Selecting Genetic Variants and Interactions Associated with Amyotrophic Lateral Sclerosis: A Group LASSO Approach

Area of Science:

• Neuroscience
• Genetics
• Biostatistics

Background:

• Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease influenced by genetic, environmental, and lifestyle factors.
• Traditional methods for identifying genetic associations with ALS often test single-nucleotide polymorphisms (SNPs) individually, limiting the detection of gene-gene interactions.
• A novel approach is needed to analyze complex genetic patterns, including interactions, in ALS.

Purpose of the Study:

• To develop and apply a two-step statistical procedure for identifying SNPs and pairwise interactions associated with ALS.
• To investigate the genetic underpinnings of ALS beyond individual SNP associations.

Main Methods:

• A two-step group LASSO methodology was employed on SNP data from 276 ALS patients and 268 controls.
• The first step screened for important SNPs using group LASSO on bootstrap samples and random predictor subsets.
• The second step evaluated pairwise interactions using a hierarchical group LASSO model, followed by in silico analysis.

Main Results:

• Seven specific SNPs (rs16984239, rs10459680, rs1436918, rs1037666, rs4552942, rs10773543, and rs2241493) were identified as potentially associated with ALS.
• Two significant pairwise SNP interactions (rs16984239:rs2118657 and rs16984239:rs3172469) were detected, suggesting complex genetic contributions.
• The identified genetic factors are potentially involved in nervous system conservation and function.

Conclusions:

• The study successfully identified novel SNPs and pairwise interactions implicated in ALS pathogenesis.
• These findings enhance the understanding of ALS genetic architecture, moving beyond single-locus associations.
• The results provide a foundation for improved diagnostic approaches and the development of targeted therapeutic strategies for ALS.