AbstractThe serotonin transporter (SLC6A4), 5-HT_2A (HTR2A) and 5-HT_2B (HTR2B) recepter genes, express proteins that are important regulators of serotonin reuptake and signaling, and thereby may contribute to the pathogenesis of aggressive criminal behavior. 370 sentenced murderers in Pakistani prisons and 359 men without any history of violence or criminal delinquency were genotyped for six candidate polymorphisms in SLC6A4, HTR2A and HTR2B genes. An association of higher expressing L/L and L_A/L_A variants of the 5-HTTLPR polymorphism was observed with homicidal behavior (bi-allelic: OR = 1.29, p = 0.016, tri-allelic: OR = 1.32, p = 0.015) and in the murderer group only with response to verbal abuse (OR = 2.11, p = 0.015), but not with other measures of self-reported aggression. L/L and L_A/L_A genotypes of the 5-HTTLPR polymorphism were associated with higher aggression scores on STAX1 scale of aggression compared to lower expressing genotypes (S/S, S/L_G, L_G/L_G) in prison inmates. No associations were apparent for other serotonergic gene polymorphisms analyzed. Using the Braineac and GTEx databases, we demonstrated significant eQTL based functional effects for rs25531 in HTTLPR and other serotonergic polymorphisms analyzed in different brain regions and peripheral tissues. In conclusion, these findings implicate SLC6A4* HTTLPR as a major genetic determinant associated with criminal aggression. Future studies are needed to replicate this finding and establish the biologic intermediate phenotypes mediating this relationship.