2.4  Enzyme system
Molecular studies have provided compelling evidence for the association of ADHD with genes that encode enzymes involved in the metabolism of catecholamine and serotonin.

2.4.1  Catechol-O-methyltransferase (COMT)
COMT catalyzes a major step in the degradation of dopamine, norepinephrine, and epinephrine; about 60% of the DA degradation in the PFC is performed by COMT.[68] The most popular marker for the COMT gene is the Val/Met functional SNP (rs4680). In spite of the negative findings from a Hong Kong meta-analysis[69] and a recent systematic review, [70] this marker is currently the most actively researched SNP listed on the ADHD gene database[71] (http://adhd.psych.ac.cn/). In China, Qian and colleagues[72],[73] did notfind an association between COMT and ADHD but did find some sexspecific associations: compared to controls, the Met allele was preferentially transmitted to boys with ADHD and the Val allele was preferentially transmitted to girls with ADHD; they also found that male ADHD comorbid with ODD was associated with homozygosity of the high-activity Val allele, while the ADHD-I was associated with the low-activity Met allele. Other studies in Chinese samples also failed to identify a significant association between ADHD and COMT.[74],[75],[76],[77] Zhang and colleagues[78] reported that the rs6267 of COMTwas not associated with the susceptibility to ADHD but it was associated to some of the clinical characteristics of ADHD.

2.4.2  Tryptophan hydroxylase (TPH and TPH-2)
TPH is the rate-limiting enzyme in the synthesis of serotonin, and TPH polymorphisms have been associated with aggression and impulsivity.[79] Two family-based studies in Chinese samples have examined the TPH gene in ADHD. One study of 69 Han Chinese trios found no association between ADHD and a SNP (A218C) in intron 7.[80] Another study examined two SNPs among more than 350 Han Chinese youth with ADHD (including those with and without learning disability) and their families; neither SNP showed biased transmission individually, but a haplotype composed of the A-218 and G-6526 alleles appeared to be undertransmitted.[81],[82] These findings have been replicated in independent samples.[44],[83],[84],[85] Another study found two tagging SNPs that were associated with comorbid ADHD and tic disorder (TD) in a Chinese Han sample.[86] In a Taiwanese sample, Hsu[66] failed to replicate the result of a preferential transmission for two polymorphisms in TPH2’s regulatory region initially reported in German families with ADHD.

2.4.3  Dopamine beta-hydroxylase (DBH)
DBH catalyzes the primary enzyme responsible for conversion of DA to NE, and is found in sympathetic terminals, adrenal glands, and in the prefrontal cortex.[87] Many studies have focused on a TaqI restriction polymorphism (rs2519152) of DBH, and two metaanalysis reported a significant association between rs2519152 and ADHD.[10],[88] Guo and colleagues also found that the A2 allele was a risk factor for ADHD.[89] A -1021C>T polymorphism in the 5’ flanking region of DBH has been shown to account for as much as 50% of plasma DBH activity and to be associated with ADHD in the Han Chinese; Zhang and colleagues[36] found the this polymorphism was associated with the ADHD-C subtype in male trios.[90] Guan identified four statistically significant SNPs of DBH in ADHD-I and one statistically significant SNP (rs1076150) in ADHD-C.[36] Using a much larger sample, Ji also found an association between three SNPs (including rs1076150) and ADHD-HI.[91]

2.4.4  Monoamine oxidase A (MAOA)
MAOA also plays an important role in the metabolism of monoamine neurotransmitters including 5-HT, NE, and DA. A linkage study showed that ADHD might be in linkage with the MAOA gene.[92],[93],[94] A small (n=86) study identified significant associations between two SNP MAOA polymorphisms and ADHD remission.[95] Guan and colleagues observed nominal associations with all of the 12 SNPs of MAOA tested, among which 9 consecutive SNPs approached statistical significance with (p<0.02).[36] The identified locations were identical to those reported in an IMAGE (International Multisite ADHD Genetics) study of 776 Caucasian families.[96] Liu and colleagues assessed five SNPs in 1253 ADHD trios, and found that rs5905859, rs3027400, and rs1137070 were related to ADHD-HI trios, providing support for the association between MAOA and impulsivity.[97] Using a Taiwanese sample, Xu [98] replicated previously published findings from a Caucasian sample that the G-allele of 941G/T in MAOA was associated with ADHD.

2.4.5  Monoamine oxidase B (MAOB)
MAOB preferentially metabolizes dopamine, while MAOA preferentially metabolizes serotonin and norepinephrine. Li and colleagues[99] screened exons and the 5’ and 3’ flanking regions of the MAOB gene and found two novel polymorphisms (2276C>T and 2327C>T) that were closely associated with ADHD. However, Jiang conducted a transmission disequilibrium test (TDT) to assess the linkage between a VNTR polymorphism at the MAOA(CA) (n) or MAOB(GT) (n) locus, and found no significant linkage between ADHD and MAOB.[92]

2.4.6  Dopamine decarboxylase (DDC)
Dopa decarboxylase catalyses the formation of functional dopamine through decarboxylation of a precursor tyrosine derivative and it participates in the synthesis of trace amine compounds that are believed to act as modulators of central neurotransmission.[100] In a high-density screen, the rs6592952 of DDC was associated with ADHD-I (at trend level only).[36]