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

TitleGenome-wide epistasis analysis for Alzheimer's disease and implications for genetic risk prediction.
Publication TypeJournal Article
Year of Publication2021
AuthorsWang H, Bennett DA, De Jager PL, Zhang Q-Y, Zhang H-Y
JournalAlzheimers Res Ther
Date Published2021 03 04
KeywordsAlzheimer Disease, Epistasis, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors

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 <  0.05 (RAMP3-SEMA3A and NSMCE1-DGKE/C17orf67) and another 5 genetic interactions with P <  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.

Pubmed Link
Alternate JournalAlzheimers Res Ther
PubMed ID33663605
PubMed Central IDPMC7934265
Grant ListR01 AG017917 / AG / NIA NIH HHS / United States

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