s00401-018-1881-4