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Sex differences in the genetic predictors of Alzheimer's pathology

Artikel i vetenskaplig tidskrift
Författare L. Dumitrescu
L. L. Barnes
M. Thambisetty
G. Beecham
B. Kunkle
W. S. Bush
K. A. Gifford
L. B. Chibnik
S. Mukherjee
P. L. De Jager
W. Kukull
P. K. Crane
S. M. Resnick
C. D. Keene
T. J. Montine
G. D. Schellenberg
Y. Deming
M. J. Chao
M. Huentelman
E. R. Martin
K. Hamilton-Nelson
L. M. Shaw
J. Q. Trojanowski
E. R. Peskind
C. Cruchaga
M. A. Pericak-Vance
A. M. Goate
N. J. Cox
J. L. Haines
Henrik Zetterberg
Kaj Blennow
E. B. Larson
S. C. Johnson
M. Albert
D. A. Bennett
J. A. Schneider
A. L. Jefferson
T. J. Hohman
Publicerad i Brain
Volym 142
Sidor 2581-2589
ISSN 0006-8950
Publiceringsår 2019
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Sidor 2581-2589
Språk en
Länkar dx.doi.org/10.1093/brain/awz206
Ämneskategorier Neurovetenskaper

Sammanfattning

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.

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