The DRD4 (Dopamine Receptor D4) Gene
This is a Neurodivergence blog post about the DRD4 (Dopamine Receptor D4) gene. Its position is Chromosome 11:637,269-640,706. I have been interested in this gene for almost two decades because of its connection to novelty seeking and Attention Deficit Hyperactivity Disorder (ADHD). Approximately 2.6% adults worldwide have persistent ADHD from childhood. Approximately 6.8% adults worldwide have symptomatic ADHD.
Almost two decades ago, I got Thom Hartmann's book, The Edison Gene. It is based on the research studies of DRD4 7 Repeat allele which is present in 20% of the human population. DRD4 7R allele has high frequency in the Americas but low frequency in Asia. It has been strongly linked to both ADHD (Attention Deficit Hyperactivity Disorder) and a behavior trait called "novelty seeking" which often underlies addiction. Scientists suggest that DRD4 7R occurred recently in human evolution between 10,000 and 40,000 years ago which was the period that anthropologists concur that humans were developing the first signs of complex societies involving agriculture, rudimentary governments, and the creation of cities for the first time. Humans were also rapidly expanding and exploring the planet. The DRD4 7R is shown to be an unusual, spontaneous mutation which became an advantage for humans, and so it became increasingly prevalent.
page 4 - 5 THE EDISON GENE ADHD And The Gift Of The Hunter Child by Thom Hartmann
What exactly defines those bearing this genetic makeup?
Edison-gene children and adults are by nature
Enthusiastic
Disorganized
Non-linear in their thinking (they leap to new conclusions or observations)
Innovative
Easily distracted (or,to put it differently, easily attracted to new stimuli)
Capable of extraordinary hyperfous
Understanding of what it means to be an "outsider"
Determined
Eccentric
Easily Bored
Impulsive
Entrepreneurial
Energetic
All of these qualities lead them to be natural:
Explorers
Inventors
Discoverers
Leaders
https://www.goodreads.com/book/show/548387.The_Edison_Gene
Thom Hartmann points out that those carrying the DRD4 7 R often find themselves in environments where they're coerced, threatened, or shoehorned into a classroom or job that doesn't fit. He said when Edison-gene children can be have great emotional and spiritual wounding when they are aren't recognized for their gifts but instead are told that they're disordered, broken, or failures. He points out that the wounding can bring all sorts of problems for children, for the adults they grow into, and for our society. He and many scientists, educations, physicians, and therapists believe that when these unique children don't succeed in public schools, it's often because of a disconnect between them---their brains are wired to make them brilliant inventors and entrepreneurs--and our schools, which are set up for children whose brains are wired to make them good workers in the structured environments of a factory of office cubicle.
Over a decade ago, I got tested for the DRD4 7 Repeat allele through FamilyTreeDNA. I was told that I didn't have it. I was a bit disappointed because I strongly felt that I had it. I can strongly relate to the DRD4 traits which I see in my mother and run strongly in my maternal grandfather's side of the family. From what my mother and paternal Aunt Carrie told me, my father had them too. After doing testing through the DNA company Sequencing around a year and half ago, I found out that I have a 5 Prime Untranslated Region (5'UTR) single nucleotide variant 11-637294-C-T in the Promoter in DRD4 and has an allele frequency of 5.169%. Promoter is a binding site in a DNA chain at which RNA polymerase binds to initiate transcription of messenger RNA by one or more nearby structural genes. I have another variants that is in Promoter in DRD4. It is an intronic variant 11-637622-C-T that is 328 base pairs downstream of 11-637294-C-T with an allele frequency of 5.871%. I have a 2 KB Upstream variant in a Transcription Factor binding site 11-636929-C-T that is 365 base pairs upstream of 11-637294-C-T with an allele frequency of 3.415%. I have an intronic variant in a CTCF binding site 11-637933-G-A that is 639 base pairs downstream of 11-637294-C-T with an allele frequency of 22.86%. Finding out that I have these DRD4 variants has definitely increased my interest in DRD4 by a lot to the point that I had to make a blog post about it. 11-637294-C-T has been reported as Uncertain Significance for Hereditary Attention Deficit Hyperactivity Disorder in ClinVar. Both my mother and I have the 5'UTR Promoter variant, but the other variants data are unavailable for my mother. My father is dead, and so I have no way of knowing if I inherted DRD4 variants from him.
The DRD4 gene, which encodes the D4 dopamine receptor, is found in the p15.5 region of chromosome 11. The DRD4 receptor is found at the synaptic end of neurons and has a high affinity for dopamine and norepinephrine in the synaptic gap. It is a catecholamine receptor that participates in the transmission of the DA neurotransmitter between neurons. The D4 is a presynaptic dopamine receptor that regulates dopamine synthesis and release as well as controlling motor behavior, drug misuse, hormone production, and antipsychotic targets in schizophrenia. DRD4 is the top gene that is associated with ADHD. It is also the 11th top gene associated with co-morbid Dyslexia and ADHD according to 2023 Published 'Associative gene networks reveal novel candidates important for ADHD and dyslexia comorbidity'. I am working on a blog post based on the study and will include my potential indicators for my ADHD-Dyslexia co-morbidity. ADHD is commonly associated with Developmental Dyslexia. Clinically, the co-morbidity incidence of DD and ADHD is between 25 and 48%. As a neurodivergent with Dyslexia, Dyspraxia, ADHD co-morbidity, I find that very interesting.
As an excitatory neurotransmitter in the brain, dopamine primarily governs a number of central nervous system activities. When dopamine levels in the brain are low, children’s brains lose their capacity to manage irrelevant inputs, causing them to selectively filter irrelevant stimuli and become unable to maintain focus, resulting in ADHD. The expression of DRD4 was observed to be up-regulated in ADHD.
DRD4 is an established drug target for the treatment of ADHD. Dopaminergic function is considered to be critical for the modulation of neural activity in the striato-thalamo-cortical circuit, which is involved in complex goal-directed or context-dependent changes in human speech and bird song output. The dopaminergic system also plays an important role in maintaining linguistic functions such as speech fluency and reading, and a number of genetic polymorphisms in this system have been identified as important risk factors for dyslexia. For instance, a dyslexia susceptibility locus (DYX7) has been found to be linked to the dopamine D4 receptor (DRD4) region on chromosome 11p15.5 in participants of European ancestry.
DRD4 variants are linked to selective cognitive impairment of working memory and behavioral flexibility. Working memory is a type of temporary information processing and storage that aids in the coordination of many actions and tasks. People with dyslexia have been shown to have deficiencies in particular language abilities and working memory. Therefore, variants in the DRD4 gene might potentially impair working memory in people with dyslexia. Working memory is definitely one of my problems. I scored in the impaired range in immediate visual memory and borderline impaired range in immediate verbal memory but both my visual and immediate memory scores were low average after time of delay. Therefore, the Veteran Affairs neuropsychologist noted that it was a problem of encoding and organizing information for I had retained much of what I learned. My memory problems include remembering what I read, listen, and actions being shown to me in very short amount of time. They included problems remembering a sequence of words and actions. The VA neuropsychologist told me that I have problems with strings of oral and written words.
DRD4 gene also has connection to high sensitivity. DRD1, DRD2, DRD3, DRD4, and DRD5 were 5 of the 16 dopamine-related neurotransmitter genes that were included in 2011 Published 'Contributions of Dopamine-Related Genes and Environmental Factors to Highly Sensitive Personality: A Multi-Step Neuronal System-Level Approach' which is the genetic study of The Highly Sensitive Person (HSP) trait which is present in around 15 to 20 percent of the human population. I am an ultrasensitive person like many neurodivergents are. I got Elaine Aron's books and even created a MSN group based on her books back in 1999. The dopamine system is believed to play a major role in personality. Previous research on gene-personality associations implicated various dopamine genes in personality variations. Previous research on gene-personality associations has also implicated various dopamine genes in personality variations. Some of DRD4's biological processes are involvement in behavioral fear response, involvement in fear response, and involvement in social behavior. I know that I tend to easily feel threatened and have strong reaction to perceived danger. I have a strong 'fight or flight' response. If people have looks of anger and in my personal space, I feel very threatened and get very angry. I tend to overreact to emotional/social cues.
I do wonder if my DRD4 variants factor into my being a very fast runner with quick reflexes when I was a young. I definitely believe that they're connected to my having a great reservoir of energy that keeps me from being tired from doing cardio even now in my early 50s, and that also factored in my being very fast runner when I was young because I was able to push myself very hard. My former track coach claimed in front of me and my track mates that I didn't get tired when running. He and other track coaches said that I run very hard. I believe that my speed and hyperactivity were strongly connected. I also believed that intensity was involved. I had a tendency to ball up my fists when I run. The track coach often reminding to relax when I am running. I would tense up a lot. I ran track only briefly in sophomore year of high school because my grades were bad.
I was diagnosed as having inattentive type ADHD in my 30s. I believe that I have a combined type. I didn't get diagnosed as having ADHD in childhood because my other neurodivergent conditions were masking it. There was much more concern about my speech, auditory processing, and coordination problems. I got spanked a lot in my special education childhood years, and so that influenced me to have adequate behavior. Instead of running around in the classroom, I was running around in my head. I saved my hyperactivity for outside the classroom except for fidgeting and talking a lot in classroom. Looking back, I now understand that I was always very nervous, highstrung, and anxious in classroom and work environments. I now realize much of it was in connection to being overstimulated by the bright, flourescent lights that tend to be in the indoor environments and not just my feelings of intellectual inadequacy and information processing difficulties.
Having any of these DRD4 variants doesn't necessarily mean that you have ADHD nor Dyslexia. It could just be that you have abnormalities in the molecular functions and the biological processes of DRD4 that manifest into particular phenotypes. It could be that you're just a highly sensitive person that's a non-linear, visual, picture thinker and novelty seeker.
Having all four of the variants seems to point to being at high risk for ADHD and Dyslexia. I have variants in other genes that are thought to have connections to ADHD and Dyslexia, and some are uncommon and even rare. I am working on a blog post about them.
I also have Ataxia which is rare neurological condition, and I have some rare variants that show potential for serious neurological problems.
https://neurodivergence.blogspot.com/2024/01/my-neurological-makeup-includes-both.html
My DRD4 variants are interesting from an evolutionary and population genetics standpoint.
The 11-637294-C-T's frequency is highest in Amish with a frequency of 9.051%. The second highest frequency is in Ashkenazi Jews with a frequency of 7.914% closely followed by South Asians with a frequency of 7.873%. My mother has the variant, and so I inherited it from her. The segment where she and I share the variant is Ashkenazi Jewish according to 23andme. My maternal grandmother's mother Ruth Rosenthal was a first generation American daughter of Ashkenazi Jewish immigrants. Her father Max Rosenthal was born in Romania, and her mother Rachel 'Irene' Hosias was born in Courland in the area in the Russian Empire that became Latvia. 11-637294-C-T's frequency is lowest in East Asians with a frequency of 0.01913%.
In strong contrast, two of the other DRD4 variants are common in East Asians.
The 11-636929-C-T's frequency is highest in East Asians with a frequency of 16.81%. It is lowest in Africans/African Americans with a frequency of 0.8413%. Data is unavailable for my mother, and so I don't know about the inheritance.
The 11-637622-C-T's frequency is highest in East Asians with a frequency of 14.62%. It is lowest in Africans/African Americans with a frequency of 2.017%. Data is unavailable for my mother, and so I don't know about the inheritance.
https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-023-01502-1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135587/
https://www.nature.com/articles/s41398-021-01473-w
https://link.springer.com/article/10.1007/s11682-021-00521-9
https://pubmed.ncbi.nlm.nih.gov/14755455/
https://www.psychologytoday.com/us/blog/the-gift-adhd/201604/adhd-and-the-rock-star-gene
Youtube Videos about DRD4
https://www.youtube.com/watch?v=mK3iiN9iUBU&t=231s
https://www.youtube.com/watch?v=QhhnKujYNw8
https://www.youtube.com/watch?v=U7n8ANrYEVs
https://www.youtube.com/watch?v=R9AOBLyxwEA
https://www.youtube.com/watch?v=sDRcVOl9res
Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements
Lucy W. Barrett,corresponding author Sue Fletcher, and Steve D. Wilton
There is now compelling evidence that the complexity of higher organisms correlates with the relative amount of non-coding RNA rather than the number of protein-coding genes. Previously dismissed as “junk DNA”, it is the non-coding regions of the genome that are responsible for regulation, facilitating complex temporal and spatial gene expression through the combinatorial effect of numerous mechanisms and interactions working together to fine-tune gene expression. The major regions involved in regulation of a particular gene are the 5′ and 3′ untranslated regions and introns. In addition, pervasive transcription of complex genomes produces a variety of non-coding transcripts that interact with these regions and contribute to regulation. This review discusses recent insights into the regulatory roles of the untranslated gene regions and non-coding RNAs in the control of complex gene expression, as well as the implications of this in terms of organism complexity and evolution.
5′ untranslated region
The 5′ untranslated region (UTR) is a regulatory region of DNA situated at the 5′ end of all protein-coding genes that is transcribed into mRNA but not translated into protein. 5′UTRs contain various regulatory elements (Fig. 1b) and play a major role in the control of translation initiation. Here, we discuss the regulatory roles of the 5′UTR, highlighting how the number and nature of regulatory elements present as well as the secondary structure of the mRNA and factor accessibility have major impacts on the expression of the downstream open reading frame [16].
Promoter
The eukaryotic promoter is a regulatory region of DNA located upstream of a gene that binds transcription factor II D (TFIID) and allows the subsequent coordination of components of the transcription initiation complex, facilitating recruitment of RNA polymerase II and initiation of transcription [79, 162]. The core promoter generally spans ~80 bp around the transcription start site (TSS), and, in mammals, can be separated into two distinct classes: conserved TATA-box enriched promoters that initiate at a single TSS, and variable CpG-rich promoters containing multiple TSS [20]. The latter class is enriched in vertebrates, and expression from these promoters involves the combinatorial effects from a multitude of binding motifs within the promoter region. Some of the major elements involved in regulation by these complex promoters are enhancers, including upstream and downstream promoter elements (UPE and DPEs) that contain transcription factor binding sites, and may act independently or synergistically with the core promoter to facilitate transcription initiation.
Intronic regions
Introns are regions of DNA that are transcribed into pre-messenger RNA but are removed during splicing to generate a mature mRNA. Spliceosomal introns are present in all studied eukaryotic organisms. The exact origin of introns is debated, but it is widely accepted that introns evolved soon after the divergence of prokaryotic and eukaryotic organisms and that the current intron content of any particular genome is the result of both intron loss and gain over time (for thoughts and reviews on the topic of intron evolution, see [103, 154]. Regardless of when and how introns arose, it is clear that the appearance of introns was an important catalyst for evolution, facilitating rapid evolution at the protein level through increased rates of meiotic crossing over within coding regions, as well as rapid evolution of regulatory elements due to relaxed sequence constraints within non-coding introns [54]. Introns would also have allowed evolution of RNA regulatory pathways without interfering with protein expression, an important distinction that was only made possible by the separation of transcription and translation [103].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474909/
DRD4 Gene - Dopamine Receptor D4
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NCBI Gene Summary for DRD4 Gene
This gene encodes the D4 subtype of the dopamine receptor. The D4 subtype is a G-protein coupled receptor which inhibits adenylyl cyclase. It is a target for drugs which treat schizophrenia and Parkinson disease. Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder, and the personality trait of novelty seeking. This gene contains a polymorphic number (2-10 copies) of tandem 48 nt repeats; the sequence shown contains four repeats. [provided by RefSeq, Jul 2008]
GeneCards Summary for DRD4 Gene
DRD4 (Dopamine Receptor D4) is a Protein Coding gene. Diseases associated with DRD4 include Attention Deficit-Hyperactivity Disorder and Autonomic Nervous System Disease. Among its related pathways are GPCR downstream signalling and Class A/1 (Rhodopsin-like receptors). Gene Ontology (GO) annotations related to this gene include G protein-coupled receptor activity and SH3 domain binding. An important paralog of this gene is DRD3.
UniProtKB/Swiss-Prot Summary for DRD4 Gene
Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Activated by dopamine, but also by epinephrine and norepinephrine, and by numerous synthetic agonists and drugs (PubMed:9003072, 16423344, 27659709, 29051383). Agonist binding triggers signaling via G proteins that inhibit adenylyl cyclase (PubMed:7512953, 7643093, 16423344, 27659709, 29051383). Modulates the circadian rhythm of contrast sensitivity by regulating the rhythmic expression of NPAS2 in the retinal ganglion cells (By similarity). ( DRD4_HUMAN,P21917 )
Tocris Summary for DRD4 Gene
D4 receptors are members of the dopamine receptor G-protein-coupled receptor family that also includes D1, D2, D3 and D5. They are located primarily in the frontal cortex, midbrain, amygdala and the cardiovascular system. A role in cognition and emotion has been proposed.
rs146680769 11-637294-C-T my mother has it too
5'UTR Variant in Promoter
5.169%
https://gnomad.broadinstitute.org/variant/11-637294-C-T?dataset=gnomad_r4
Reported as Uncertain Significance for Hereditary Attention Deficit-Hyperactivity Disorder in ClinVar
https://www.ncbi.nlm.nih.gov/clinvar/RCV003239302/
rs752306 11-637622-C-T data unavailable for my mother
Intronic Variant in Promoter
5.871%
https://gnomad.broadinstitute.org/variant/11-637622-C-T?dataset=gnomad_r4
https://www.ncbi.nlm.nih.gov/snp/rs752306#publications
rs916455 11-636929-C-T data unavailable for my mother
2 KB Upstream Variant in Transcription Factor binding site
3.415%
https://gnomad.broadinstitute.org/variant/11-636929-C-T?dataset=gnomad_r4
https://www.ncbi.nlm.nih.gov/snp/rs916455#publications
https://www.sciencedirect.com/science/article/abs/pii/S0165178112004489?via%3Dihub
Intronic Variant in CTCF binding site
22.86%
https://gnomad.broadinstitute.org/variant/11-637933-G-A?dataset=gnomad_r4
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Progress Report Confirming my Dyslexia and Dyspraxia
my Veteran Affairs Problem List record noting my Dyslexia, Abnormal Auditory Perception, Eye and Overall Coordination issues (Ataxia, Deficiencies of Saccadic Eye Movements, Deficiencies of Smooth Pursuit Movements)
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