Beyond Single Variants: A Pathway-Based Approach to Explore the Genetic Basis of Memory

Area of Science:

• Neuroscience
• Genetics
• Bioinformatics

Background:

• Memory is vital for daily function but its genetic basis is complex.
• Identifying specific genetic variants for memory is challenging due to the polygenic nature of the trait.
• Conventional genome-wide association studies (GWAS) often lack power for complex traits, especially with smaller, deeply phenotyped cohorts.

Purpose of the Study:

• To investigate the genetic architecture of memory performance using a novel approach.
• To identify candidate genes and biological pathways associated with different types of memory.
• To explore shared biological mechanisms underlying memory across distinct memory tests.

Main Methods:

• Conducted three independent genome-wide association studies (GWAS) on verbal episodic memory, visual episodic memory, and verbal working memory within the Human Connectome Project.
• Employed a less stringent p-value threshold combined with variant mapping and functional annotation using tools like FUMA, Cytoscape, KEGG, Reactome, and WikiPathways.
• Analyzed results at the pathway level to identify overlapping biological signals across memory tests and with previous research.

Main Results:

• Pathway-level analysis revealed substantial overlap across the three memory tests and with prior findings, suggesting shared biological mechanisms.
• Identified several genes and pathways previously linked to memory disorders, cognition, neurodevelopment, and neurological dysfunction.
• No significant overlap was observed at the single variant or gene level, highlighting the utility of pathway-based analysis.

Conclusions:

• The proposed approach, combining relaxed significance thresholds with pathway analysis, effectively identifies shared biological mechanisms for complex traits like memory.
• The identified pathways reflect common biological underpinnings of memory performance.
• This openly accessible pipeline offers a valuable tool for exploring the genetic basis of other complex polygenic traits.