Genome-wide association study identifies novel variants in olfactory, vitamin A, vitamin B, and cadherin pathways associated with learning and memory

Learning and memory, as fundamental components of human cognition, are heritable traits that are highly variable between individuals and within populations. Investigation into the genetic basis of cognition is a prominent area of research, with genetic associations being previously reported for a wide range of cognitive phenotypes. Here we utilise a genome-wide association study (GWAS) approach to evaluate the contribution of genetic variation to learning and memory phenotypes in a comprehensively phenotyped, well-characterised, healthy, and unrelated cohort of individuals (n = 613). Cognitive phenotypes were assessed using nine comprehensive test batteries consisting of twenty-one cognitive performance assessments including IQ, five measures for visual and verbal learning, and fifteen measures for semantic, working, episodic and prospective memory. Principal component analysis was utilised to amalgamate correlated test scores into additional new cognitive phenotypes. Our study identified genome wide significant associations for 13 loci across all phenotypes. A novel association was identified between the rs817826 SNP at 9q31.2 and verbal learning discrimination (p = 2.71 × 10^{- 9}). GWAS of cognitive PCs identified three variants in the vicinity of thiamine (Vitamin B₁) transporter gene SLC19A3 (most significant SNP rs12105620, p = 2.17 × 10^{- 9}), a 3' UTR variant in PPARD (rs9658167, p = 1.47 × 10^{- 8}), and an intronic variant in RBFOX1 (rs17138790, p = 4.24 × 10^{- 8}) associated with the cognitive PC related to visual and verbal learning. The cognitive PC relating to prospective and retrospective memory revealed a locus containing a synonymous variant in NXPE3 (rs2305990, p = 6.56 × 10^{- 9}) and intronic variants in RD3 (rs17189035, p = 2.71 × 10^{- 8}) and WLS/GNG12-AS1 (rs17130484, p = 4.13 × 10^{- 8}). Pathway analysis identified olfactory, vitamin A, and cadherin pathways as being significantly overrepresented across multiple cognitive domains. The novel associations identified provide candidates for further investigation and necessitate replication in similarly characterised independent cohorts.