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Sex-specific genetic predictors of Alzheimer's disease biomarkers.

ABSTRACT: Cerebrospinal fluid (CSF) levels of amyloid-? 42 (A?42) 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 A?42 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 A?42, 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?=?4.25?×?10-8; ??=?0.03, p?=?3.97?×?10-8) 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??0.38). 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?=?4.57?×?10-10) compared to males (??=?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.

SUBMITTER: Deming Y

PROVIDER: S-EPMC6280657 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Deming Yuetiva Y Dumitrescu Logan L Barnes Lisa L LL Thambisetty Madhav M Kunkle Brian B Gifford Katherine A KA Bush William S WS Chibnik Lori B LB Mukherjee Shubhabrata S De Jager Philip L PL Kukull Walter W Huentelman Matt M Crane Paul K PK Resnick Susan M SM Keene C Dirk CD Montine Thomas J TJ Schellenberg Gerard D GD Haines Jonathan L JL Zetterberg Henrik H Blennow Kaj K Larson Eric B EB Johnson Sterling C SC Albert Marilyn M Moghekar Abhay A Del Aguila Jorge L JL Fernandez Maria Victoria MV Budde John J Hassenstab Jason J Fagan Anne M AM Riemenschneider Matthias M Petersen Ronald C RC Minthon Lennart L Chao Michael J MJ Van Deerlin Vivianna M VM Lee Virginia M-Y VM Shaw Leslie M LM Trojanowski John Q JQ Peskind Elaine R ER Li Gail G Davis Lea K LK Sealock Julia M JM Cox Nancy J NJ Goate Alison M AM Bennett David A DA Schneider Julie A JA Jefferson Angela L AL Cruchaga Carlos C Hohman Timothy J TJ

Acta neuropathologica 20180702 6

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 fe ...[more]

PMID: 29967939

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Project description:BackgroundSex is increasingly recognized as a significant factor contributing to the biological and clinical heterogeneity in AD. There is also growing evidence for the prominent role of DNA methylation (DNAm) in Alzheimer's disease (AD).MethodsWe studied sex-specific DNA methylation differences in the blood samples of AD subjects compared to cognitively normal subjects, by performing sex-specific meta-analyses of two large blood-based epigenome-wide association studies (ADNI and AIBL), which included DNA methylation data for a total of 1284 whole blood samples (632 females and 652 males). Within each dataset, we used two complementary analytical strategies, a sex-stratified analysis that examined methylation to AD associations in male and female samples separately, and a methylation-by-sex interaction analysis that compared the magnitude of these associations between different sexes. After adjusting for age, estimated immune cell type proportions, batch effects, and correcting for inflation, the inverse-variance fixed-effects meta-analysis model was used to identify the most consistent DNAm differences across datasets. In addition, we also evaluated the performance of the sex-specific methylation-based risk prediction models for AD diagnosis using an independent external dataset.ResultsIn the sex-stratified analysis, we identified 2 CpGs, mapped to the PRRC2A and RPS8 genes, significantly associated with AD in females at a 5% false discovery rate, and an additional 25 significant CpGs (21 in females, 4 in males) at P-value < 1×10-5. In methylation-by-sex interaction analysis, we identified 5 significant CpGs at P-value < 10-5. Out-of-sample validations using the AddNeuroMed dataset showed in females, the best logistic prediction model included age, estimated immune cell-type proportions, and methylation risk scores (MRS) computed from 9 of the 23 CpGs identified in AD vs. CN analysis that are also available in AddNeuroMed dataset (AUC = 0.74, 95% CI: 0.65-0.83). In males, the best logistic prediction model included only age and MRS computed from 2 of the 5 CpGs identified in methylation-by-sex interaction analysis that are also available in the AddNeuroMed dataset (AUC = 0.70, 95% CI: 0.56-0.82).ConclusionsOverall, our results show that the DNA methylation differences in AD are largely distinct between males and females. Our best-performing sex-specific methylation-based prediction model in females performed better than that for males and additionally included estimated cell-type proportions. The significant discriminatory classification of AD samples with our methylation-based prediction models demonstrates that sex-specific DNA methylation could be a predictive biomarker for AD. As sex is a strong factor underlying phenotypic variability in AD, the results of our study are particularly relevant for a better understanding of the epigenetic architecture that underlie AD and for promoting precision medicine in AD.

Project description:BackgroundAlzheimer's disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate sex-specific molecular networks of AD.MethodsWe integrated large-scale human postmortem brain transcriptomic data of AD from two cohorts (MSBB and ROSMAP) via multiscale network analysis and identified key drivers with sexually dimorphic expression patterns and/or different responses to APOE genotypes between sexes. The expression patterns and functional relevance of the top sex-specific network driver of AD were further investigated using postmortem human brain samples and gene perturbation experiments in AD mouse models.ResultsGene expression changes in AD versus control were identified for each sex. Gene co-expression networks were constructed for each sex to identify AD-associated co-expressed gene modules shared by males and females or specific to each sex. Key network regulators were further identified as potential drivers of sex differences in AD development. LRP10 was identified as a top driver of the sex differences in AD pathogenesis and manifestation. Changes of LRP10 expression at the mRNA and protein levels were further validated in human AD brain samples. Gene perturbation experiments in EFAD mouse models demonstrated that LRP10 differentially affected cognitive function and AD pathology in sex- and APOE genotype-specific manners. A comprehensive mapping of brain cells in LRP10 over-expressed (OE) female E4FAD mice suggested neurons and microglia as the most affected cell populations. The female-specific targets of LRP10 identified from the single cell RNA-sequencing (scRNA-seq) data of the LRP10 OE E4FAD mouse brains were significantly enriched in the LRP10-centered subnetworks in female AD subjects, validating LRP10 as a key network regulator of AD in females. Eight LRP10 binding partners were identified by the yeast two-hybrid system screening, and LRP10 over-expression reduced the association of LRP10 with one binding partner CD34.ConclusionsThese findings provide insights into key mechanisms mediating sex differences in AD pathogenesis and will facilitate the development of sex- and APOE genotype-specific therapies for AD.

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Sex-specific genetic predictors of Alzheimer's disease biomarkers.

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Sex-specific genetic predictors of Alzheimer's disease biomarkers.

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