HMGA2 regulates fear and growth: Canine GWAS and functional evidence.

Fear is an evolutionarily conserved survival mechanism. Fear behavior is strongly correlated with body size in dogs, the genetic basis of fear regulation independent of size-related traits remains unclear. Through cross-breed genome-wide association analysis, we identified association between HMGA2 gene and fear traits. Our functional validation revealed that viral overexpression of Hmga2 in the mouse basolateral amygdala attenuated fear memory formation independent of body weight, while Hmga2 knockout (KO) mice exhibited enhanced fear memory. Transcriptomic analyses linked Hmga2 to modulation of neurotransmitter activity, synaptic plasticity (including GABAergic signaling), and neurogenesis, with additional roles in early brain development revealed by embryonic KO studies. We also identified a mutation in an enhancer that can regulate HMGA2 expression in human HEK293T cell line. Our findings establish HMGA2 as a pleiotropic regulator of fear behavior decoupled from its effects on body size, resolving a long-standing confound in canine behavioral genetics.