Genome-wide association study in 404,302 individuals identifies 7 significant loci for reaction time variability

Abstract

Reaction time variability (RTV), reflecting fluctuations in response time on cognitive tasks, has been proposed as an endophenotype for many neuropsychiatric disorders. There have been no large-scale genome-wide association studies (GWAS) of RTV and little is known about its genetic underpinnings. Here, we used data from the UK Biobank to conduct a GWAS of RTV in participants of white British ancestry (n = 404,302) as well as a trans-ancestry GWAS meta-analysis (n = 44,873) to assess replication. We found 161 genome-wide significant single nucleotide polymorphisms (SNPs) distributed across 7 genomic loci in our discovery GWAS. Functional annotation of the variants implicated genes involved in synaptic function and neural development. The SNP-based heritability (h²_SNP) estimate for RTV was 3%. We investigated genetic correlations between RTV and selected neuropsychological traits using linkage disequilibrium score regression, and found significant correlations with several traits, including a positive correlation with mean reaction time and schizophrenia. Despite the high genetic correlation between RTV and mean reaction time, we demonstrate distinctions in the genetic underpinnings of these traits. Lastly, we assessed the predictive ability of a polygenic score (PGS) for RTV, calculated using PRSice and PRS-CS, and found that the RTV-PGS significantly predicted RTV in independent cohorts, but that the generalisability to other ancestry groups was poor. These results identify genetic underpinnings of RTV, and support the use of RTV as an endophenotype for neurological and psychiatric disorders.

Fig. 1. Manhattan plot of discovery GWAS for RTV in the UK Biobank.

Manhattan plot for the observed -log10 p-values for an association with RTV in the discovery GWAS. The dotted line indicates a genome-wide significance threshold of 5 × 10^-8. The lead SNPs from the GWAS are outlined in black and the candidate SNPs are shown in bold.

Fig. 2. Regional association plots for three genome-wide significant loci in the discovery RTV-GWAS.

Regional plots for rs17167210 (A), rs35859241 (B) and rs1863115 (C). The dotted line denotes a genome-wide significance threshold of 5 × 10^–8. SNPs in the genomic risk loci are colour-coded as a function of their linkage disequilibrium r² to the lead SNP in the region.

Fig. 3. Genetic correlations and phenotypic associations between RTV and 19 selected traits.

A Genetic correlations were calculated with LD score regression using SNP summary statistics from discovery RTV-GWAS and publicly available summary statistics for other traits (Supplementary Table 1). B Associations between RTV and the same 19 traits were calculated using phenotypic data from the UK Biobank (Supplementary Methods). Point estimates for correlations and beta coefficients are shown with 95% confidence intervals. Dark blue dots indicate nominally significant p-values and light blue dots indicate significant p-values after Bonferroni correction.

Fig. 4. Bar chart showing the predictive accuracy of the RTV-PGS in three independent cohorts.

Prediction of RTV by polygenic score (PGS) in the African, non-British European, and South Asian ancestry groups from the UK Biobank. The predictive accuracy of the PGS (R²) was assessed in each cohort for a PGS calculated using two methodologies, PRSice and PRS-CS. PRSice PGS were calculated using all single nucleotide polymorphisms surviving LD pruning from the discovery GWAS (p-value threshold of 1). *p < 0.05, ***p < 2.63 × 10^-3.