Ament. The findings are consistent with a substantial literature showing that the effects of 5-HTTLPR on depression are moderated by stress and trauma (Caspi et al., 2003; Karg et al., 2011). Together, these findings suggest that 5-HTTLPR is associated with inhibited temperament and the impact of 5-HTTLPR on inhibited temperament is likely moderated by environmental factors, such as low social support or overprotective parenting. 3.2. Dopamine Dopamine Receptor Gene (DRD4)–Dopamine has a prominent role in reward processing and exploration and has been associated with novelty seeking traits in humans (Zald et al., 2008). Several early reports suggested that novelty-seeking was associated with variation in a polymorphism in the dopamine D4 receptor gene (DRD4); specifically, theAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptProg Neurobiol. Author manuscript; available in PMC 2016 April 01.Clauss et al.Pagepresence of a 7-allele repeat in exon 3 was associated with higher scores on a noveltyseeking trait (Ebstein et al., 1996). Based on these findings, it was expected that inhibited individuals would be less likely to have the 7-allele repeat. Several studies investigated this candidate gene in both shy children (Arbelle et al., 2003; Schmidt et al., 2002) and adolescents who were categorized as inhibited as children (P ez-Edgar et al., 2013) and no studies found evidence for an association. This lack of a relationship is consistent with two recent meta-analyses showing that the initial finding of the 7-allele repeat and novelty seeking did not withstand replication (Kluger et al., 2002; Munaf?et al., 2008b). However, the study by Perez-Edgar and colleagues also included brain imaging measures of reward processing. In that study, the 7-allele repeat moderated the relationship between brain activation and inhibited temperament. For adolescents with the 7 llele repeat, greater inhibition correlated with stronger caudate activation to medium amounts of monetary incentives. This study highlights the complexity of genetic effects on temperament and suggests that additional measures, such as brain markers, may be necessary to reveal the underlying influence of genetic variation. Dopamine Transporter Gene (DAT)–Because many genes are involved in the effective signaling of any given neurotransmitter, it is possible that variations in other parts of the dopamine system are involved in temperament, despite the lack of findings for DRD4. Davies and colleagues (2013) were the first to examine the dopamine transporter gene (DAT) in inhibited temperament. Inhibited children had a DAT Pyrvinium pamoate site composite score (formed from alleles from three different DAT polymorphisms) that reflected less efficient transporter activity. 3.3. GABA Glutamic acid decarboxylase gene (GAD)–GAD is the rate-limiting enzyme for converting glutamate to gamma-aminobutyric acid (GABA), the primary inhibitory BAY 11-7083 side effects neurotransmitter in the brain. GABA is thought to play a role in anxiety, given the potent effects of GABA agonists on reducing anxiety. The Smoller lab investigated a polymorphism in intron 3 of the GAD2 gene (also known as GAD65; Smoller et al., 2001b). Children with a 168-bp allele in GAD65 were significantly less likely to have an inhibited temperament. A subsequent study in adults, found several single nucleotide polymorphisms (SNPs) that were associated with inhibited temperament in healthy controls and in patients with an anxiety disorder (Unschuld et a.Ament. The findings are consistent with a substantial literature showing that the effects of 5-HTTLPR on depression are moderated by stress and trauma (Caspi et al., 2003; Karg et al., 2011). Together, these findings suggest that 5-HTTLPR is associated with inhibited temperament and the impact of 5-HTTLPR on inhibited temperament is likely moderated by environmental factors, such as low social support or overprotective parenting. 3.2. Dopamine Dopamine Receptor Gene (DRD4)–Dopamine has a prominent role in reward processing and exploration and has been associated with novelty seeking traits in humans (Zald et al., 2008). Several early reports suggested that novelty-seeking was associated with variation in a polymorphism in the dopamine D4 receptor gene (DRD4); specifically, theAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptProg Neurobiol. Author manuscript; available in PMC 2016 April 01.Clauss et al.Pagepresence of a 7-allele repeat in exon 3 was associated with higher scores on a noveltyseeking trait (Ebstein et al., 1996). Based on these findings, it was expected that inhibited individuals would be less likely to have the 7-allele repeat. Several studies investigated this candidate gene in both shy children (Arbelle et al., 2003; Schmidt et al., 2002) and adolescents who were categorized as inhibited as children (P ez-Edgar et al., 2013) and no studies found evidence for an association. This lack of a relationship is consistent with two recent meta-analyses showing that the initial finding of the 7-allele repeat and novelty seeking did not withstand replication (Kluger et al., 2002; Munaf?et al., 2008b). However, the study by Perez-Edgar and colleagues also included brain imaging measures of reward processing. In that study, the 7-allele repeat moderated the relationship between brain activation and inhibited temperament. For adolescents with the 7 llele repeat, greater inhibition correlated with stronger caudate activation to medium amounts of monetary incentives. This study highlights the complexity of genetic effects on temperament and suggests that additional measures, such as brain markers, may be necessary to reveal the underlying influence of genetic variation. Dopamine Transporter Gene (DAT)–Because many genes are involved in the effective signaling of any given neurotransmitter, it is possible that variations in other parts of the dopamine system are involved in temperament, despite the lack of findings for DRD4. Davies and colleagues (2013) were the first to examine the dopamine transporter gene (DAT) in inhibited temperament. Inhibited children had a DAT composite score (formed from alleles from three different DAT polymorphisms) that reflected less efficient transporter activity. 3.3. GABA Glutamic acid decarboxylase gene (GAD)–GAD is the rate-limiting enzyme for converting glutamate to gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. GABA is thought to play a role in anxiety, given the potent effects of GABA agonists on reducing anxiety. The Smoller lab investigated a polymorphism in intron 3 of the GAD2 gene (also known as GAD65; Smoller et al., 2001b). Children with a 168-bp allele in GAD65 were significantly less likely to have an inhibited temperament. A subsequent study in adults, found several single nucleotide polymorphisms (SNPs) that were associated with inhibited temperament in healthy controls and in patients with an anxiety disorder (Unschuld et a.