Fig. 2: Colocalization analysis reveals a shared causal variant reducing FADS1 gene expression in the frontal cortex and increasing napping liability, and a shared causal missense variant in HCRTR2 influencing daytime napping, chronotype, and ease of awakening.

A Regional association plots for daytime napping and FADS1 gene expression in the frontal cortex at rs174561 and variants within 400 kb on chromosome 11. The y-axis shows the −log₁₀ P value for each variant in the region, and the x-axis shows the genomic position. Each variant is represented by a filled circle, with the rs174561 variant colored purple, and nearby variants colored according to degree of linkage disequilibrium (r²) with rs174561. The lower panel shows genes located in the displayed region and the blue line corresponds to the recombination rate. B Forest plot of associations between the C allele of genetic variant rs174561 in FADS1 with daytime napping and gene expression of FADS1 in the frontal cortex. Units of daytime napping reflect an increase on the ordinal scale of the trait, and gene expression is in standard deviation units. P values are two-sided and were obtained using linear regression. Black box indicates the effect estimate and lines represent 95% confidence intervals. C Regional association plot for colocalized sleep phenotypes at rs2653349 and variants within 400 kb on chromosome 6. D Crystal structure of HCRTR2 (PDB ID 6TPJ) showing localization of rs2653349 that changes Isoleucine to Phenylalanine or to valine at the transmembrane domain of HCRTR2. Protein sequence was visualized using iCn3D (https://www.ncbi.nlm.nih.gov/Structure/icn3d/full.html). The variant rs2653349 was aligned with the sequence (arrows to Human Missense variant in Figure) and the previously published canine HCRTR2 mutations¹⁰⁵, which disrupt transmembrane and signaling domains or truncate the HCRTR2 protein are highlighted in cyan. E Forest plot of associations between the A allele of genetic variant rs2653349 in HCRTR2 and the colocalized sleep phenotypes. P values are two-sided and were obtained using linear regression. Black boxes show effect estimates, and surrounding lines display 95% confidence intervals.