American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:430–433 (2007)

Monoamine Oxidase A Gene PolymorphismPredicts Adolescent Outcome of Attention-Deficit/Hyperactivity DisorderJun Li,1 Chuanyuan Kang,1 Haobo Zhang,1 Yufeng Wang,1* Rulun Zhou,1 Bing Wang,1

Lili Guan,1 Li Yang,1 and Stephen V. Faraone2

1Institute of Mental Health, Peking University (Peking University sixth hospital), China2Medical Genetics Research Program and Department of Psychiatry and Behavioral Sciences,SUNY Upstate Medical University, Syracuse, New York

ADHD is generally deemed to be a highly heritabledisorder with mean heritability of 0.75. Theenzyme monoamine oxidase (MAO), which hasboth A and B types, has long been considered acandidate pathological substrate for ADHD, andmore recently, the genes for both MAO enzymeshave been examined as mediators of the illness.Previous studies indicated that 30–50% ofchildren with ADHD will experience symptomsthat persist into adolescence and will havemore significant impairment in social and neu-ropsychological functioning compared to thosewhose symptoms have remitted. Genes may alsoinfluence these characteristics of the disorder,and in this context MAO genes may also becandidates for moderating the presentation ofADHD. The current study examined the associa-tion between adolescent outcome of ADHD andMAO gene polymorphisms, including the 941T>Gpolymorphism in exon 8 (rs1799835) and 1460C>Tpolymorphism in exon 14 (rs1137070) of the MAOAgene, and the A>G polymorphism in intron13(rs1799836), C>T polymorphism in the 3’UTR(rs1040399), and 2327T>C polymorphism inexon15 of the MAOB gene. Significant associationswere observed between the MAOA gene poly-morphisms and ADHD remission. Due to the smallsample size and the possibility of phenotypic andetiologic heterogeneity of ADHD outcomes acrossethnic or geographic groups, these results must bereplicated before they can be generalized to otherpopulations. � 2007 Wiley-Liss, Inc.

KEY WORDS: serotonin; dopamine; MAO; atten-tion-deficit/hyperactivity disorder(ADHD); outcome

Please cite this article as follows: Li J, Kang C, Zhang H,Wang Y, Zhou R, Wang B, Guan L, Yang L, Faraone SV.2007. Monoamine Oxidase A Gene PolymorphismPredicts Adolescent Outcome of Attention-Deficit/Hyperactivity Disorder. Am J Med Genet Part B 144B:430–433.

INTRODUCTION

ADHD is a common disorder with a prevalence of about8–12% worldwide [Faraone et al., 2003]. Both the DSM-IV andICD-10 systems include 18 symptoms as diagnostic criteria forthe disorder. The disorder usually emerges prior to 7 years ofage, and persists into adolescence in about 30–50% of cases[Gittelman et al., 1985; Lambert et al., 1987; Faraone et al.,2006]. Besides the continuation of symptoms, ADHD persist-ing into adolescence is also associated with impaired schoolperformance, peer relationships, parent–child relationships,behavior, and emotion [Barkley et al., 1990, 1991; Biedermanet al., 1996; Faraone, 2005].

Adolescence is an important period of divergence in thecourse of ADHD. Studies have indicated that symptoms ofADHD may decrease or even disappear after adolescence[Biederman et al., 2000]. In addition, subjects whose ADHDsymptoms persisted beyond adolescence differed from thosewhose ADHD symptoms remitted on cognitive and socialfunctioning and so on [Biederman et al., 1996]. Several twinstudies have indicated a strong genetic basis for the persis-tence/remission of ADHD symptoms from 8 to 14 years of age[Larsson et al., 2004; Kuntsi et al., 2005] and Faraone et al.[2000]; Faraone [2004a,b] suggested that persistent ADHDmay be a highly familial form of the disorder. Biederman et al.[1996] reported that one of the main predictors of adolescentoutcome of ADHD was familiality, with persistent ADHDshowing a greater degree of familiality than remitted ADHD,indicating that persistent ADHD may have a stronger geneticfoundation compared with remitted ADHD.

ADHD is generally accepted as a genetically influenceddisorder with mean heritability of 0.75 [Faraone et al., 2005].Molecular genetic studies have identified those coding forneurotransmitter receptors and enzymes, especially those inthe dopamine, serotonin, and norepinephrine systems as thestrongest candidate genes [Faraone et al., 2001; Hawi et al.,2002; Bobb et al., 2005]. Monoamine oxidase (MAO) is one ofthe main metabolic enzymes for the degradation of the abovethree transmitters. Although both types of MAO (MAOA andMAOB) have similar structure [Bach et al., 1988; Hsu et al.,1988] and can degrade all three neurotransmitters, thepreferential substrate for MAOA is serotonin and norepi-nephrine, and the preferential substrate for MAOB isdopamine.

Evidence from pharmacologic studies [Volkow et al., 2002]and neuroimaging studies [Faraone, 2004a] suggest that

Jun Li and Chuanyuan Kang contributed equally to this work.

Grant sponsor: Ministry of Science and Technology, China;Grant number: 2004BA720A20; Grant sponsor: Project of Scienceand Technology, Beijing; Grant number: Y0204003040831; Grantsponsor: Key Project for Clinical Faculty Foundation, Ministry ofHealth, China; Grant number: 2004-468.

*Correspondence to: Dr. Yufeng Wang, Institute of MentalHealth, Peking University (Peking University sixth hospital),Beijing 100083, People’s Republic of China.E-mail: wangyf@bjmu.edu.cn

Received 8 May 2006; Accepted 18 July 2006

DOI 10.1002/ajmg.b.30421

� 2007 Wiley-Liss, Inc.

dopamine is the most important neurotransmitter in theetiology of ADHD. As such, dopamine system genes are usuallythe main candidates for molecular genetic studies of bothADHD and its associated endophenotypes. Recently, Schulzet al. [2005] reported a functional magnetic resonance imagingstudy in which they compared normal adolescent controls aged15–19 with same-aged subjects with persistent or remittedADHD. The results of this study suggested that the develop-mental changes in ADHD symptoms were associated withfunctional changes in activity of the ventrolateral prefrontalcortex, where dopamine is the main neurotransmitter.

The serotonin neurotransmitter system has developmentalcharacteristics that may underlie the age-dependent emer-gence and presentation of ADHD as well [Pick et al., 1999]. Forexample, the longitudinal study from Pick et al. [1999] revealedthat central 5-HT function of ADHD patients decreased from8 to 11 years old. During this period, ADHD symptoms(especially hyperactivity-impulsivity) declined with increas-ing age [Hart et al., 1995; Biederman et al., 2000]. The curverelating serotonin levels and age is thus similar to that relatingADHD symptoms and age [Biegon and Greuner, 1992].

Based on the collective evidence implicating central mono-amine systems in the etiology and course of ADHD, genes inthese systems continue to gather attention as prime candidatesfor molecular genetic analysis. The current study thereforeexamined the association between adolescent outcome ofADHD and five polymorphisms of MAO genes, including twopolymorphisms in the MAOA gene and three in the MAOBgene.

METHODS AND MATERIALS

Subjects

Subjects were ascertained through the ADHD outpatientclinic at the Child and Adolescent Psychiatry Division of SixthHospital, Peking University in Beijing, PRC. All patientsfulfilled DSM-IV diagnostic criteria for ADHD at baselineassessment, based on interviews by at least two different childpsychiatrists with the aid of information from biologicalparents and teachers. All patients were males of Han Chinesedescent. Written informed consent was obtained from parents.The study was reviewed and approved by the Ethics Commit-tee of Peking University. The 68 ADHD patients included inthe current study were between 7.5 and 10.5 years old atbaseline assessment. Follow-up assessments were completed3–5 years after baseline; the mean duration between the twoassessments was 3.7� 0.5 years. However, no subject hadreceived treatment for the 6 months prior to the study.

According to the DSM-IV system, two subgroups of ADHD(inattention and hyperacitivity/impulsivity) can be defined,each of which can be identified by nine symptoms. Based on the

method described by Keck et al. [1998] and Biederman et al.[2000], syndromatic, symptomatic, and functional remissionwere defined as follows: ‘‘syndromatic remission’’ referred tohaving four to five symptoms of each cluster; ‘‘symptomaticremission’’ referred to having fewer than four symptoms of theeach cluster without functional recovery; and ‘‘functionalremission’’ referred to having fewer than four symptoms ofeach cluster plus functional recovery. To assess the functioningof children, we used a questionnaire requiring parents togive scores on their child’s functioning on five aspects,including: school competence, peer relationship, parent–childrelationship, behavior, and emotion. The score ranged from 0 to100, and we defined scores �70 as functional recovery.

The interview instrument used in this study was the ClinicalDiagnostic Interview Scales (CDIS) [Barkley, 1998], which is astructured interview derived from the DSM-IV. The scale isscored with a 0 if the DSM-IV symptom is absent or a 1 if theDSM-IV symptom is present. Forty-seven (69.1%) subjects andtheir parents were directly interviewed, while 21 (30.9%) wereinterviewed by telephone. Both interviewers involved inthe current study had master’s degrees in psychiatry and weretrained to high levels of inter-rater reliability.

Genotyping

Genomic DNA was extracted from whole blood by stan-dard procedures. Genetic polymorphisms, including the941T>G polymorphism in exon 8 (rs1799835) and the1460C>T polymorphism in exon 14 (rs1137070) of MAOAgene (Genebank accession number: 4128), and the A>Gpolymorphism in intron13 (rs1799836), the C>T polymorph-ism in the 3’UTR (rs1040399), and the 2327T>C polymorph-ism in exon15 of the MAOB gene (Genebank accession number:4129) were genotyped using the conditions previously reported[Hotamisligil and Breakefield, 1991; Costa et al., 1997].

Statistics

The w2-test was used to compare genotype frequenciesbetween remitted children and non-remitted children. Inaddition, change scores on the 18 DSM-IV symptoms assessedby the CDIS were calculated from baseline assessment tofollow-up, and summary change scores were determined fortotal symptoms, inattention symptoms, and hyperactivity/impulsivity scores. One-way ANOVA was performed tocompare change scores across genotypes. All statistical testswere conducted using SPSS software (version 11.0) forWindows.

RESULTS

Table I displays the change scores in total, inattention, andhyperactivity/impulsivity symptom cluster scores associated

TABLE I. Influence of Different Alleles of MAO Genes on Change Scores in DSM-IV Symptom Clusters

Gene Polymorphism Allele Total score F (P)*Inattention

score F (P)*Hyperactivity/

impulsivity score F (P)*

MAOA 941T>G G 4.85� 4.66 2.454 (0.122) 2.46� 2.52 0.619 (0.434) 2.38�2.79 3.354 (0.072)T 6.66� 4.78 2.97� 2.73 3.69�3.06

1460C>T‘ T 4.56� 4.48 4.729 (0.033) 2.33� 2.46 1.600 (0.210) 2.23�2.69 5.645 (0.020)C 7.03� 4.86 3.14� 2.76 3.90�3.07

MAOB rs1799836 A 5.67� 4.83 0.053 (0818) 2.67� 2.67 0.007 (0.933) 3.00�2.97 1.990 (0.654)G 5.25� 4.46 2.75� 2.12 2.50�2.98

rs1040399 C 5.47� 4.75 0.399 (0.530) 2.51� 2.47 1.877 (0.175) 2.97�3.08 0.031 (0.860)T 6.56� 4.98 3.78� 3.35 2.78�2.05

2327T>C T 5.73� 4.96 0.007 (0.934) 3.36� 3.14 0.911 (0.343) 2.36�2.34 0.497 (0.483)C 5.60� 4.77 2.54� 2.50 3.05�3.07

*Test statistics and P-values are relative to the wild-type allele.

MAOA and Adolescent Outcome of ADHD 431

with each allele of the five MAO gene polymorphisms. A one-way ANOVA revealed that significantly better adolescentoutcomes (i.e., greater change scores) were associated withpossession of at least one C allele of the 1460C>T polymorph-ism of MAOA. This association was evident for both total scores(P¼ 0.033) and hyperactivity/impulsivity scores (P¼ 0.02), butnot inattention scores. The T allele of the 941T>G polymorph-ism also showed a tendency toward a similar beneficial effect onhyperactivity/impulsivity change scores; however, neither this(P¼ 0.07) nor any of the remaining polymorphisms affectedsymptom change scores to a statistically significant degree.

Table II displays the allele frequencies of these five MAOgene polymorphisms in groups meeting various criteria ofremission or non-remission of ADHD symptoms. Relative tosubjects showing no remission of ADHD symptoms, subjectswho met criteria for functional recovery had a significantlyhigher frequency of the G allele of the 941T>G polymorphism(P¼ 0.03) and the T allele of the 1460C>T polymorphism(P¼ 0.03) of MAOA. Allele frequencies of these or any of theMAOB polymorphisms did not differ significantly betweennon-remitted subjects and subjects showing either syndro-matic or symptomatic remission.

DISCUSSION

The results of this study provide modest evidence for anassociation between MAOA gene polymorphisms and theadolescent outcome of ADHD. These effects were significantfor two MAOA polymorphisms, but no evidence for associationwas observed for any of the three MAOB polymorphisms.MAOB degrades dopamine primarily, while MAOA preferen-tially degrades serotonin; thus, the current study mightsuggest a stronger role for serotonin than dopamine inmoderating the adolescent outcome of ADHD. This is consis-tent with previous studies which identified striking similarityin developmental timelines between the emergence of ADHDsymptoms and the serotonin (rather than dopamine) neuro-transmitter system [Pick et al., 1999].

Our analyses also revealed an association between theseMAOA gene polymorphisms and changes in symptoms ofhyperactivity/impulsivity but not inattention. This is consis-tent with the known effects of serotonin on impulsive behavior[Oades, 2002; Oades et al., 2002] and prior findings associatingADHD with serotonergic genes [Kent et al., 2002; Li et al.,2004; Faraone et al., 2005; Smoller et al., 2005]. Longitudinaltwin studies have provided systematic support for thetendency of hyperactivity and impulsivity symptoms to declineat a higher rate after age 7, however, inattention symptomshowed greater stability during this age period [Biedermanet al., 2000; Rietveld et al., 2004]. Changes in hyperactivity/impulsivity over time were due largely to emerging geneticinfluences in adolescents, while the stability of inattention over

time was due largely to the genetic foundation establishedearlier in development [Larsson et al., 2004; Rietveld et al.,2004]. Thus, the genetic foundation for hyperactivity/impul-sivity may differ across ages, which might increase our abilityto detect genetic influences on changes in behavior; theopposite may be true for inattentive symptoms, which have astable genetic contribution across developmental stages.

The MAOA gene was found to relate to functional remissionin this study; however, MAOA polymorphisms did not relatesignificantly to less pronounced categories of remission.Compared to syndromatic and symptomatic remission, func-tional remission was defined by functional recovery in at leastfive aspects of performance, including school performance,peer relationship, parent–child relationship, behavior, andemotion, in addition to symptomatic decline. Functionalremission therefore represents full recovery [Biedermanet al., 2000], which our results suggest may have a strongergenetic foundation than other categories of remission. It ispossible that ADHD with full functional remission thereforerepresents a distinct form of the illness relative to ADHD thatdoes not remit or only remits at the symptom or syndrome level.

The results of the current study must be considered in light ofits limitations. The sample size of this study was relativelysmall, which decreased statistical power and, althoughnominally significant, our results could be due to chance.Given population differences in the clinical presentation ofADHD [Yang et al., 2004; Rohde et al., 2005], it is possible thatadolescent outcome of ADHD also varies across populations. Assuch, the present findings must be replicated in otherpopulations and extended to larger samples before theassociations between these MAOA polymorphisms and symp-tom reduction and remission can be accepted as generalphenomena of clinical relevance.

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