Sex-specific genetic predictors of Alzheimer's disease biomarkers

被引：85

作者：

Deming, Yuetiva ^{[1
]}

Dumitrescu, Logan ^{[2
]}

Barnes, Lisa L. ^{[3
]}

Thambisetty, Madhav ^{[4
]}

Kunkle, Brian ^{[5
]}

Gifford, Katherine A. ^{[2
]}

Bush, William S. ^{[5
]}

Chibnik, Lori B. ^{[6
,7
]}

Mukherjee, Shubhabrata ^{[8
]}

De Jager, Philip L. ^{[9
,10
]}

Kukull, Walter ^{[11
]}

Huentelman, Matt ^{[12
]}

Crane, Paul K. ^{[8
]}

Resnick, Susan M. ^{[4
]}

Keene, C. Dirk ^{[13
]}

Montine, Thomas J. ^{[14
]}

Schellenberg, Gerard D. ^{[15
]}

Haines, Jonathan L. ^{[5
]}

Zetterberg, Henrik ^{[16
,17
,18
,19
]}

Blennow, Kaj ^{[16
,17
]}

Larson, Eric B. ^{[8
,20
]}

Johnson, Sterling C. ^{[21
,22
]}

Albert, Marilyn ^{[23
]}

Moghekar, Abhay ^{[23
]}

del Aguila, Jorge L. ^{[1
]}

Fernandez, Maria Victoria ^{[1
]}

Budde, John ^{[1
]}

Hassenstab, Jason ^{[1
]}

Fagan, Anne M. ^{[24
]}

Riemenschneider, Matthias ^{[25
]}

Petersen, Ronald C. ^{[26
]}

Minthon, Lennart ^{[27
]}

Chao, Michael J. ^{[28
]}

Van Deerlin, Vivianna M. ^{[29
]}

Lee, Virginia M. -Y. ^{[29
]}

Shaw, Leslie M. ^{[29
]}

Trojanowski, John Q. ^{[29
]}

Peskind, Elaine R. ^{[30
]}

Li, Gail ^{[30
,31
]}

Davis, Lea K. ^{[32
]}

Sealock, Julia M. ^{[32
]}

Cox, Nancy J. ^{[32
]}

Goate, Alison M. ^{[28
]}

Bennett, David A. ^{[3
]}

Schneider, Julie A. ^{[3
]}

Jefferson, Angela L. ^{[2
]}

Cruchaga, Carlos ^{[1
]}

Hohman, Timothy J. ^{[2
]}

机构：

[1] Washington Univ, Dept Psychiat, Sch Med, 660 S Euclid Ave, St Louis, MO 63110 USA

[2] Washington Univ, Dept Psychiat, Sch Med, 660 S Euclid Ave, St Louis, MO 63110 USA

[3] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

[4] NIA, Unit Clin & Translat Neuroscience, Lab Behav Neurosci, NIH, Bethesda, MD 20892 USA

[5] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Inst Computat Biol, Cleveland, OH 44106 USA

[6] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[7] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA

[8] Univ Washington, Dept Med, Seattle, WA USA

[9] Columbia Univ, Dept Neurol, Ctr Translat & Computat Neuroimmunol, New York, NY USA

[10] Broad Inst, Cell Circuits Program, Cambridge, MA USA

[11] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA

[12] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA

[13] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[14] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[15] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA

[16] Univ Gothenburg, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Sahlgrenska Acad, Molndal, Sweden

[17] Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden

[18] UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England

[19] UCL, UK Dementia Res Inst, London, England

[20] Kaiser Permanente, Washington Hlth Res Inst, Seattle, WA USA

[21] Univ Wisconsin, Sch Med & Publ Hlth, Alzheimers Dis Res Ctr, Madison, WI USA

[22] Wm S Middleton Mem VA Hosp, Geriatr Res Educ & Clin Ctr, Madison, WI USA

[23] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[24] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[25] Saarland Univ, Clin Psychiat & Psychotherapy, Homburg, Germany

[26] Mayo Clin, Dept Neurol, Rochester, MN USA

[27] Lund Univ, Clin Memory Res Unit, Dept Clin Sci, Lund, Sweden

[28] Icahn Sch Med Mt Sinai, Ronald M Loeb Ctr Alzheimers Dis, Dept Neurosci, New York, NY 10029 USA

[29] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA

[30] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

[31] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA

[32] Vanderbilt Univ, Med Ctr, Dept Med, Vanderbilt Genet Inst, Nashville, TN USA

来源：

ACTA NEUROPATHOLOGICA | 2018年 / 136卷 / 06期

关键词：

Alzheimer disease; Cerebrospinal fluid biomarkers; Neuropathology; Sex difference; APOE; Amyloid; Tau; APOLIPOPROTEIN-E GENOTYPE; GENOME-WIDE ASSOCIATION; SURFACE-BASED ANALYSIS; CEREBROSPINAL-FLUID; COGNITIVE IMPAIRMENT; HYPOTHETICAL MODEL; COMPOSITE SCORE; EXPRESSION; MEMORY; RISK;

D O I：

10.1007/s00401-018-1881-4

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Cerebrospinal fluid (CSF) levels of amyloid- 42 (A42) 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 A42 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 A42, 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 (=-0.03, p=4.25x10(-8); =0.03, p=3.97x10(-8)) than males (=-0.02, p=0.009; =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 (=0.05, p=4.57x10(-10)) compared to males (=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 (p0.32). 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.

引用

页码：857 / 872

页数：16

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