text: Contributions of dopamine related genes and environmental factors to highly sensitive personality a multi step neuronal system level approach Traditional behavioral genetic studies e g twin adoption studies have shown that human personality has moderate to high heritability but recent molecular behavioral genetic studies have failed to identify quantitative trait loci QTL with consistent effects The current study adopted a multi step approach ANOVA followed by multiple regression and permutation to assess the cumulative effects of multiple QTLs Using a system level dopamine system genetic approach we investigated a personality trait deeply rooted in the nervous system the Highly Sensitive Personality HSP 480 healthy Chinese college students were given the HSP scale and genotyped for 98 representative polymorphisms in all major dopamine neurotransmitter genes In addition two environment factors stressful life events and parental warmth that have been implicated for their contributions to personality development were included to investigate their relative contributions as compared to genetic factors In Step 1 using ANOVA we identified 10 polymorphisms that made statistically significant contributions to HSP In Step 2 these polymorphisms main effects and interactions were assessed using multiple regression This model accounted for 15 of the variance of HSP p 0 001 Recent stressful life events accounted for an additional 2 of the variance Finally permutation analyses ascertained the probability of obtaining these findings by chance to be very low p ranging from 0 001 to 0 006 Dividing these loci by the subsystems of dopamine synthesis degradation transport receptor and modulation we found that the modulation and receptor subsystems made the most significant contribution to HSP The results of this study demonstrate the utility of a multi step neuronal system level approach in assessing genetic contributions to individual differences in human behavior It can potentially bridge the gap between the high heritability estimates based on traditional behavioral genetics and the lack of reproducible genetic effects observed currently from molecular genetic studies 