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bioRxiv · 10.1101/2024.12.20.629593

Sparse Multitask group Lasso for Genome-Wide Association Studies

Nouira, A.·Azencott, C.-A.
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Abstract

A critical hurdle in Genome-Wide Association Studies (GWAS) involves population stratification, wherein differences in allele frequencies among subpopulations within samples are influenced by distinct ancestry. This stratification implies that risk variants may be distinct across populations with different allele frequencies. This study introduces Sparse Multitask Group Lasso (SMuGLasso) to tackle this challenge. SMuGLasso is based on MuGLasso, which formulates this problem using a multitask group lasso framework in which tasks are subpopulations, and groups are population-specific Linkage-Disequilibrium (LD)-groups of strongly correlated Single Nucleotide Polymorphisms (SNPs). The novelty in SMuGLasso is the incorporation of an additional [l]1-norm regularization for the selection of population-specific genetic variants. As MuGLasso, SMuGLasso uses a stability selection procedure to improve robustness and gap-safe screening rules for computational efficiency. We evaluate MuGLasso and SMuGLasso on simulated data sets as well as on a case-control breast cancer data set and a quantitative GWAS in Arabidopsis thaliana. We show that SMuGLasso is well suited to addressing linkage disequilibrium and population stratification in GWAS data, and show the superiority of SMuGLasso over MuGLasso in identifying population-specific SNPs. On real data, we confirm the relevance of the identified loci through pathway and network analysis, and observe that the findings of SMuGLasso are more consistent with the literature than those of MuGLasso. All in all, SMuGLasso is a promising tool for analyzing GWAS data and furthering our understanding of population-specific biological mechanisms. Author summaryGenome-Wide Association Studies (GWAS) scan thousands of genomes to identify loci associated with a complex trait. However, population stratification, which is the presence in the data of multiple subpopulations with differing allele frequencies, can lead to false associations or mask true population-specific associations. We recently proposed MuGLasso, a new computational method to address this issue. However, MuGLasso relied on an ad-hoc post-processing of the results to identify population-specific associations. Here, we present SMuGLasso, which directly identifies both global and population-specific associations. We evaluate both MuGLasso and SMuGLasso on several datasets, including both case-control (such as breast cancer vs. controls) and quantitative (for example, plant flowering time) traits, and show on simulations that SMuGLasso is better suited than MuGLasso for the identification of population-specific associations. In addition, SMuGLassos findings on real case studies are more consistant with the literature than that of MuGLasso, which is possibly due to false discoveries of MuGLasso. These results show that SMuGLasso could be applied to other complex traits to better elucidate the underlying biological mechanisms.

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Nouira, A., Azencott, C.-A.. 2024-12-20. Sparse Multitask group Lasso for Genome-Wide Association Studies. https://doi.org/10.1101/2024.12.20.629593

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