Neurobehavioural genes exert indirect genetic effects on blood lipid profiles through behavioural traits.

Growing evidence reveals that indirect genetic effects (IGEs) contribute substantially to human complex traits. However, the genomic architecture and underlying mechanistic pathways of IGEs remain poorly understood. In this study, we employed a two-stage family study design to investigate IGEs and direct genetic effects (DGEs) on blood lipid profiles in the Fangshan Family-based Ischemic Stroke Study in China (FISSIC) cohort. We identified 16 IGE loci resulting in 14 candidate IGE genes, and 20 DGE loci resulting in 22 DGE genes, by an integrative functional mapping approach. The identified IGE genes were predominantly related to behavioral and neuropsychiatric phenotypes, while DGE genes were primarily involved in lipid metabolic pathways. To examine whether IGE genes are associated with lipids through behavioral factors in IGEs, we compared IGE estimates before and after adjusting for behavioral covariates, including healthy food score, drinking status, educational attainment, obesity, physical activity, sleep duration, and smoking status. Adjustment for behavioral factors attenuated the IGE associations, and mediation analysis further indicated that healthy food score partially mediated the association between IGE-GRS and HDL-C (mediation proportion: 17.9%), whereas the proportion mediated by behavioral mediators in the DGE pathway was negligible. Our results suggest that lifestyle behaviors may substantially mediate IGE effects, indicating that they could serve as modifiable factors to mitigate IGE-related genetic susceptibility for lipid or other complex traits.