Table 1. Genetic Variants Included in the Composite Score and their Effects on Dopaminergic Function.

Gene variant	Genotype	Effects on striatal dopaminergic function
DRD2 rs2283265	G/T	Intronic SNP in DRD2 moderates alternative splicing of exon 6, influencing the proportion of dopamine D2 long (D2L) and D2 short (D2S) receptor expression.
D2S receptors are presynaptic, located on mesencephalic and corticostriatal projection axons (Khan et al, 1998). D2L receptors are predominantly located postsynaptically on striatal GABAergic neurons (Khan et al, 1998; Usiello et al, 2000). Presence of the T-allele favors D2L over D2S expression, and this potentiates corticostriatal glutamate release (De Mei et al, 2009) leading to the activation of striatal GABAergic medium spiny neurons. The result is the inhibition of striatal DA release through the inhibition of midbrain dopamine neurons (Centonze et al, 2003; Cepeda et al, 2001). TT and GT genotypes, score=0; GG homozygotes, score=1
DRD3 rs6280	Ser9Gly	Nonsynonymous SNP in DRD3 results in serine (ser) to glycine (gly) substitution and enhanced dopamine D3 receptor affinity.
D3 receptors, expressed on mesolimbic dopaminergic terminals, function in downregulating DA transmission. Compared with the ser allele, the gly allele is associated with greater striatal DA release, presumably through the effects on prostaglandin E2 production. Activation of EP1 receptors on GABAergic efferents by prostaglandin E2 potentiates inhibitory synaptic input to midbrain, resulting in the inhibition of striatal DA release. The gly variant has been associated with less prostaglandin E2 production (Hellstrand et al, 2004) and greater reward-related DA release than the ser variant (Savitz et al, 2013). ser/ser genotype, score=0; ser/gly and gly/gly, score=1
DRD4 48-bp VNTR	2–11 repeat	VNTR repeat number, encoding a 16-amino acid segment in the third cytoplasmic loop of the dopamine D4 receptor, affects ability of the D4 dopamine receptor to heteromerize with D2S receptors.
D4 receptors on corticostriatal terminals contribute to regulating glutamate release and thereby striatal DA release (Lauzon and Laviolette, 2010). DRD4 contains a polymorphic repeat in the third exon, most frequently consisting of 2, 4, or 7 repeats (D4.2, D4.4, and D4.7; Van Tol et al, 1992). Receptors containing 2 or 4 repeats form heteromers with D2-S isoforms; co-activation of D2S and DRD4.2 or DRD4.4 isoforms inhibits glutamate release from corticostriatal afferents, while the DRD4.7 variant does not dimerize with D2S receptors, and its expression may enhance glutamatergic neurotransmission and attenuate striatal DA release (Gonzalez et al, 2012). 7-repeat carriers (one or two 7-alleles), score=0; all other variants, score=1
DAT 1 SLC6A3	2–11 repeat	VNTR repeat number in the 3′UTR of DAT1 affects transporter expression.
A meta-analysis of twelve studies, including 511 subjects, indicated that presence of the 9R allele results in greater DAT expression (Faraone et al, 2013). 9/9 and 9/10 genotypes, score=0; 10/10 homozygotes, score=1
COMT rs4680	Val158Met	Nonsynonymous SNP in COMT results in valine (val) to methionine (met) substitution, with reduced thermostability of the enzyme.
Compared with the met allele, the val allele has been associated with greater tyrosine hydroxylase gene expression in the substantia nigra (Akil et al, 2003) and greater dopamine synthesis rate, inferred from [F-18]fluorodopa uptake (Meyer-Lindenberg et al, 2005). The val allele has also been related to greater disinhibition of mesencephalic DA activity than the met allele, through lower prefrontal cortical DA signaling and greater intrasynaptic levels of phasic striatal DA release (Bilder et al, 2004). Scores of 0, 0.5, and 1 were assigned to met/met, val/met, and val/val, respectively.