although the etiology of attention - deficit / hyperactivity disorder ( adhd ) is not completely understood , it is well known that the disorder has a moderate to high genetic component , with an estimated heritability of 76% . the mode of transmission is likely to be due to many susceptibility genes with small effects . moreover , recent research findings have highlighted the relevance of gene - gene and gene - environment interactions in explaining the heterogeneous adhd phenotype [ 2 - 4 ] . several susceptibility genes have been proposed in almost 15 years of molecular research on adhd , mainly on the basis of neurobiological hypotheses for adhd . however , the success of these investigations can be considered as limited , because many studies were not able to replicate the positive results . here , we review the main results obtained so far in the adhd molecular genetics field and suggest new ways of investigation that might help to clarify the genetic component of adhd . the dopaminergic theory proposed to explain the neurobiology of the disorder , initially largely based on pharmacological evidence , states that abnormal levels of dopamine cause adhd . this led in 1995 to the first association study by cook et al . , who investigated a 40 bp variable number tandem repeat ( vntr ) in the 3 ' untranslated region of the dopamine transporter gene ( dat1 ) in adhd families . using the family - based approach called ' haplotype relative risk ' , an association with the ten - repeat allele was detected . in the following year , lahoste et al . investigated another dopaminergic gene , the dopamine d4 receptor gene ( drd4 ) . in this study , the frequency of a 48 bp vntr in exon 3 was compared between adhd cases and controls and an association with the seven - repeat allele was observed . these two genes , specifically through these variants , became the most studied genes in adhd molecular genetics , with some positive and some negative results . other polymorphisms in the two genes and in genes coding for other dopaminergic components were also investigated , although in fewer studies . several other candidate genes were extensively studied on the basis of noradrenergic and serotonergic hypotheses for adhd , as were genes encoding components of other neurotransmission systems and functions [ 8 - 10 ] . meta - analyses have suggested that the dat1 , drd4 , dopamine d5 receptor ( drd5 ) , dopamine  hydroxylase ( dbh ) , serotonin transporter ( 5htt ) , serotonin 1b receptor ( 5ht1b ) and synaptosomal - associated protein of 25 kda ( snap25 ) genes are susceptibility genes for adhd . however , the odds ratios for these genes range from 1.00 to 1.30 , so they can have only a very small effect on adhd symptoms . the existence of many negative association reports , together with the small effects detected in meta - analyses , suggests that the putative susceptibility genes can be responsible for only a minority of adhd cases , explaining only a tiny part of its development or phenotypic hetero geneity . moreover , the candidate gene approach may not be the only strategy for detecting susceptibility genes in complex diseases like adhd . genome - wide linkage and association scans , in which hundreds to thousands of genetic markers are evaluated , have shown promising results . evidence for linkage was obtained for regions in chromosomes 5 , 10 , 12 and 16 . after this initial report , other genome scans testing for linkage were conducted , suggesting different loci on several chromosomes . the meta - analysis by zhou et al .   identified 16q23.1 to q terminal as the genomic region with the most consistent linkage evidence across these studies , a region in which , surprisingly , no genes related to previous neurobiological adhd hypotheses are mapped . because linkage approaches seem to be more useful for genes of moderate to major effects , researchers have turned to genome - wide association studies . in a recent review , franke and colleagues   have shown that none of the individual investigations report any association that remains significant at the genome - wide level after correction for multiple testing . however , the most important finding is that there is little evidence supporting a role for the ' classic ' adhd genes , namely the ones related to dopaminergic , noradrenergic and serotonergic systems , in the genome - linkage scans . on the other hand , genes related to other neurotransmission and cell - cell communication systems are suggested , including processes such as cell division , adhesion and polarity , neuronal migration and plasticity , extracellular matrix regulation and cytoskeletal remodeling processes . thus , although without statistically significant results ( probably because of the insufficient power in all the studies ) , the findings from genome - wide approaches indicate a whole range of new and promising possibilities for adhd molecular genetic studies . a recent report by ribass and colleagues   is one example of this new emphasis on candidate gene investigations . considering the abnormal left - right brain asymmetries observed in several adhd neurobiological studies , the authors   selected six functional genes shown to be expressed differentially between brain hemispheres in a previous report by sun et al . . these are the genes encoding brain - specific angiogenesis inhibitor 1-associated protein 2 ( baiap2 ) , dapper antagonist of -catenin homolog 1 ( dapper1 ) , lim domain only 4 ( lmo4 ) , neurogenic differentiation 6 ( neurod6 ) , atpase , catransporting plasma membrane 3 ( atp2b3 ) and inhibitor of dna binding 2 ( id2 ) . an initial case - control study was conducted in a sample of 587 participants with adhd ( children and adults ) and 587 matched control individuals from spain . the results obtained were then tested in two other case - control samples from germany and norway ( 639 and 417 adult adhd participants and 612 and 469 control individuals , respectively ) . from a total of 30 single nucleotide polymorphisms ( snps ) investigated in these six genes , an association with baiap2 was detected , by both the single- and multiple - marker analyses , in the adult adhd spanish sample . in the replication study , the association with this locus was also observed in the german sample , although there was a slight difference in the putative risk snps . , the authors   concluded that genetic factors possibly influencing abnormal cerebral lateralization may be involved in adhd etiology , with baiap2 acting specifically in cases of persistent adhd . baiap2 is located at 17q25 and encodes the 53 kda insulin receptor tyrosine kinase substrate protein ( irsp53 ) , a molecule that participates in the signal transduction pathways of insulin and insulin - like growth factors . this protein is highly expressed in the left cortex and seems to be involved in neuronal proliferation , survival and maturation . the baiap2 locus is not only a new gene to be investigated in adhd , but it also indicates that genes related to general brain functions , rather than specific aspects of the disorder , may contribute to adhd development ; common variants in these genes could then confer susceptibility to a group of related psychiatric disorders . further evidence for this hypothesis has recently been provided by gratacs and colleagues , who observed an association of the bradykinin receptor b2 gene ( bdkrb2 ) with panic disorder , substance abuse , bipolar disorder , obsessive - compulsive disorder and major depression . bdkrb2 is located at 14q32 and encodes a transmembrane receptor for the non - peptide bradykinin , which activates various second messenger systems . in response to this signal , several processes are modulated , including blood - brain barrier permeability , blood pressure regulation , pain perception , release of glutamate from astrocytes , neuronal differentiation and nitric oxide production . many more studies are still needed to raise new biological hypotheses linked to neurotransmission and neurodevelopment in general in order to define new candidate genes for association studies with adhd . in addition , defining target genes is the first step toward thehomo development of novel drug therapies for adhd . adhd : attention - deficit / hyperactivity disorder ; baiap2 : brain - specific angiogenesis inhibitor 1-associated protein 2 gene ; bdkrb2 : brady - kinin receptor b2 gene ; dat1 : dopamine transporter gene ; drd4 : dopamine d4 receptor gene ; snp : single nucleotide polymorphism ; vntr : variable number tandem repeat . lar has served as a speaker and/or consultant for eli lilly , janssen - cilag and novartis in the past 5 years . currently , his only industry - related activity is taking part in the advisory board / speakers ' bureau for eli lilly and novartis ( less than us$10,000 per year and reflecting less than 5% of his gross income per year ) . the adhd and juvenile bipolar disorder outpatient programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the past three years : abbott , bristol - myers squibb , eli lilly , janssen - cilag , novartis and shire .
attention - deficit / hyperactivity disorder ( adhd ) has a moderate to high genetic component , probably due to many genes with small effects . 
 several susceptibility genes have been suggested on the basis of hypotheses that catecholaminergic pathways in the brain are responsible for adhd . 
 however , many negative association findings have been reported , indicating a limited success for investigations using this approach . 
 the results from genome - wide association studies have suggested that genes related to general brain functions rather than specific aspects of the disorder may contribute to its development . 
 plausible biological hypotheses linked to neurotransmission and neurodevelopment in general and common to different psychiatric conditions need to be considered when defining candidate genes for adhd association studies .