Naghmeh Kian·Noosha Samieefar·Nima Rezaei

Abstract Background Attention deficit/hyperactivity disorder (ADHD) is a common disease among children;it affected 5–7% of the population in 2015.ADHD is a multifactorial disease,and its etiology is still not clearly understood.Data Sources This narrative review has been done by searching the PubMed and Embase databases using attention deficit/hyperactivity disorder,ADHD,risk factors;genetics;pediatrics;psychiatrics as keywords.Results ADHD is considered to be a hereditary disorder in which genes play the fundamental role in the pathogenesis;however,findings from genetic–environmental studies support the hypothesis that genetic factors can exert effects on an individual’s condition by determining his/her responses to environmental exposures,especially those during the prenatal stage.Conclusion ADHD is considered as a hereditary disorder in which genes and prenatal risk factors play fundamental roles in the pathogenesis.

Keywords Attention deficit/hyperactivity disorder genetics·Risk factors·Pediatrics·Psychiatrics

Introduction

Attention deficit/hyperactivity disorder (ADHD) is a multifactorial disease that is attributed to a variety of causes which are not yet fully understood.Although a large body of studies have focused on exploring the etiology of ADHD,a definite answer to the mechanism of this disease’s development is not available.In 2015,ADHD affected 5–7% of the population [1];this number increased in recent years,since the update of ADHD’s definition in the latest edition of Diagnostic and Statistical Manual of Mental Disorders(DSM-5) [2].

ADHD is classified as a familial neurodevelopmental disorder that is most commonly seen in school children and is characterized by difficulty in problem-solving,paying attention and hyperactivity [3].Multiple studies have largely investigated the underlying causes leading to ADHD phenotypes.Most of these studies have focused on the environmental,prenatal or postnatal risk factors,which comprise the smaller proportion of ADHD etiology (10–40%) [3].

Despite being responsible for about 70% of ADHD causes,the research on genetic risk factors has been limited and has been growing slowly [4].Interestingly,the international twin studies on children with ADHD found a hereditary rate ranging from 71% to 90%.The likelihood of having ADHD in first degree relatives of ADHD patients is estimated to be 2 to 8 folds higher than normal individuals [5].

The early investigations on genetic and molecular basis of ADHD were limited to a number of candidate gene studies involved in ADHD pathology [5].Despite the discovery of specific candidate genes,such asDRD4,DRD5,DAT1,HTR1B,SLC6A4,SNAP25,they were not confirmed as major predictors of ADHD.Genomic wide association studies (GWAS) on common genetic variants were not accompanied with promising findings either [6].Furthermore,researches on rare genetic variant abnormalities have suggested an overlap between ADHD and other neurological disorders,namely,autism and schizophrenia in terms of high number of copy number variants (CNVs) in certain chromosomal regions [5].

Environmental risk factors predisposing to ADHD pathogenesis have been widely explored either generally or distinctively.Among them,prenatal risk factors and maternal exposures before birth gained a lot of attention,because they were thought to be involved in completion of the ADHD puzzle.Environmental factors are not independent of genetic ones;in fact,their interaction is commonly referred to as ADHD pathogenesis.Formation of de novo mutations,in addition to epigenetic alterations,has been suggested as a possible role of environmental risk factors but researches are still insufficient [5].

The most commonly cited prenatal risk factors linked to ADHD were maternal smoking during pregnancy,maternal substance and alcohol use,maternal stresses,birth complications (namely,low birth weight and prematurity),and being exposed to chemical substances,such as lead,toxins,pesticides,and drugs [4];yet these findings are inconclusive.

Generally speaking,ADHD is more a hereditary disorder than an acquired one.Having said that,authors have firmly proposed the concept of “genetic–environmental interaction”in the literature,shedding the light on the interplay between pre-and post-natal risk factors and genetic predisposition.

In spite of the recent reduction in the research rate of ADHD pathogenesis field,some new clinical trials and review studies have yielded important findings that call for a general review of the literature.The present study aims to review the recent literature on genetic and prenatal risk factors of ADHD with an eye on genetic–environmental interplay and the role of genetic predisposition in children who have been exposed to environmental risk factors before birth.

Genetic risk factors of ADHD

Studies have reported different numbers for the role of heritability in ADHD that range from 54% to more than 70%of the causes [7],making ADHD one of the neurodevelopmental disorders with the highest heritability rate [8].Overall,ADHD is more prevalent in males,but different studies have reported different male to female ratios.Ujjwal et al.reported a male to female ratio of 2.28:1,which is relatively lower than the results of other similar studies;authors have suggested that under-diagnosing female ADHD cases in previous studies was the underlying reason [9].

One study compared the severity of ADHD between offspring of parents who had ADHD and those without;the results were supportive of the inheritable nature of this condition,showing that offspring of parents with ADHD were more likely to develop severe forms.Interestingly,this study did not provide any evidence for a synergistic effect of bi-parental ADHD;in fact,the results suggest that paternal and maternal ADHD status would have different effects on the severity of hyperactive–impulsive and inattentive symptoms in their children [10].

Separate family,twin and adoption studies have concluded that ADHD is more likely to be inherited by children who have a genetic connection.Twin and adoption studies have shown a high heritability rate of 60–90% for ADHD.Siblings and parents of ADHD patients are two to eight folds more affected by ADHD than relatives of healthy individuals.The results from twin studies have shown that monozygotic twins are more concordant in having ADHD than dizygotic twins.In line with these studies,comparing biological parents of ADHD children with their adoptive parents and parents of controlled children without ADHD revealed that the rate of ADHD is highest in biological parents of ADHD children [11].A 4-year followup of siblings of ADHD children was also indicative of ADHD’s high heritability rate,because the rate of school failure,as well as neuropsychological and psychosocial dysfunction,was higher in those siblings [12].

Investigating the genome of children and adults with ADHD,Bovicini et al.reported that the genes involved in ADHD pathology,differed in the two age groups[13].Children who had participated in this study shared some genetic polymorphisms in certain regions of their genome,including genes involved in dopaminergic pathway (SLC6A3,DRD4andMAOA) and neurodevelopmental(LPHN3andDIRAS2) systems andOPRM1.The study also concluded that adults and kids share some genetic abnormalities in terms of oxidative stress proteins (MAD,SOD,PON1,ARES,TOS,TASandOSI),DISC1,DBH,DDC,microRNA and adiponectin genes [13].

Now,it is well known that ADHD is a multifactorial disorder,which occurs mostly due to genetic abnormalities rather than pure environmental factors.However,the exact genetic defects are not fully established.Previous studies tried to find the best gene–trait correlation,using candidate gene studies,genome-wide association studies,copy number variants and more recently epigenetics.

Epigenetic modification during a key developmental period during pregnancy has shown a significant association with environmental insults during or around this period [14].Mitotic activity is higher in the developmental stages,and therefore,the neurons are more prone to epigenetic modifications after exposure to environmental triggers [15].Examples of these epigenetic changes include,cytosine methylation in CpG islands that leads to silencing of gene and to compaction of chromatin;histone acetylation,methylation,and phosphorylation;and RNA-mediated modifications with an example being small interfering RNAs that can suppress the activity of specific genes through targeted RNA interference and micro-RNA(miRNA) [14].

Studies have suggested a significant association between severity of behavioral abnormalities of ADHD children with differential methylation patterns in dopaminergic and serotonergic genes [16].For example,Park et al.reported an increased methylation of the pro-motor region of the serotonin–transporter gene (5HTT) associated with more severe ADHD signs and changes in the thickness of occipitofrontal cortex [17].Similarly,another study found an association between severity of mental disorders,such as ADHD,bipolar disorder and borderline personality disorder and methylation of5-HT3Agene [18].Ding et al.also found an effect ofDAT1methylation on the responsiveness of ADHD patients to methylphenidate [19].

Candidate gene studies failed to establish certain genetic abnormalities,except for some valuable findings that will be discussed later.The findings from GWAS—which examined the whole genome of ADHD patients and healthy individuals to point out gene polymorphisms—were inconsistent.In the last decades,scientists have accomplished ten GWAS searching for ADHD etiology [20].The first locus that had been discovered by GWAS was located near genetic regions that were involved in neurodevelopmental processes related to ADHD,includingFOXP2,SORCS3,andDUSP6[21].The most recent GWAS found 12 independent loci of genes that were known to be involved in brain function regulation[22].

Copy number variants (CNV) studies were established recently to find rare (i.e.,less frequent than 1% in the general population) genetic variants for ADHD.Although CNV studies were accompanied by new findings on ADHD pathogenesis,they only contributed to 0.2% of ADHD heritability[22].Most CNVs found to be associated with ADHD,also were linked to the pathogenesis of other psychiatric disorders (namely,autism and schizophrenia),suggesting an overlap in the impaired mechanisms involved in them,such as cell–cell communication,neuronal plasticity and regulation of extracellular matrix [23].Scientists also found an association between fragile X syndrome,tuberous sclerosis and other microdeletion syndromes,such as Smith Magenis and Velocardiofacial (VCFS;22q11 microdeletion) syndromes with ADHD,especially the inattentive form [11].

As is typical in multifactorial disorders,the results from different studies do not always come to identical conclusions.Some studies have investigated chromosomal regions expected to exert an effect in ADHD pathology through disrupted neurotransmission,while others have considered genes involved in cell functions,such as cell division,adhesion,and synaptic plasticity.It seems that scientists are more eager to find an association between neurotransmitter signaling pathways defects and ADHD,because most studies have reported dopaminergic,serotonergic,noradrenergic or glutamatergic genes,at least as one of the most common genetic variations seen in ADHD patients.As a matter of fact,most medications used for ADHD would deliberately affect those systems.For example,dopaminergic agonists can improve impulsivity,hyperactivity and inattention.Norepinephrine agonists have the same effects in treating this condition,as well.The impairment of neurotransmitter’s pathway disrupts attention,inhibitory control and working memory [24].

Recently,Hayman and Fernandez completed an analysis of the 105 genes that were pooled from the literature and were thought to be most robustly associated with ADHD.Following this analysis,the authors found 14 core genes that showed the most prominent connection with ADHD.These genes were separated into two groups,including nitric oxide synthase and α-1 adrenergic pathways and had enriched expression in the cerebellum and the cortex.They also supported the role of dysfunctional neurotransmission in ADHD.Investigating candidate genes,this study reports that nicotine signaling pathway,N-methyl-D-aspartate receptor (NMDAR) and cannabinoid pathway were correlated with ADHD pathology,but yet it requires further studies [25].

One study investigated the possible role of dopamine,norepinephrine and serotonin pathways as well as neurite outgrowth genes in ADHD development.The authors concluded that hyperactive/impulsive component of ADHD is affected by the genes involved in these neurohormonal pathways,whereas inattentive traits do not seem to be relevant to them [26].

Scientists found multiple gene associations with ADHD through different approaches.The most robust predisposing genes are:dopamine transporterDAT1,SLC6A3,dopamine receptorsDRD4andDRD5,neuronal isoform of the nitric oxide synthase (NOS1),synaptosomal-associated protein(SNAP25),G-protein-coupled receptor kinase interacting ArfGAP 1 (GIT1),and cannabinoid receptor gene 1 (CNR1)[20].

One study summarized the gene polymorphisms found in ADHD in comparison to a control group.The findings were variants including theTaqIApolymorphism ofDRD2gene,theA1allele of theDRD2gene in the hyperkinetic patients,abnormal genotypes of theDAT1gene in boys with ADHD,and polymorphism ofIL-6gene.The study discovered a correlation between certain genes involved in the immunological pathways,such asIL-2,IL-6,TNF-alphaandBDNF,and the risk of ADHD [27].

Dopamine alteration is one of the first and most studied genes in ADHD neurobiology.Some variants ofDRD4gene,which are located on the chromosome 11p15.5,have been widely reported to play a role in ADHD [6].DRD is a dopamine receptor that can bind to dopamine and norepinephrine.The polymorphism in the 3 rd exon of this gene has been extensively studied and linked to ADHD.A rare 7 repeat (7R) variant ofDRD4gene is another risk factor associated with this condition,but both common and rare polymorphisms of this gene can play a role in the condition.DRD5,another dopamine receptor,has also been implicated in ADHD studies [11].

Dopamine transporter (DAT1)—also known asSLC6A3—is one of the most replicated genes in ADHD.DAT1is responsible for dopamine reuptake at the site of neuronal communication.Methylphenidate,the most common ADHD medication,targets this receptor and leads to accumulation of dopamine in the site of synapses [6].This gene is one of the most robust genetic factors that have been related to ADHD,as seen in animal and human studies.In fact,DAT1knocked-out mice have shown hyperactive symptoms.480-bp allele of the most common studied polymorphism—which is a variable number of tandem repeat(VNTR) in the 3’ untranslated region (UTR) region of the gene—is shown to be significantly correlated with ADHD.The 3’ UTR VNTR polymorphism ofDAT1gene also may predispose an individual to ADHD through an interaction between genetic and prenatal risk factors,such as mother’s smoking or alcohol use [11].

A recent GWAS supported the role ofCDH13andLPHN3in ADHD pathology.CDH13gene,which is involved in neurodevelopment was found to be associated with ADHD etiology.CDH13expresses the protein cadherin-13,which is responsible for neuronal growth and cell adhesion.Two independent samples found the association ofCDH13and ADHD [20].

A common haplotype ofLPHN3has also been suggested to raise the risk of ADHD and the response to stimulant drugs.This gene is predominantly expressed in the brain regions that are found to be associated with ADHD,such as amygdala.LPHN3is involved in axon signaling,the development of glutaminergic synapses,and plasticity of synapses [20].Acosta et al.found an interesting interaction between SNPs ofLPHN3and specific genes in the 11q region,namely,DRD2andNCAM1.The interaction would probably increase the risk of ADHD and its severity as well[28].

Studies also reported a possible role forSPOCK3and glutamate receptor (GRM5) genes in ADHD development.SPOCK3is known for coding a proteoglycan called Ca2+-binding extracellular heparan/chondroitin–sulfate–proteoglycan,which exerts inhibitory effects on neurite growth by matrix-metalloproteinases [20].Many studies focused on the polymorphisms of catecholOmethyl transferase(COMT) gene,a dopamine degrading enzyme.They found a valine–methionine transition that can affect the enzyme’s function and may be related to ADHD through dopamine changes [11].

Several microRNAs have been shown to play a role in regulation of ADHD-associated genes,such asBDNF,DAT1,HTR2C,HTR1B,andSNAP25[20].MicroRNAs are short,noncoding RNAs responsible for gene regulation after transcriptional stage.Among the few studies that have investigated the role of microRNAs in the ADHD etio-pathology,one study found the altered expression levels of microRNA 5692b and microRNA let-7d in the blood of ADHD affected children and adults,supporting the possible role of them in this condition [29].

The genetic findings have supported several possible genes that are involved in ADHD pathology;yet they also show a considerable inconsistency and uncertainty.Although genetic risk factors appear to be the most determining causes of ADHD,these risk factors have not been firmly established and require further investigations with higher sample sizes.

Prenatal environmental risk factors

Despite being the less contributing factor in developing ADHD,environmental risk factors have been investigated considerably.Prenatal exposures consist of an important proportion of ADHD risk factors,because multiple studies have focused on their contribution to offsprings’ ADHD.The literature on ADHD prenatal risk factors lacks consistency;in fact,it has been suggested that a single risk factor is not capable of developing ADHD symptoms in a child.Rather,it is the combination of multiple environmental exposures and genetic predisposition that might lead to the condition.

A study has supported evidence for different environmental factors that can influence inattentive or hyperactive–impulsive symptoms.Inattentive symptoms seem to be significantly influenced by psychosocial risk factors,whereas hyperactive–impulsive symptoms are more likely to be the result of biological risk factors [30].

A recent meta-analysis that integrated the results of previous studies on environmental risk factors,protective factors,and peripheral biomarkers for ADHD found nine specific associations between environmental risk factors and ADHD.The most prominence of these associations is acetaminophen use during pregnancy,maternal smoking,pre-pregnancy obesity and overweightness[31].

Reviewing the extended literature around prenatal risk factors of ADHD,multiple exposures and complications during pregnancy or during labor come into play.Most clinical trials have focused only on one or two of these variables,but it’s not yet known whether their convolution can add further risk for having ADHD.Many studies have suggested an association between different prenatal risk factors and ADHD in children.This review has classified them into three groups that will be discussed further:chemical exposures during pregnancy,pregnancy or birth complications and maternal health status.

Chemical exposures during pregnancy

Exposure to smoking

Maternal cigarette smoking is a key risk factor that has been significantly associated with ADHD in offspring.Milberger et al.reported a higher rate (2.7-fold) of ADHD risk in children with mothers who smoke [32].Similarly,another study has found a twofold greater risk of ADHD in offspring who had been exposed to tobacco during pregnancy [33].Prenatal exposure to nicotine also was associated with a significant cognitive impairment in animals [34].Nicotine exposures during brain development window can affect catecholaminergic (i.e.,dopaminergic and noradrenergic) systems in certain parts of the brain,resulting in their hypo-responsiveness to stimulants and eventually developing ADHD [35].Cigarette smoking can have multiple adverse effects on the embryonic development:interfering with placental function,disrupting fetal blood flow,depriving the fetus of oxygen and nutrients,and finally causing fetal retardation [3].Carbon monoxide and other ingredients within the cigarette can also have direct harmful effects on brain development [36].

Maternal and paternal smoking is associated with ADHD in offspring,but maternal smoking seems to have a greater influence than father’s.One study supported this finding by comparing the risk of ADHD in children who were born from smoker mothers and non-smoker fathers with children with complete opposite parents;the results displayed a higher risk of ADHD in the offspring of smoker mothers and mothers who received nicotine replacement during pregnancy [37].Similarly,another study supported a significant association between offspring’s ADHD and maternal and paternal smoking but also suggested that maternal smoking doesn’t seem to have intrauterine effects on the fetus and that the effects might be confounded with genetic or household-level factors[37].The same result was concluded by Gustavson et al.who ruled out intrauterine effects of smoking during pregnancy on a child’s ADHD risk,because the association between maternal active or passive smoking disappeared after adjusting the same experiments for sibling-control analyses [38].

As suggested by another study,the risk of ADHD is higher in children of mothers who were heavy smokers than in those whose mothers were light smokers [39].In addition,one study has reported higher levels of severe psychosocial stress and higher rates of heavy smoking(>10 cigarettes per day) during pregnancy in mothers who had ADHD children compared to those who had unaffected kids [40].There are heterogeneous results pertaining to maternal passive smoking through father’s smoking habit as well,but the correlation needs further investigations.Minatoya et al.suggested an increased risk of hyperactivity/inattention symptoms in pre-school children whose mothers have experienced low and high passive smoking during pregnancy,but the correlation lacked statistical significance in contrast to what was observed for maternal active smoking [41].

Interestingly,Dong et al.found a strong correlation between maternal smoking during pregnancy and maternal smoking cessation during the first trimester,with the risk of developing ADHD in their offspring.This study recommended early smoking cessation for smoker women who aim to be pregnant soon,because they reported a much lower risk of ADHD among mothers that quit cigarette smoking before getting pregnant [42].

Simultaneous exposure to tobacco and alcohol during pregnancy might add a double risk for developing ADHD.Han et al.reported 1.55,2.64 and 1.17 folds greater risks of ADHD in offspring who were prenatally exposed to alcohol,maternal smoking and paternal smoking,respectively [43].

Exposure to diet components

Prenatal exposure to alcohol is one of the most studied risk factors related to ADHD pathogenesis.Ikonomidou et al.have demonstrated that ethanol-treated rats had higher rates of neurodegeneration in the forebrain,a key brain region involved in ADHD,than their saline-treated counterparts[44].It has also been shown that human brain is sensitive to alcohol during neurodevelopmental period and is prone to anomalies or disrupted development especially in the cerebellum [45].Apart from maternal exposures before birth,paternal alcohol use has been explored as an ADHD risk factor.One study showed no definite correlation between these two variables and further suggested that the possible influence of paternal alcohol consumption on kids’ risk of ADHD might be a result of interactions of different pathways rather than direct influence [46].

A systematic review has shown that diet components have no significant impact on ADHD risk.However,there are some evidences of a pathologic effect of eating heavy metals by mothers during pregnancy.The offspring of mothers who had consumed mercury-contaminated fish during pregnancy in New Zealand and the Faroe Islands had higher rates of memory and attention disruption and had lower IQ than the normal kids and affected motor skills [3].

Konikowska et al.carried out a study to investigate the influence of diet during pregnancy and lactation period in developing ADHD [47].The findings supported a fundamental role for long-chain polyunsaturated fatty acids and minerals,such as zinc,iron,magnesium and iodine,in the brain development of the fetus.The authors suggested an increased risk of ADHD in children whose mothers were chronically deficient from polyunsaturated omega-3 fatty acids—especially DHA—which is essential for normal development and activity of brain [47].Children diagnosed with ADHD and autism spectrum disease are reported to have lower DHA levels.One study has found controversial evidence on prenatal supplementation with DHA and unexpected neurodevelopmental disorders.This study suggested that this association might be confounded by socio-economic background and life-style [48].Manganese exposure before birth is associated with ADHD development.Animal models exposed to manganese have also shown hyperactive traits [3].

The impact of polychlorinated biphenyls (PCB) has also been investigated in multiple cohort studies.All of them concluded that prenatal PCB exposure is associated with ADHD symptoms,such as lower concentration,lack of accuracy in the performance and longer reaction time [3].

Exposure to certain drugs

Consuming acetaminophen,as an antipyretic drug,by pregnant mothers is a concern for multiple teratogenic effects that it might provoke.Masarwa et al.recently found an increased risk of ADHD and hyperactivity in the offspring of mothers who consumed acetaminophen during gestation.The study has suggested a mechanism for acetaminophen’s adverse effect,which is its interference with endogenous hormones and signaling pathways of the developing fetus [49].A previous study had concluded that short-term acetaminophen use had a negative correlation with ADHD in the born child,whereas long-term consumption was significantly associated with greater risk of developing ADHD [50].Another study also supported the association between using acetaminophen during gestation and greater odds of ADHD-like symptoms at 7 years of age.The authors proposed a greater association when mother had consumed acetaminophen in more than 1 trimester in pregnancy [51].

Prenatal exposure to anti-depressant medication and the risk of ADHD has also gained some attention.Despite multiple studies done in this field,a unique conclusion is absent due to heterogeneity of the study results possibly due to the existence of some confounding factors [52].

The studies on the risk of consuming anti-seizure drugs during pregnancy were not consistent as well.For example,maternal use of lamotrigine was not associated with elevated risk of ADHD or autism spectrum disorder,whereas valporic acid consumption raised the risk of these two conditions.A recent cohort study reported a higher likelihood of ADHD (48%) in children who were exposed to valproate during gestation compared to children without this history[53].In addition,carbamazepine association with ADHD lacked significance [54].

Prenatal antibiotic exposures are under investigation for finding a possible association with offspring’s ADHD but a recent study has shown no significant correlation between these two variables [55].

Consuming anti-ADHD medications during pregnancy is another hypothetical risk factor for offspring’s ADHD.A recent study reviewed existing evidences for this risk factor and concluded that prenatal exposure to ADHD medications is not directly linked to ADHD development.The authors suggested that this association might be the result of genetic factors or familial environmental factors [56].

Exposure to toxins

Interestingly,the study by Nilsen et al.showed that the association between chemical exposures and ADHD development in children can be explained by the monoamine oxidase A (MAOA) pathway that is involved in serotonin uptake.It has been suggested thatMAOAactivity can be altered when it is exposed to chemicals,such as naphthylamine,nicotine,bisphenol A (a plasticizer),organophosphate pesticides and Pb (lead),hence leading to higher likelihood of ADHD.It was further explained that some metals,including Pb,manganese (Mn),arsenic (As) and mercury (Hg) can inhibitN-methyl-D-aspartate receptor (NMDAR) by interfering with the calcium channels involved inNMDARregulation and can alterMAOAactivity.NMDAR is an ionotropic channel composed of different subunits including NR1 and four subtypes of NR2 family (A–D) [57].Notably,monoamine neurotransmitters,such as dopamine and serotonin,can influence the composition of NMDAR and its function which is passage of cations;hence,it is suggested that the function of MAOA,the catalyzer of monoamine degradation,is in part regulated by NMDAR function [58,59].However,the evidence for Pb is conflicting,because the authors have ruled out Pb as an agonist forNMDAR[60].This is consistent with some studies that have shown lead exposure before birth is not significantly associated with ADHD pathogenesis [3].

The correlation between children’s low level pesticide exposure and onset of ADHD symptoms also was supported by another study by Roberts et al.This finding is consistent with animal studies that treated animals with a controlled concentration of pesticides and found correlation with ADHD and autistic symptoms [61].

Prenatal exposure to air pollutants is an interesting concept in the context of ADHD etiology.However,the study by Oudin et al.did not find a significant association between prenatal exposure to theses toxic substances and the risk of developing ADHD in the offspring [62].

In line with maternal exposure to chemicals during pregnancy,one large,cohort study has investigated the influence of amalgam,a chemical used for filling teethes in dentistry,on the offspring’s ADHD risk.The authors failed to find any significant correlation between mother's amalgam fillings during pregnancy and children’s risk of ADHD [63].

Inborn errors of metabolism

According to the literature,a number of inborn errors of metabolism are associated with attention deficit and hyperactive behavior.The characteristic symptoms of ADHD as mentioned earlier,were observed in 28% of cases born with succinic semialdehyde dehydrogenase deficiency [64].Interestingly,Antshel et al.revealed that prenatal exposure to elevated levels of phenylalanine as in phenylketonuria is correlated with expressing hyperactive/impulsive behavior,while postnatal exposure to this metabolite is associated with inattentive symptoms [65,66].According to Arnold et al.26% of 38 children with phenylketonuria consumed anti-inattentive medications [67].

In line with metabolic defects,different case reports have reported 3-methylcrotonyl-CoA carboxylase deficiency [68],argininosuccinate lyase deficiency [69] and succinyl-CoA:3-oxoacid CoA transferase deficiency in pediatric cases of ADHD [70].Moreover,ADHD is also thought to be associated with mitochondrial dysfunction [71].ADHD is one of the conditions that is suggested to be linked to a hyperammonemic crisis [72].

Pregnancy birth complications

Maternal age

The association between maternal age and the risk of ADHD in the offspring was the subject of many investigations.Presumably,the mother’s age at first birth can predict the ADHD risk in their kids.The results of one study had shown that mothers who have started childbearing early in their lives have children that are more likely to show ADHD symptoms.The study further suggested that this association is probably due to genetic confounding,which makes the mothers more likely to have children at an early age and predisposes their children to ADHD [73].

Prematurity and low birth weight

Prematurity is a possible risk factor for ADHD.One study suggested an association between prematurity and risk of ADHD based on the results of three studies exploring the effect of prematurity.The study suggested a negative correlation between the risk and the gestational age of the children [4].Another study showed that children who were born prematurely (less than 26 weeks of gestational age) and thus had lower birth weight were four times more prone to have ADHD [74].However,the results did not show whether prematurity or the lower birth weight increases the risk;so,another study was done by Heinonen et al.that controlled the effects of both variables;the authors reported no association between pre-maturity and later clinical manifestations of ADHD.However,being small for gestational age was correlated with a threefold higher likelihood of reaching clinical cutoff criteria for ADHD in comparison with children who were born with an average normal weight [75].Despite gaining a significant odds ratio of 2.6 in a metaanalysis study,low birth weight and prematurity,which are frequently mentioned in the list of possible ADHD causes,need further investigation,because only a small number of ADHD patients present with these complications [76].

Gestational problems

Gestational bleeding can increase the risk of ADHD or specific ADHD symptoms.As one study suggested,bleeding during pregnancy was linked to higher risks for inattentive traits.The study concluded that fetal hypoxia could be the linkage between gestational bleeding and elevated inattentive symptoms in ADHD,as was previously demonstrated for autism [30].The role of neuro-inflammation in the development of ADHD is not yet stablished but is proposed to interfere with development of gray matter volume,especially in certain cortical areas relevant to ADHD.Animal studies have added further evidence for the role of neuro-inflammation in terms of disrupting the development and function of dopaminergic,serotonergic and glutamatergic systems [77].Hypoxia and ischemia during fetal life can have irreversible effects on the development of different body organs,especially in brain tissue.One study has explained the mechanisms by which it can produce ADHD in the fetus.First,hypoxemia and ischemia are known to cause lower birth weight in the offspring,which itself is a prominent risk factor for ADHD.Second,the activity of ischemia–hypoxia response pathway is altered through epigenetic modification to promote the vitality of hypoxic tissue.If ischemia–hypoxia response modifications last for a long time in the brain tissue,the occurrence of ADHD will be more probable in the child [78].Pre-eclampsia,which is characterized by high blood pressure,proteinuria and swelling in the limbs during pregnancy,has been under investigation as another prenatal risk factor of ADHD.One study firmly suggested that children who were born of mothers with pre-eclampsia have an increased risk of ADHD [79].

Maternal health status

Maternal health during pregnancy is effective on the child’s normal development.Several studies have investigated the influence of mother’s sickness on developing ADHD.

One example is maternal anemia during pregnancy.Wiegersma et al.have demonstrated that maternal anemia that is diagnosed early during gestation is correlated with higher rates of diagnosing neurodevelopmental disorders in the offspring,including ADHD,while such correlation was absent with later anemia diagnosis [80].

Maternal obesity and overweightness is among multiple factors that are strongly associated with ADHD development in the offspring.However,the effect of genetic and familial confounding factors should not be neglected in this context [31].

Parental asthma also has been linked to greeter risks of ADHD in children,but no significant correlation was observed between using asthmatic medications during pregnancy and offspring’s ADHD [81].

Psychological status of parents,and more importantly of mothers before birth,is also thought to play roles in ADHD development in their children.Joelsson et al.reported a significant association between parental diagnosis with psychological disorders before birth and higher probability of ADHD in their born childs.Maternal diagnosis was more significantly correlated with her offspring’s condition[82].In addition,a Swedish study has shown that maternal stress during the 3 rd gestational trimester increases the risk of ADHD in their offspring [83].As supported by Clement et al.maternal history of major depressive disorder is also correlated with increased risk of ADHD [84].

Gene–environment interaction

It has become clear that ADHD develops when an individual with underlying genetic predispositions faces some stresses,either prenatally or postnatally.The studies are supportive of a combination of factors,both genetically and environmentally,to be involved in ADHD pathogenesis.

The role of gene–environment interaction gained a lot of attention in the last decade.A considerable number of studies have tried to clarify the possible association between genetic variants and environmental exposures.Some have even taken a step further and suggested that genetic variations are even responsible for higher risk of being exposed to some environmental factors.For example,one study has shown a strong correlation between the likelihood of early life exposure to environmental risks and the maternal neurodevelopmental risk alleles,suggesting a possible mechanism for those alleles in elevating the risk of neurodevelopmental disorders in the offspring [85].

One study has proposed an interaction between genetic variation inDRD4region and exposure to organophosphates and oxidative stresses.The authors reported a higher likelihood of ADHD in children who hadDRD4 GGgenotype than in whom aDRD4 GA/AAgenotypes (rs752306) was present.They also emphasized the importance ofDRD4polymorphism in terms of susceptibility to chemicals,such as organophosphate,because the levels of dimethyl phosphate and 4-hydroxy-2-nonenal-mercapturic acid also were higher in ADHD kids,which might predispose them to ADHD,possibly through the mechanism of lipid peroxidation [86].

Kahn et al.have shown an interaction betweenDAT1 VNTRgenotype and prenatal smoking exposure,which predisposes the child to oppositional and hyperactive–impulsive symptoms [87].A later study found a different interaction betweenDAT1 VNTRalleles and maternal alcohol use with a greater risk of ADHD in childhood;the interaction between maternal alcohol use andDAT1haplotype showed an increased risk of ADHD in children from southeast England and Taipei,Taiwan [88].

However,not all studies were supportive of gene–environment interaction.Altink et al.have reported no significant interaction betweenDRD47-repeat allele and maternal smoking as a risk factor for ADHD [89].In contrast,another study has found a robust interconnection between prenatal smoking exposure and theADRA2Ars553668 variant for ADHD.The authors concluded that the risk of having genetic variant indicative of ADHD is higher in children who were exposed to tobacco smoking before birth [90].Another study has reported a significant correlation between maternal smoking during pregnancy and a genetic predisposition of the child to have ADHD further in life.The authors further reported that twins who were exposed to prenatal maternal smoking and who had inheritedDAT1440 allele had a greater odds ratio (2.9) for having ADHD than twins who had none of these genetic or environmental risk factors [91].

A 2016 study done on opiate-dependent parents and their offspring has reported valuable findings by exploring six risk alleles of four different gene regions—DAT1,5HTTLPR,D4DR4andMAO-A,which mostly are ADHD risk factors.They concluded that opiate-dependent parents were more likely to carry almost all of those risk alleles (except forDRD4EX3) indicating that these risk alleles can predispose a person to opioid-dependence and possibly to ADHD.Children of opiate-dependent mothers were also more diagnosed with ADHD than the children of opiate-dependent fathers.Although the study did not directly mention the interaction between opioid exposure and ADHD risk alleles,it could be understood that the same gene polymorphisms that have been frequently referred to as ADHD risk alleles,might also play a role in opioid-dependence of parents and possibly predispose their children to ADHD,either through those risk alleles or opioid effects during pregnancy [92].

Conversely,another study looking for gene–environment interaction in the population of female twins showed no significant interaction between genetic risk factors and prenatal substance or alcohol use of mothers.The authors concluded that this lack of interaction might be the result of indirect association that might be present between those distinct variables [93].Interestingly,one study found that the maternal alcohol use and inheriting genetic risk factors will lead to development of ADHD in an additive way rather than an interactive way.This result means that children who have inherited the genetic polymorphisms from their mothers are more susceptible to experience environmental harms,such as maternal alcohol use,as well [94].Genetic–environment interaction—the most probable etiology for ADHD—is summarized in Fig.1.

Fig.1 Gene–environment interaction in the course of ADHD.ADHD development in a child is the result of an interaction between genetic risk factors and environmental assaults.Children who have been exposed to environmental risk factors and also have genetic predisposition are at greater risk of having ADHD

Conclusions

This narrative review aimed to provide an overview of the most studied risk factors of ADHD,both genetically and environmentally.The literature on genetic findings of this condition is vast and scattered.Given the polygenic nature of ADHD,each study has focused on only a small fraction of genetic abnormalities.Apart from genetic causes,prenatal risk factors of ADHD are also the place of controversy.Various study designs have investigated their contribution to ADHD development in the offspring,but the results are not always consistent.In addition,potential prenatal risk factors that can be correlated with ADHD are varied and need separate and comprehensive trials to be established as ADHD risk factors.

ADHD etiology is still the place of many discussions.Despite the great evidences that have covered the pathogenesis of ADHD,there is still a vague understanding about the exact causes that lead to the development of ADHD in children.Altogether,ADHD is considered as a hereditary disorder in which genes play the fundamental role in the pathogenesis.However,the findings from genetic–environmental studies support the hypothesis that genetic factors can exert their effects on the condition by determining the individual’s responses to the environmental exposures,especially those at the prenatal stage.

Author contributionsNK:conceptualization and writing—original draft.NS:conceptualization,writing—review and editing,and supervision.NR:conceptualization,writing—review and editing,and supervision.

FundingNone.

Declarations

Ethical approvalNot required for this review article.

Conflict of interestNo financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.