Sex differences in the genetic predictors of Alzheimer's pathology

被引：59

作者：

Dumitrescu, Logan ^{[1
,2
]}

Barnes, Lisa L. ^{[3
]}

Thambisetty, Madhav ^{[4
]}

Beecham, Gary ^{[5
,6
]}

Kunkle, Brian ^{[6
]}

Bush, William S. ^{[7
]}

Gifford, Katherine A. ^{[1
]}

Chibnik, Lori B. ^{[8
,9
]}

Mukherjee, Shubhabrata ^{[10
]}

De Jager, Philip L. ^{[11
,12
]}

Kukull, Walter ^{[13
]}

Crane, Paul K. ^{[10
]}

Resnick, Susan M. ^{[4
]}

Keene, C. Dirk ^{[14
]}

Montine, Thomas J. ^{[15
]}

Schellenberg, Gerard D. ^{[16
]}

Deming, Yuetiva ^{[17
]}

Chao, Michael J. ^{[18
]}

Huentelman, Matt ^{[19
]}

Martin, Eden R. ^{[5
,6
]}

Hamilton-Nelson, Kara ^{[6
]}

Shaw, Leslie M. ^{[16
]}

Trojanowski, John Q. ^{[16
]}

Peskind, Elaine R. ^{[20
]}

Cruchaga, Carlos ^{[17
]}

Pericak-Vance, Margaret A. ^{[6
]}

Goate, Alison M. ^{[18
]}

Cox, Nancy J. ^{[2
]}

Haines, Jonathan L. ^{[7
]}

Zetterberg, Henrik ^{[21
,22
,23
,24
]}

Blennow, Kaj ^{[21
,22
]}

Larson, Eric B. ^{[10
,25
]}

Johnson, Sterling C. ^{[26
]}

Albert, Marilyn ^{[27
]}

Bennett, David A. ^{[3
]}

Schneider, Julie A. ^{[3
]}

Jefferson, Angela L. ^{[1
]}

Hohman, Timothy J. ^{[1
,2
]}

机构：

[1] Vanderbilt Univ, Vanderbilt Memory & Alzheimers Ctr, Med Ctr, 1207 17th Ave S, Nashville, TN 37212 USA

[2] Vanderbilt Univ, Vanderbilt Genet Inst, Dept Med, Med Ctr, Nashville, TN 37212 USA

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

[4] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA

[5] Univ Miami, Dept Human Genet, John T MacDonald Fdn, Miami, FL USA

[6] Univ Miami, Sch Med, John P Hussman Inst Human Genom, Miami, FL USA

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

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

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

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

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

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

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

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

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

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

[17] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

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

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

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

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

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

[23] UCL Inst Neurol, Dept Neurodegenerat Dis, Queen Sq, London, England

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

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

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

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

来源：

BRAIN | 2019年 / 142卷

基金：

欧洲研究理事会; 瑞典研究理事会;

关键词：

Alzheimer's disease; neuropathology; beta-amyloid; tau; genome-wide association study; GENOME-WIDE ASSOCIATION; NATIONAL INSTITUTE; COGNITIVE DECLINE; DISEASE; RISK; HAPLOTYPE; TAU; EXPRESSION; GUIDELINES; DIAGNOSIS;

D O I：

10.1093/brain/awz206

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 x 10(-8)) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 x 10(-8)) but not females (P = 0.85, sex-interaction P = 2.9 x 10(-4)). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

引用

页码：2581 / 2589

页数：9

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