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P1‐139: THE CONTRIBUTION OF SEX‐SPECIFIC ASSOCIATIONS IN GENETIC STUDIES OF ALZHEIMER'S DISEASE PATHOLOGY
Author(s) -
Dumitrescu Logan,
Deming Yuetiva,
Lu Qiongshi,
Beecham Gary W.,
Kunkle Brian W.,
Del-Aguila Jorge L.,
Fernandez Maria Victoria,
Budde John P.,
Fagan Anne M.,
De Jager Philip L.,
Albert Marilyn S.,
Moghekar Abhay,
Riemenschneider Matthias,
Petersen Ronald C.,
Barnes Lisa L.,
Thambisetty Madhav,
Gifford Katherine A.,
Bush William S.,
Chibnik Lori B.,
Mukherjee Shubhabrata,
Kukull Walter A.,
Crane Paul K.,
Resnick Susan M.,
Keene Dirk,
Montine Thomas J.,
Blennow Kaj,
Zetterberg Henrik,
Minthon Lennart,
Van Deerlin Vivianna M.,
Lee Virginia M-Y.,
Shaw Leslie M.,
Trojanowski John Q.,
Larson Eric B.,
Johnson Sterling C.,
Schellenberg Gerard D.,
Haines Jonathan L.,
Peskind Elaine R.,
Li Ge,
Cox Nancy J.,
Jefferson Angela L.,
Goate Alison M.,
Cruchaga Carlos,
Bennett David A.,
Schneider Julie A.,
Hohman Timothy J.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.142
Subject(s) - neuropathology , genome wide association study , bonferroni correction , disease , genetic association , alzheimer's disease , pathology , biology , medicine , genetics , genotype , gene , single nucleotide polymorphism , statistics , mathematics
Figure 2. X Chromosome variant rs11094635-G demonstrates a protective effect on longitudinal beta-amyloid accumulation. A. Mean annual percent 18 Leigh Christopher, Grace Tam, Valerio Napolioni, Yongha Kim, Michael D. Greicius, Stanford University, Stanford, CA, USA. Contact e-mail: lchris@stanford.edu change in [ F] AV45 in males according to genotype demonstrating reduced beta-amyloid accumulation in the G genotype. B. Mean annual percent change in [F] AV45 in females demonstrating reduced beta-amyloid accumulation with increasing G allele dosage. Background:Brain beta-amyloid accumulation is a hallmark characteristic of Alzheimer’s disease (AD); however, it is unknown whether common genetic variation on the X-Chromosome plays a role. Thus, we performed an X Chromosome-Wide Association Study (XWAS) to discover single nucleotide polymorphisms (SNPs) associated with longitudinal accumulation of beta-amyloid in the brain as a proxy for disease progression. Methods: Participants were part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n1⁄4 621). [F] AV45 PET scans were acquired and pre-processed. [F] AV45 is a radiotracer that binds to beta-amyloid plaques. Genotype data underwent standard quality control and were imputed. XWAS 2.0 was used to run a sex-stratified test (analyzed according to Stouffer’s method) with mean annual percent change in global [F] AV45 (cerebellum normalized) as the quantitative trait. We then tested whether significant variants associated with 1) baseline CSF tau levels 2) longitudinal change in cognitive performance (memory, language and global cognition) using a linear mixed effects model in an independent dataset. Results:A variant upstream of the geneMTM1, rs11094635, was significantly associated with beta-amyloid accumulation (Figure 1, rs11094635 C/G, MAF1⁄4 0.30, Stouffers Z 1⁄4 -4.81, p 1⁄4 1.5 x 10). The minor allele (G) demonstrated a protective effect on beta-amyloid accumulation (Figure 2). Dosage of the minor allele was also associated with lower baseline CSF tau levels (p< 0.05) and a less rapid decline on Boston Naming Task scores in individuals who converted to AD (p1⁄40.012). As a post-hoc analysis, we ran a gene-based test for both beta-amyloid accumulation and AD risk (in a separate case control dataset) to see whether overlapping genes contribute