Genetic Dimension of Attention Deficit Hiperactivity Disorder

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neuropsychiatric disorders among children with 8-12% incidence. ADHD in our country is seen between 8.6 and 8.1 % in normal population; and 8.6-29.4 % in clinical samples. ADHD diagnosed in childhood, continues to seen in adolescence with 50-80% ratio, and in adulthood with 30-50% ratio. Effects on functionality of ADHD diagnosis proceed lifetime. So, this disorder has also drawn attention of adulthood psychiatry.

 

Imaging studies determined functional and structural brain abnormalities in children, adolescents and adults who have ADHD. These studies found that there are decreaeses in orbitofrontal cortex, basal ganglions, some parts of corpus collosum and cerebellum. In addition, people with ADHD have lower brain volume. These findings are interpreted as distortions in fronto-subcortical and cerebellar circuits.

 

Neurophysiological and neuropsychological studies also support that ADHD is related with frontal structures. According to this, it was found that there are distortions in executive functions, and decrease in electrical activity of frontal lobe detected by quantitative electroencephalography (Q-EEG), electroencephalography (EEG). More than one neurotransmitters can play a role in ADHD mechanism. However,  since children, adolescents, and adults with ADHD respond to the dopaminergic and noradrenergic treatments, etiology of the disorder focuses on dopamine and noradrenalin.

 

The importance of genetic factors of ADHD is firstly demostrated by Cantwell, Morrison and Stewart. Even other studies support the importance of these factors, further researches should be performed to determine unique genetic abnormalities and a special genetic model.

 

The genetic dimensions of ADHD has drawn attention in the world and in our country lately. Researches on genetic dimensions of ADHD, twin studies, adoption studies, family studies, segregation analyses, and molecular genetic studies are tackled. The importance of comorbidity with family studies is also evaluated. 

 

 

Family Studies

           

Researches have shown that if one parent had ADHD diagnosis, incidence of disease in children is 20-54%. Therefore, it can be concluded that ADHD can pass through the family. It has been suggested that trasmission of hyperactivity-impulsivity is less than attention deficit.

 

A meta-analysis, which is conducted on parents of ADHD diagnosed children, showed that relative risk is 2-8 times higher for their children. These studies supported familial transmission of ADHD.

 

There are to studies applied in our country, which evaluate the pathology of parents of ADHD children, adolescents and adults. First study showed that ADHD symptoms of these parents are significantly higher than control group. Parents with ADHD have incidence 33.8%, whereas in control group, the incidence is 6.3%. Another study showed that incidence of adulthood ADHD is 6.8% in parents of children with ADHD.

 

Sibling Studies

 

Risk of encountering in akin’s of people with ADHD varies between 10% and 35%. Risk of encountering in siblings of people with ADHD is about 25-35% and the risk is 3 times more than normal population. If both parents have ADHD diagnosis, then the risk raises to 57% in this children. According to one study, which compared ADHD incidence in 19 blood siblings and 22 step siblings raised by same mother, almost half of blood siblings and only 2 of step siblings had ADHD diagnosis at the same time. This significant difference proved the importance of genetic factors. Another studies also found that ADHD incidence is raised 2.1-3.5 times in siblings of children with ADHD.

 

These findings supported that ADHD has familial tranmission. Also, it was concluded that molecular genetic studies of ADHD which becomes permanent in adulthood should be researched due to these findings.

 

Other studies also supported that ADHD has familial transmission especially for siblings.

 

Family and Comorbidity Studies

 

In one the first examples of family and comorbidity studies, Cantwell determined higher ratio of sociopathy, hysteria and alcoholizm in parents of ADHD diagnosed children. Also, Morrison found that incidence of unipolar affective disorder is higher in second degree relatives of children with ADHD.

Lahey and colleagues compared the psychopathology incidence of parents of children who have both conduct disorder and ADHD. This study showed that parents of these children have higher rates of substance abuse. Also, mothers of children with conduct disorder are found to be more depressive. This study also found that parents of children with ADHD, have no important disorders; however, fathers of children with ADHD accompanied with conduct disorder, have higher ratio of aggression, arrestment, and conviction.

Other studies have also supported that ADHD and major depression show mutual familial predisposition. Grouping ADHD children according to bipolar disorder and conduct disorder comorbid diagnoses may provide more homogene samples for family studies.

 

 

Twin Studies

 

There are two kinds of twins according to their hereditary structures: monozygotic (MZ) and dyzigotic (DZ). MZ twins share the whole genes; whereas, DZ twins share 50% of the genes. So, twin births are natural experiments and help researchers to differentiate genes and environmental factors in psychiatric and neurodevelopmental disorders.

 

If a disorder is affected by genetic factors, MZ twins have higher risks for concordance. Data provided from twins is necessary for evaluating heritability, which is a measurment that shows effecting degree from genetic factors. Heritability varies between 0 and 1, and higher scores show the increase in genetic effect size. When 15 studies conducted by Faraone and Doyle are evaluated, it was found that etiology of ADHD occurs 80% by genetic factors. Concordance ratio show that this disorder can not be explained only with genetic factors.

 

One of the researches found that MZ twins are more alike than DZ twins on psychomotor activities. Other studies showed that MZ twins have more similar motor hyperactivity (59%) than DZ twins (33%).

 

Another study evaluated the attention level of the twins. It was found that MZ twins have more similar attention levels (correlation of 0.68) than DZ twins (correlation of 0.29). Same study supported that school performance and conduct problems are affected by genetic factors.

 

On the other hand, environmental factors are also very important on attendance to academic activities, anxiety/depression, and conduct disorder. A study that evaluates genetic dimensions of ADHD found that ADHD concordance in MZ twins is 50-84%. This concordance is 30-40% in DZ twins.

 

Some studies found that heritability on both motor activities and attention is 75%, attetion and attention related behaviors are 98%

 

Other studies conducted for ADHD symptomatology support that the effects of heritability is higher than environmental factors. Rhee and colleagues evaluated gender differences between siblings in ADHD. They found that genetic and environmental factors show similarity both for boys and girls. They also found that environment for girls and genetic factors for boys are more dominant.

 

Adoption Studies

 

Just like twins studies, adoption studies offered and important opportunity to determine genetic and environmental dimensions on psychiatric disorders. Biological parents can transmit the risk for a diseases in genetic and envrionmental way. However, they can transmit it to the children they adopt only in environmental way. So, examining adoptive parents and biological relatives of adopted children can help us differentiate genetic and envrionmental factors.

 

Some adoption studies support the genetic etiology for ADHD. Early studies found that parents who adopt hyperactive children show higher performance than biological relatives of adopted children on attention measurements.

 

Segregation Analyses

 

Segregation analyses provide a prove for genetic transmission by evaluating dysfunction pattern in families and known genetic mechanisms. One of the first researches that focuses on heredity models, transmission with y chromosomes is examined. However, it was concluded that because of the high frequency of genetic transmissions between father and the child, this transmission can not be the basis of pathophsiology of ADHD.

 

Deutsch and colleagues evaluated dysmorphic children with ADHD diagnosis and claimed that dysmorphic changes are inherited otosomal dominant. 48 family trees were evaluated in this study and results were obtained about one dominant gene which can have on ADHD diagnosis and faded physical abnormalities. However, the sample is small in this study and further studies should be applied with larger sample groups.

 

Similarly, another researcher found that familial distribution of ADHD can be compatible with the effect of one major gene.

 

However, one certain description couldn’t be determined for ADHD heredity. If there is a more than one genetic factor for ADHD, evidences for one transmission will be insufficient. On the other hand, few genee which have medium degree of effect can interact with each other and cause ADHD to occur.

 

Available data show that ADHD can be a complicated genetic disorder which is formed by many genes that interact with each other and environment.

 

Molecular Genetic Studies

 

Abnormalities in numbers or structures of chromosomes may cause many disorders such as mental retardation, pshysical abnormalities or severe clinical diseases.

 

Structural abnormalities of chromosomes are not researhed systematically. Fragile X, Clinefelter (47, XYY) and Turner (45, XO) syndromes have found to have a relationship with hyperactivity and/or attention problems. Since these syndromes are rarely found, they explain small amount of clinical cases with ADHD diagnosis.

 

Molecular genetic studies to enlight genetic dimensions of ADHD use 2 main approaches; Genome Scannings and Candidate Gene Approach. Genome scannings, scan all chromosomal campuses. Candidate gene approach evaluated one or few possible genes which may have affect on the disorder. In a genome scanning for ADHD, 125 siblings were evaluated and correlation imbalance is found for 5p12, 10q26, 12q23 and 16p13.

 

Candidate gene studies for ADHD also provide clues for causes of disease. For example, Hauser and colleagues found that a rare and familial form of ADHD occurs as a result of mutation in tyroid receptor b gene and resistance of tyroid hormone (THGD). Since this form is extremely rare in people with ADHD diagnosis (1:2500), it can’t be responsible for most of the ADHD cases. 

 

Researches applied in our country showed that tyroid functions of children and adolescents with ADHD is normal.

 

Any theory about the pathophysiology of ADHD should consider the pharmacotherapy of this disease. Dopamine or norepinephrine reuptakes are prevented in the treatment of ADHD. Whereas, the effects of drugs which have influence upon nicotinic system, is lower. Also, drugs that have influence on serotonergic system, are not used for the treatment of this disease.

 

Animal Models

 

To model symptoms of ADHD in experimental animals, dopaminergic pathways are damaged by using 6-OH-dopamine. Since hyperactivity is developed in these rats, ADHD can be modelled in an effective way. Also, monkeys can be used for modeling in ADHD researches by damaging function of fronto-striatal pathways with a neurotoxin. Attention deficits and vigilance disorders are also observed in these monkeys just like children and adolescents with ADHD. 

 

Because of the locomotor hyperactivity and performance distortions in rats, researchers used these animals for modelling of ADHD. Studies with these rats supported that neurodrenergic and dopaminergic systems have an important role in the formation of ADHD. For example, when compared with rats in control group, spontaneous hypertensive rats have lower dopamine release.

 

In another study, changes in presynaptic regulation of dopamine cause down regulation in dopaminergic system. Researchers claimed that this finding was happened as an answer to the abnormally increased dopamine release in early phases of development.

 

Some other researchers claimed that, in formation of ADHD-like behaviors in spontaneous hipertensive rats, cortico-striatopallidal system plays an important role.

 

Functional Candidate Gene Association Studies

 

·         Dopamine D4 Receptor Gene (DRD4)

 

DRD4 gene got great attention as a candidate gene for demonstrating normal and abnormal people behaviors, since the day it discovered. Candidate gene studies spesifically focused on 48 base double consecutive repeated number in exon 3. This region connects to G proteins and regulates its signal transmission with changes in cAMP levels. Allele frequencies differentiate among societies.

 

Early researches claimed that 7R allele is related with ADHD and seeking innovation. Even if these two are related phenotypes, relationships about seeking innovation is controversal. These findings contradict with ADHD and 7R allele relationship.

 

Faraone and colleagues conducted a meta analyses and found a relationship with ADHD and 7 repeated DRD4.

 

It was reported that when compared with 4R variant, 7R variant has lower function in reducing cAMP. However, recently, it was found that 7R variant showed more imbalanced connection to adjacent polymorphism. The increased frequency of 7R can be related with positive selection. This finding supports that 7R has adaptiveness for characterictics of human behaviors.

 

There are additional findings that support these molecular genetic data. For example, both noradrenaline and dopamine show strong agonistic effect for DRD4. In vitro studies showed that response of DRD4-7 allele to dopamine is reduced.

 

·         Dopamine Transporter Gene (SLC6A3)

 

Considering effects of stimulant drugs in ADHD, SLC6A3 is one of the most important genes. Almost all studies showed that this gene is related with 480 base-double and 10 repeaed allele.

 

ADHD is considered with DAT1 protein which is produced by 10-repeated allele. This finding supoorts the proposition of being removed of dopamine from synaptic cleft. However, this finding has not repeated in additional studies.

 

When SLC6A3 gene became functionless in rats, they showed hyperactivity and disinhibition-like behaviors. Also, hyperactivity in these rats is decreased with stimulant treatments.

 

Dougherty and colleagues evaluated dopamine transporter density with SPECT and found a 70% increase in dopamine transporter of adults with ADHD. These findings were verified by other researchers. They also found that findings went back to normal after treatment with methylphenidate.

 

·         Dopamine D5 Receptör Gene (DRD5)

 

DRD5 was found related with ADHD and proved by many studies. Even if this reationship is possible, there is still no evidence about functional role of  repeated dinucleotide.

 

In a study, which is important for relationship of ADHD and comorbid diseases, it was found that DRD5 148 base allele is related with Oppositional Defiant Disorder, which is common in children and adolescents with ADHD diagnosis.

 

·         Catechol-O-Methyl Transferase Gene (COMT)

 

In studies that investigate the relationship of performance in neuropsychological tests and molecular genetik findings, it was found that COMT-val allele and monoamine ocsidase A (MAO A) are realted with attention problems. Four studies evaluated the relationship of ADHD and COMT gene which plays a role on destruction of dopamine and noradrenaline. As a result, these studies find a relationship between COMT gene and ADHD

 

·         SNAP-25 (Synaptosomal-Associated Protein)

 

Some researchers used coloboma rat model to investigate genetic basis of ADHD. These rats carry coloboma mutation. This mutation is characterized with distortions in dopamine release which may cause learning disorders, hyperactivity and hippocampal function disorders. Coloboma rat mutant shows a determined motor hyperactivity which is caused by stimulant drug (D-amphetamine). Hess and colleagues claimed that hyperactivity in these rats is related with SNAP-25 function distortion. Therefore, when the SNAP-25 gene is activated, hyperactivity of these rats is decresed. Additional findings showed that decrease in SNAP-25 gene causes functional distortions in dopamine and serotonine.

 

Even if there is insufficient findings, SNAP-25 may cause ADHD by affecting the release of dopamine and other neurotransmitters.

 

·         Genes that Code Serotonine Transporter (SLC6A4) and Receptor (5HT1B, HTR1B,5HT2A)

 

Some researches showed that when DAT gene becomes functionless in rats, hte positive effects of stimulants include serotonergic system. Puumala and Sirvio demostrated that frontal cortex dopamine and serotonine function is important in regulating attention and motor reactions. In another study, the unfunction of 5-HT1B gene caused decrease in anxiety, and increase in motor activities of rats.

 

Even if some association studies found a relationship between ADHD diagnosis and SLC6A4-HTR1B, number of cases is not enough for meta-analysis.

 

 

Correlation Studies

 

There are 3 kinds of genome correlation studies available in ADHD etiology. Two of them are conducted in USA and Holland on sibligns with ADHD, and one of them is conducted in Colombia on mixed family members. In study of Holland, there are two possible correlations indicated in chromosome 7p and 15q. In study of USA, there was a significant correlation in 16p13 gene.

 

Gene-Phenotype Relationship

 

ADHD exhibits a mixed table in terms of causality and look, just like other neuropsychiatric disorders. Therefore, it can be determined in a better way with stimulation, concentration, motivation and many other subdimensions.

 

Gene – Environment Relationship

 

The evaluated data showed that genetic factors are not enough for ADHD, environmantal factors also play an important role. The most consistent findings for environmental factors are; exposure to smoking in the womb, and low weight of birth. Also, it can occur with features such as personal resistance and predisposition. Therefore, all individuals exposed to risk factors may not develop ADHD. 

 

Results and Limitations of Studies

 

 

The available data show that genetic factors play a role in formation of ADHD and it can last lifetime. Researhes found neuroanatomic and neurochemical evidences that include various neurotransmitter systems. Frontal lobe, dopaminergic and noradrenergic neurotransmitter systems found to be related with ADHD. Molecular genetic studies indicated some candidate gense related with dopamine system. the most attractive ones of these are DRD4 and DAT1 genes. 

 

The ADHD phenotype is found nonspecific and it can be seen in some other genetic diseases such as Fragile X Syndrome and Turner Syndrome. The relationship of DAT1 allele and DRD4 allele with ADHD is not fully explained and further studies should be performed.

 

CONCLUSION

 

ADHD is an important psychiatric disorder which has high rates of genetic transmission. Despite the importance on diagnosis and treatment, the etiology of ADHD is not enlightened in an effective way. So, this disorder is seen as a complex problem that occurs both with genetic and environmental factors. Recently, molecular genetic basis of ADHD is studied to find certain reasons of the disease.

 

Gene studies didn’t overlap with each other beacuse of the heterogenity and statistical limitations.

 

 

 

 

(Gizem Melissa Akgün, A. Evren Tufan, Nihal Yurteri, Ayten Erdoğan-Current Approaches in Psychiatry 2011; 3(1): 15-48; T. Banachewski, L.A. Rohde, Biological Child Psychiatry, Vol.24, 2008)

 

 

 

(Published in www.ozlemozcan.com  website on 15.05.2013)

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