Variability in working memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• The ZNF804A gene is a key susceptibility gene for psychosis.
• Understanding genetic contributions to neuropsychological function in psychosis is crucial.

Purpose of the Study:

• To assess the association between ZNF804A single nucleotide polymorphisms (SNPs) and polygenic scores with cognitive measures in psychosis cases.
• To determine if epistasis within the ZNF804A pathway explains additional cognitive variation beyond polygenic scores.

Main Methods:

• Neuropsychological assessments were administered to 424 psychosis patients.
• Polygenic scores were calculated using GWAS data for ZNF804A risk variants.
• Epistatic effects were analyzed using linear regression models with 2-SNP interactions in training and independent test sets.

Main Results:

• Higher ZNF804A polygenic scores correlated with poorer performance in IQ, memory, and social cognition, explaining 1-3% of variation.
• Epistasis, using 2-SNP interactions, increased the explained variation for spatial working memory from 1.2% to 4.8% in psychosis cases.

Conclusions:

• The ZNF804A pathway plays a significant role in cognitive functions (IQ, memory, social cognition) in individuals with psychosis.
• Epistasis contributes to explaining cognitive variation in psychosis, offering insights beyond polygenic scores.