Dataset Information

Genome-wide epistasis analysis for Alzheimer's disease and implications for genetic risk prediction.

ABSTRACT:

Background

Single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies only explain part of the heritability of Alzheimer's disease (AD). Epistasis has been considered as one of the main causes of "missing heritability" in AD.

Methods

We performed genome-wide epistasis screening (N = 10,389) for the clinical diagnosis of AD using three popularly adopted methods. Subsequent analyses were performed to eliminate spurious associations caused by possible confounding factors. Then, candidate genetic interactions were examined for their co-expression in the brains of AD patients and analyzed for their association with intermediate AD phenotypes. Moreover, a new approach was developed to compile the epistasis risk factors into an epistasis risk score (ERS) based on multifactor dimensional reduction. Two independent datasets were used to evaluate the feasibility of ERSs in AD risk prediction.

Results

We identified 2 candidate genetic interactions with P_FDR < 0.05 (RAMP3-SEMA3A and NSMCE1-DGKE/C17orf67) and another 5 genetic interactions with P_FDR < 0.1. Co-expression between the identified interactions supported the existence of possible biological interactions underlying the observed statistical significance. Further association of candidate interactions with intermediate phenotypes helps explain the mechanisms of neuropathological alterations involved in AD. Importantly, we found that ERSs can identify high-risk individuals showing earlier onset of AD. Combined risk scores of SNPs and SNP-SNP interactions showed slightly but steadily increased AUC in predicting the clinical status of AD.

Conclusions

In summary, we performed a genome-wide epistasis analysis to identify novel genetic interactions potentially implicated in AD. We found that ERS can serve as an indicator of the genetic risk of AD.

SUBMITTER: Wang H

PROVIDER: S-EPMC7934265 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Genome-wide epistasis analysis for Alzheimer's disease and implications for genetic risk prediction.

Wang Hui H Bennett David A DA De Jager Philip L PL Zhang Qing-Ye QY Zhang Hong-Yu HY

Alzheimer's research & therapy 20210304 1

<h4>Background</h4>Single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies only explain part of the heritability of Alzheimer's disease (AD). Epistasis has been considered as one of the main causes of "missing heritability" in AD.<h4>Methods</h4>We performed genome-wide epistasis screening (N = 10,389) for the clinical diagnosis of AD using three popularly adopted methods. Subsequent analyses were performed to eliminate spurious associations caused by possible confou ...[more]

PMID: 33663605

Similar Datasets

Project description:BackgroundAlzheimer's disease (AD) is the most common cause of dementia in the elderly and the sixth leading cause of death in the United States. AD is mainly considered a complex disorder with polygenic inheritance. Despite discovering many susceptibility loci, a major proportion of AD genetic variance remains to be explained.MethodsWe investigated the genetic architecture of AD in four publicly available independent datasets through genome-wide association, transcriptome-wide association, and gene-based and pathway-based analyses. To explore differences in the genetic basis of AD between males and females, analyses were performed on three samples in each dataset: males and females combined, only males, or only females.ResultsOur genome-wide association analyses corroborated the associations of several previously detected AD loci and revealed novel significant associations of 35 single-nucleotide polymorphisms (SNPs) outside the chromosome 19q13 region at the suggestive significance level of p < 5E-06. These SNPs were mapped to 21 genes in 19 chromosomal regions. Of these, 17 genes were not associated with AD at genome-wide or suggestive levels of associations by previous genome-wide association studies. Also, the chromosomal regions corresponding to 8 genes did not contain any previously detected AD-associated SNPs with p < 5E-06. Our transcriptome-wide association and gene-based analyses revealed that 26 genes located in 20 chromosomal regions outside chromosome 19q13 had evidence of potential associations with AD at a false discovery rate of 0.05. Of these, 13 genes/regions did not contain any previously AD-associated SNPs at genome-wide or suggestive levels of associations. Most of the newly detected AD-associated SNPs and genes were sex specific, indicating sex disparities in the genetic basis of AD. Also, 7 of 26 pathways that showed evidence of associations with AD in our pathway-bases analyses were significant only in females.ConclusionsOur findings, particularly the newly discovered sex-specific genetic contributors, provide novel insight into the genetic architecture of AD and can advance our understanding of its pathogenesis.

Dataset Information

Genome-wide epistasis analysis for Alzheimer's disease and implications for genetic risk prediction.

Background

Methods

Results

Conclusions

Publications

Genome-wide epistasis analysis for Alzheimer's disease and implications for genetic risk prediction.

Similar Datasets

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