Molecular Genetics of Attention Deficit Hyperactivity Disorder

“Although some overlap is present in nominally significant linkage peaks, no evidence exists for the replication of a genome-wide significant finding using strict criteria.(16) To”

“A polymorphism producing an amino acid substitution (valine to methionine) at codon 66 of the BDNF may impact intracellular trafficking and activity-dependent secretion of BDNF.157 Kent and colleagues158 found over transmission of the Val66 allele and that this was accounted for by paternal (P 5 .0005) rather than mat…”

“The worldwide prevalence of ADHD in children is 8% to 12%,1 and estimated to be 4% in adults in the United States by the National Comorbidity Survey.2 Early studies found the risk for ADHD among parents of children who had ADHD to be increased by between two- and eightfold, with similarly elevated risk among siblings.…”

“Treating these ‘‘knockout’’ mice with stimulants reduces their hyperactivity.(52,53) Using a family-based association study, Cook and colleagues(54) first reported an association between ADHD and the 10-repeat allele of the 30UTR VNTR.”

“Several meta-analyses suggest strong association with ADHD and the dopamine D4 receptor gene (DRD4, 48-bp VNTR),(18,19) the dopamine D5 receptor gene (DRD5, 148-bp microsatellite marker),(18,20) the dopamine b-hydroxylase gene (DBH, 50 taq1 A allele),(8) the synaptosomal-associated protein 25 gene (SNAP25, T1065G sing…”

“focused on a tandem repeat polymorphism in exon III of DRD4 because in vitro studies have shown that one variant (the 7-repeat allele) produces a blunted response to dopamine.(26,27) Faraone and colleagues(8) conducted a meta analysis of the 7-repeat allele of the exon III polymorphism and found statistically signific…”

“Treating these ‘‘knockout’’ mice with stimulants reduces their hyperactivity.(52,53) Using a family-based association study, Cook and colleagues(54) first reported an association between ADHD and the 10-repeat allele of the 30UTR VNTR.”

“focused on a tandem repeat polymorphism in exon III of DRD4 because in vitro studies have shown that one variant (the 7-repeat allele) produces a blunted response to dopamine.(26,27) Faraone and colleagues(8) conducted a meta analysis of the 7-repeat allele of the exon III polymorphism and found statistically signific…”

“Aim of and rationale for this investigation was to test whether some ADHD and/or OCD behavioural symptoms, like impulsive and/or compulsive behaviour, may be generated in-vivo via an auto-immune challenge.”

“allele of the dopamine (DA) D4 receptor gene and the 148-bp allele of the DA D5 receptor gene [2,5].”

“The 10R allele has been associated with increased impulsivity (Congdon et al. 2009) and ADHD, although there are also non-replications and contradictory results (Rommelse et al. 2008; Yang et al. 2007; Faraone et al. 2005).”

“To test this hypothesis, we used a large previously collected sample of ADHD children to examine the impact of: (1) being male (73), (2) carrying at least one copy of the DRD4 7 repeat allele (92), (3) having comorbid mood disorder (93), (4) having comorbid anxiety disorder (93), and/or (5) having reduced right-sided…”

“However, fi ndings (Faraone and Mick 2010; Sigurdardottir et al. 2021; Yadav et al. 2021) indicate that NET, SERT, and BDNF polymorphisms do not raise the risk for adult ADHD, nor can they prove or exclude their role in adult ADHD.”

“Faraone et al. [17] provide a review of family, twin, and adoption studies and found convincing evidence that genes play an important role in transmitting vulnerability to ADHD.”

“While many candidate genes were investigated due to associations with increased risk of ADHD [45] and the presumed mechanisms of action of psychostimulants, significant polymorphic variations related to hypothesized genetic moderators were not evident in this study.”

“10 The involvement of a dopaminergic dysfunction is further heralded by the fact that stimulant medication used to treat ADHD symptoms increase synaptic dopamine levels.”

“Given the high heritability rate of ADHD (Faraone et al., 2005), many parents of children with ADHD may also find themselves experiencing symptoms and impairment related to ADHD.”

“As a kind of multiple-factor and complicated developmental diseases, ADHD is majorly associated with genetics with a heritability of about 76% (Faraone and Mick, 2010).”

“The heritability of ADHD is approximately 76% (Faraone & Mick, 2010).”

“Variants of genes involved in the dopaminergic and serotonergic neurotransmission and metabolism are suggested to involve in the pathogenesis of both disorders (8,9,10,11,12,13,14,15).”

“Studies have shown that ADHD is a highly heritable disorder, with heritability estimated at 76% (Faraone et al. 2005; Haberstick et al. 2008; Franke et al. 2009).”

“…associated with attention deficit hyperactivity dis- order (Camarena et al., 2007), obsessive compulsive disor- der (Walitza et al., 2008), autism spectrum disorders (Faraone et al., 2005), impulsivity (Eisenberg et al., 2007) and prosocial behaviors (Bakermans-Kranenburg and van Ijzendoorn, 2011).”

“ADHD is recognized as a multifactorial disorder caused by independent and interactive effects of multiple genes (Faraone et al., 2005; Gabriela et al., 2009; Guan et al., 2009; Qian et al., 2007).”

“While the aetiology of ADHD is largely unknown, there is evidence that both genetics and early life environment contribute to the development of the disorder (Faraone and Doyle, 2000, Faraone et al., 2005, Lasky-Su et al., 2008, Muller et al., 2008, Faraone and Mick, 2010).”

“76.(12) This has sparked numerous genetic studies of ADHD including”

“In addition, a family history of mental/behavioral problems should be sought during the interview because of the significant genetic components in the etiology of ADHD (Faraone et al., 2005; Pliszka et al., 2007).”

“On the other hand, genetic polymorphisms of the dopamine system are described which are associated with ADHD (Banaschewski et al., 2010; Faraone et al. 2005; Levy et al., 1997; Tannock, 1998).”

“The dopamine-deficit hypothesis postulates that patients with ADHD show a deficiency in the amount of available dopamine and noradrenalin, resulting in uninhibited behavior (Faraone et al., 2005; Prince, 2008).”

“Attention-deficit hyperactivity disorder (ADHD), characterized by problems in attention, impulse control and activity regulation (American Psychiatric Association, 2000), is one of the most common psychiatric disorders, with a strong genetic disposition (Faraone & Mick, 2010).”

“A variable number tandem repeat (VNTR) of 7 alleles in the dopamine D4 receptor gene (DRD4) and a 148-bp microsatellite repeat in the dopamine D5 receptor gene (DRD5) have been consistently associated with ADHD [11,12,13,14,15,16].”

“comprising the described risk genes known in the literature (Faraone and Mick 2010; Gizer et al. 2009), and corticotropin-releasing factor binding protein (CRHBP) was selected as a response to stress, which is also thought to be a risk factor for ADHD, to assess their expression profile in peripheral blood samples tak…”

“The genetic nature of this disorder is supported by the identification of various susceptibility gene variants in ADHD (16).”

“Another variation involves the dopamine D4 receptor gene (DRD4) 7-repeat allele that is found more frequently in individuals with ADHD than in typical children and has an inhibitory effect on dopamine (Faraone et al., 2005; Faraone & Biederman, 1998; Lynn et al., 2005).”

“away from the mean, (2) having no age or IQ information, (3) per-individual call rate <95% and (4) with relatives having genome identity PI_HAT ≥ 0.”

“heritability estimates derived from twin studies (Chang et al., 2013; Faraone et al., 2005).”

“Genetic heritability is reported to account for approximately 75% of ADHD cases (Faraone et al., 2005), whereas environmental factors, such as early traumatic experiences, are estimated to account for 25% of cases (Ben Amor et al., 2005).”

“…genome contributes to differences between children in emotional and behavioral problems has been estimated between 0.4 and 0.8 for a wide range of problems (e.g., Faraone et al., 2005; Geschwind, 2009; Gregory & Eley, 2007; Kan et al., 2013; Nivard et al., 2014; Rhee & Waldman, 2002; Rice, 2009).”

“Complex interactive effects of several genes with individually small impact [61] have been suggested to underlie ADHD.”

“A comprehensive review found that 5-HTTLPR was significantly associated with ADHD (Faraone et al., 2005), and a recent meta-analysis specified that the long allele increased susceptibility to ADHD (Gizer, Ficks, & Waldman, 2009).”

“It has been the hope of genetic studies that discovering new biological pathways would provide new targets for treating attention deficit hyperactivity disorder (ADHD) [Faraone and Mick, 2010].”

“The familiality of the ADHD diagnosis highlights the need for clinicians to screen parents of children with ADHD [29].”

“Attention-Deficit/Hyperactivity Disorder (ADHD) is a heritable neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, hyperactivity and impulsivity (American Psychiatric Association, 2000; Faraone et al., 2005).”

“The genes most consistently found to be associated with ADHD include the dopamine receptors D4 (DRD4) and D5 (DRD5), the dopamine transporter (DAT1), the synaptosomal protein of 25kD (SNAP25) and the serotonin receptor 1B (HTR1B) [Faraone et al., 2005; Thapar et al., 2005], but the odd ratio associated with each of th…”

“Despite these recommendations, a cross-sectional email survey study done in 2016 sent to all 1076 NCAA institutions demonstrated that only 39% of institutions had a “written plan related to identify student-athletes with mental health concerns” [7].”

“Individuals with PKU and ADHD seem to have low levels of DA in common, causing the hypodopaminergic state found in both disorders to be a possible link between these two conditions, and individuals with PKU could have a greater predisposition to the development of ADHD.”

“Genetic linkage studies, which were among the earliest genome-wide approaches used in ADHD research, sought to identify chromosomal regions associated with ADHD inheritance within families [59].”

“Heritability estimates are as high as 60–80%, and studies have showed a five-fold risk of developing ADHD and a four-fold risk of symptom persistence into adolescence and/or adulthood in children with a positive family history of the disorder [12–16].”

“Additionally, given that ADHD is highly heritable (Faraone et al., 2005), parental ADHD is likely a common feature in families with children with disruptive behavior disorders and may exacerbate familial stress (Theule et al., 2011) and other co-occurring psychopathology within these families.”

“, twin studies) has estimated up to 76% heritability for ADHD, with current consensus that multiple genes of small effects are likely to be implicated [4].”

“ADHD is highly heritable and runs in families (Faraone et al., 2005).”

“Being a multi-factorial genetic disorder with around 76 % heritability [11, 12], genetics is believed to play significant role in the etiology of ADHD [13, 14].”

“Some evidence points to a genetic basis of ADHD which is likely to involve many genes with minor individual effects [6].”

“ADHD has a strong genetic background, and many different factors play a crucial role in its aetiology and course (Faraone and Mick 2010).”

“The substantial heritability rate of 74% associated with ADHD has catalyzed extensive investigations into identifying ADHD susceptibility genes (2, 18, 19).”

“The aetiology of ADHD is multifactorial and includes both genetic and 57 environmental factors (6,7).”

“Additional pathogenetic variants (small CNV and SNV) can be identified by exome sequencing as showed by Lima et al14 who sequenced 30 Brazilian trios with sporadic ADHD.”

“Specific single dopaminergic, noradrenergic, and serotonergic candidate genes have been significantly associated with ADHD status (Faraone et al., 2005; Gizer et al., 2009).”

“Twin studies have established that traits of inattention and traits of hyperactivity/impulsivity are hereditary in nature, with ADHD estimated to be 76% heritable (Faraone et al., 2005).”

“Although ADHD has a heritability of .76 (Faraone & Mick, 2010), the heterogeneity and complexity of the factors contributing to ADHD result in difficulties determining its etiology and early risk factors.”

“The disorder is observed to aggregate in families, and the heritability of childhood ADHD (cADHD) has been estimated to around 76%, giving evidence of a strong genetic component (Faraone et al. 2005).”

“The resulting defect in the DAT gene would be responsible for decreasing dopamine uptake, without impairing the possibility of an increased expression of the DAT protein [31, 32].”

“Possible associated genes involved were DAT1, DRD4, NET1, ADRA2A, CES1, HTT, and GRM7 (Seeger et al. 2001; Hamarman et al. 2004; Cheon et al. 2005; Faraone et al. 2005; Cheon et al. 2007; Polanczyk et al. 2007, da Silva, et al. 2008; Kooij et al. 2008; Mick et al. 2008; PurperOuakil et al. 2008;…”

“Although the results of GWAS and candidate gene studies of ADHD thus far were not consistent, recent reviews (Faraone & Mick, 2011; Thapar et al., 2012) concluded that the dopamine transporter genes DAT1 and SLC6A3, the dopamine receptor genes DRD4 and DRD5 and SNAP25 on chromosome 20p12, and the…”

“A strong genetic contribution to ADHD problems has been demonstrated in population-based twin studies, with 75% of variation in children with ADHD explained by genes (Faraone & Mick, 2010; Faraone et al., 2005; Freitag, Rohde, Lempp, & Romanes, 2010).”

“Dos polimorfismos de tipo SNP localizados en la región 3’UTR del gen, rs3746544 y rs1051312, se han evaluado en distintas poblaciones con TDAH, y se han obtenido resultados dispares [69,74-79].”

“Faraone et al, 2005 ; Mick & Faraone, 2008 ; Thapar, Langley, Owen, & O'Donovan, 2007).”

“However, there is converging evidence coming from neuroimaging, genetic analyses, neurochemistry, neuropharmacology and animal models that points to the dysfunction of the fronto-subcortical pathways as a salient factor in the pathophysiology of ADHD [1,2,5-7].”

“177 most studies including meta-analyses found no connections between the Val158Met polymorphism and inattention (Faraone et al., 2005; Gizer et al., 2009; Hosák, 2007).”

“Variants of this gene that lead to an increased density of DAT transporters in the striatum and prefrontal cortex result in an accelerated reuptake of synaptic dopamine [27,40].”

“These developments will affect our decision to prescribe children psychostimulant medication for the treatment of ADHD.”

“2013) and ADHD (Albrecht et al.”

“Ein Beispiel: Als gut gesichert gilt der Befund, dass ADHS erblich bedingt ist und verschiedene Gene mit insgesamt kleinen Effekten zu einer Erblichkeit von 76% beitragen [Review: Faraone et al., 2005].”

“Both ADHD symptoms and EF show strong heritability (Chang, Lichtenstein, Asherson, & Larsson, 2013; Faraone et al., 2005; Friedman et al., 2008), and EF has been suggested as endophenotype for ADHD (e.g., Doyle et al., 2005; Gau & Shang, 2010), indicating that they share important genetic factors.”

“We can also intuit the continuous nature of ADHD symptoms from population twin studies of ADHD which have used continuous measurements of symptoms; those studies found that ADHD’s heritability is of the same magnitude as that found from twin studies using categorical diagnostic methods (1).”

“Although studies conducted and evidences found suggest that the disorder can most probably be associated with genetic factors [11,12], it appears as a complex structure also covering environmental factors such as lead poisoning, nutrient sensitivity or nutritional anomaly [13,14].”

“The risk of ADHD among parents of children with ADHD is increased by 2 to 8 fold comparing with the population rate (Faraone et al., 2005).”

“For example, presence of an allele with seven or more repeats (a ‘ long’ allele) is associated with attention-deficit hyperactivity disorder (ADHD; Faraone et al. 2005; Kuntsi et al. 2006) and difficulties with sustained attention in infants and young children (Auerbach et al.”

“ADHD also has a strong heritability, estimated to be as high as 76% (Faraone et al. 2005) and associated with impairment in social, academic and job-related functioning in both children and adults and constitutes a major health issue (Moriyama et al. 2012).”