Novel Alzheimer’s disease genes and epistasis identified using machine learning GWAS platform

Mischa Lundberg*, Letitia M. F. Sng, Piotr Szul, Rob Dunne, Arash Bayat, Samantha C. Burnham, Denis C. Bauer, Natalie A. Twine*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
3 Downloads (Pure)


Alzheimer’s disease (AD) is a complex genetic disease, and variants identified through genome-wide association studies (GWAS) explain only part of its heritability. Epistasis has been proposed as a major contributor to this ‘missing heritability’, however, many current methods are limited to only modelling additive effects. We use VariantSpark, a machine learning approach to GWAS, and BitEpi, a tool for epistasis detection, to identify AD associated variants and interactions across two independent cohorts, ADNI and UK Biobank. By incorporating significant epistatic interactions, we captured 10.41% more phenotypic variance than logistic regression (LR). We validate the well-established AD loci, APOE, and identify two novel genome-wide significant AD associated loci in both cohorts, SH3BP4 and SASH1, which are also in significant epistatic interactions with APOE. We show that the SH3BP4 SNP has a modulating effect on the known pathogenic APOE SNP, demonstrating a possible protective mechanism against AD. SASH1 is involved in a triplet interaction with pathogenic APOE SNP and ACOT11, where the SASH1 SNP lowered the pathogenic interaction effect between ACOT11 and APOE. Finally, we demonstrate that VariantSpark detects disease associations with 80% fewer controls than LR, unlocking discoveries in well annotated but smaller cohorts.

Original languageEnglish
Article number17662
Pages (from-to)1-12
Number of pages12
JournalScientific Reports
Issue number1
Publication statusPublished - 17 Oct 2023

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Copyright the Author(s) 2024. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


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