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  • Given the fact that most

    2019-11-12

    Given the fact that most criticism on genetic association studies is the lack of replicability (Hirschhorn, Lohmueller, Byrne, & Hirschhorn, 2002), the aim of the present study is to investigate the influence of the DBH polymorphism rs1611115 (C-970T) on RD in two independent samples of healthy participants.
    Methods
    Results
    Discussion The biosocial personality chlortetracycline of Cloninger, 1986, Cloninger, 1987a, Cloninger, 1987b has been proven to be of importance in the prediction of diverse psychopathologies (Mulder, Joyce, Sullivan, Bulik, & Carter, 1999) and therapy outcomes (Cloninger et al., 2006, Terock et al., 2015), and has yielded evidence that behavior in the normal range and psychopathologies describe both ends of the same biological continuum (e. g. Montag et al., 2012). For example, the personality dimensions anxiety, neuroticism, and harm avoidance have all been related to the serotonergic system (e. g. Lesch et al., 1996, Reuter et al., 2007) and drugs influencing 5-HT neurotransmission are common in the therapy of anxiety disorders (Hidalgo, Tupler, & Davidson, 2007). Personality dimensions related to negative emotionality were much more frequently investigated in the context of psychiatric disorders than those related to positive emotionality. With respect to RD there are plenty of studies reporting an association to drug addiction (e. g. Milivojevic et al., 2012, Zoccali et al., 2007) although especially novelty seeking (NS) seems to be of great importance in this domain as well (e. g. Lukasiewicz et al., 2008). RD reflects a tendency to sustain rewarding behaviors and to prefer behaviors previously associated with social reward. Whereas NS represents the drug seeking behavior in addiction, RD is more related to social reward and the maintenance of well-established behaviors. For example, opiate addicts tend to have low RD scores (Milivojevic et al., 2012). In the context of alcoholism, Cloninger (1987b) proposes a classification that distinguishes between Type I and Type II alcoholics. Type I alcoholism (the anxious type) is characterized by high HA, high RD and low NS whereas Type II alcoholics (the impulsive type) display the diametrically opposite personality configuration. Although there is plenty of evidence in the literature that supports Cloninger\'s biosocial personality theory and makes clearly defined assumptions on the underlying neurotransmitter systems, there are also many negative findings, especially concerning genetic association studies (e.g. Munafò et al., 2009). Moreover, the psychometric properties of the TCI have been criticized (e.g. Farmer & Goldberg, 2008). It becomes more and more apparent that there is an ultimate need for replication studies that can be used for meta-analyses (Hirschhorn et al., 2002, Munafo and Flint, 2004). This in mind the aim of the present study was to investigate the chlortetracycline theory driven hypothesis that genetic variation on the DBH gene is associated with individual differences in RD in two independent samples of healthy participants. Cloninger postulates low noradrenaline levels in subjects scoring high on RD (Cloninger, 1987b), the functional SNP rs1611115 (C-970T) on the DBH gene is related to alterations in DBH enzymatic activity (Punchaichira et al., 2016, Zabetian et al., 2001) and to drug addiction (Kosten et al., 2013, Xie et al., 2013). Given that rs1611115 (C-970T) and RD are both associated to addiction we hypothesized an effect of the candidate SNP on RD. Results show a significant association between rs1611115 (C-970T) and RD. The effect is stronger in the population based Sample2 in comparison to the data derived from Sample1 which is dominated by younger subjects. However, irrespective of these marked age differences between both samples the effect could be replicated. Results from both samples show that carriers of the TT genotype have significantly lower RD scores than carriers of at least one C allele (genotypes CC and CT). Zabetian et al. (2001) reported that rs1611115 could explain up to 50% of the variance in DBH activity. Two independent studies demonstrated an allelic load effect of rs1611115 on DBH activity, with highest enzymatic activity in carriers of the CC genotype, intermediate activity in heterozygous CT carriers and lowest activity in carriers homozygous for the T allele (Punchaichira et al., 2016, Zabetian et al., 2001). This finding suggests that CC carriers associated with high RD scores have high noradrenaline levels, because DBH metabolizes dopamine to noradrenaline. Therefore, the present study only supports Cloninger\'s general hypothesis that RD is related to noradrenaline but the directionality of the RD – noradrenaline association that high RD (C allele carriers) is related to low noradrenaline levels was not corroborated. A possible explanation is that DBH activity is likely to be dependent on the availability of its substrate, i.e. dopamine. Unfortunately, neither the existing functionality studies nor our study controlled for the availability of dopamine.