ADHD Genes: Not a 'One-Size-Fits-All'

ADHD often runs in families. Though ADHD’s high heritability of 74% motivated the search for ADHD-susceptibility-genes, no 'smoking gun' single gene has been implicated. Instead, findings have shown about a third of ADHD’s heritability is due to the combined effect of multiple mutations, together comprising many common variants, with each having small effects, adding up in a big way!

What is ADHD?

Attention Deficit Hyperactivity Disorder (ADHD) is a childhood-onset condition associated with symptoms such as difficulty with concentration, impulsivity, and hyperactivity. It is more common in males and by 2011 was occurring in more than 11% of children throughout the total population, with little geographic or cross-cultural variation in prevalence.(1) The prevalence of children ever diagnosed with ADHD increased by 42% between 2003 (7.8%) and 2011 (11.0%). (1) Studies conducted over a longer period of time with occasional check-ins show that two-thirds of ADHD youth will continue to have impairing symptoms of ADHD in adulthood.(2) If not addressed, people with ADHD are at risk for a wide range of functional impairments: school failure, peer rejection, injuries due to accidents, criminal behavior, occupational failure and premature death. ADHD often co-occurs with other conditions, including mood, anxiety, conduct, learning, and substance use disorders.(2)

Family, twin, and adoption studies show that ADHD runs in families. ADHD’s high heritability of 74% has long motivated the search for ADHD susceptibility genes;(2) however, early genetic study results in the literature were often contradictory. It wasn't until 2009 when a meta-analysis reviewed many publications and found eight candidate DNA variants showed a statistically significant association with ADHD across multiple studies. These variants implicated six genes:

• the serotonin transporter gene (5HTT),

• the dopamine transporter gene (DAT1),

• the D4 dopamine receptor gene (DRD4),

• the D5 dopamine receptor gene (DRD5),

• the serotonin 1B receptor gene (HTR1B) and

• the synaptic vesicle regulating protein gene (SNAP25) (3)

All of these but HTR1B also showed significant variety and diversity among ADHD persons affected, thus suggesting the need for further study into contributing factors which seek to better understand potential moderators of these associations (e.g., ADHD subtype diagnoses, gender, exposure to environmental risk factors, etc.).(3) Since then, other genes which have been discovered to have some level of association with ADHD include the dopamine transporter gene (SLC6A3), which has had at least two documented alternative forms of genetic expression, one associated with ADHD in youth (4) while the other is associated with ADHD in adults.(5)

Neurotransmitters: the gas-pedal and brake-pedal for the brain

The genes mentioned and the genetic variants associated with them, referred to as 'single nucleotide polymorphisms (SNPs), overwhelmingly share in common that they are involved in the regulation of neurotransmitter levels. Neurotransmitters are the signaling instructions delivered to our brain. They can be generalized into 2 categories: the excitatory neurotransmitters and the inhibitory neurotransmitters. The excitatory neurotransmitters include dopamine, norepinephrine and epinephrine. They provide stimulation signals to the brain and supporting them is the target for many prescription medications including Adderall®, Concerta®, and Focalin®. In our automotive analogy, these function like the 'gas-pedal'. Increasing their activity may increase concentration.

By contrast, the other set of neurotransmitters is the calming, inhibitory neurotransmitters. These include serotonin, GABA and glycine and are analogous to a brake-pedal to the brain. They send signals to the brain to slow down, feel good and relax. They are of interest in ADHD because often a person with ADHD has other mood related concerns too.

Genome-Wide Association Studies: The Rainstorm is Made from Many Little Drops

Though there have been several genes of interest identified, none of their mutations has been found to be a single overwhelming cause for ADHD. "It is equally clear that no common DNA variants are necessary and sufficient causes of ADHD".(2) Enter 'Genome-wide association studies' (GWAS). These are genetic scans that look to detect common DNA variants having very small

etiologic effects. They have been completed testing more than 20,000 people with ADHD and over 35,000 asymptomatic controls in such studies. (6) Findings show that a genetic susceptibility to ADHD is comprised of many common DNA variants, and this accounts for about one-third of the twin study estimates of ADHD’s heritability. We do not know yet which variants or how many of them make up the 'poly-genic' component.

Polygenic diseases are diseases which are influenced by the combined effects of multiple genes. So instead of one single gene of interest, we end up with multiple that can express mutations, and are more likely associated, but even the combination of other less overt variants, can contribute to the presentation of ADHD.

Omega-3 Fatty Acid Metabolism Plays a Major Role in ADHD

One SNP receiving attention, since at least 2006, affects the fatty acid desaturase 2 (FADS-2) gene.(7) This gene helps to maintain healthy levels of omega-fatty acids in the body, which is crucial for cognitive development and function. Omega-3 fatty acids affect cell membrane integrity, which, in turn, can affect the passage of key chemical signaling agents, including dopamine. Individuals with ADHD frequently have dopamine deficiencies in specific regions of their brain, including dopamine.(8) And abnormalities to FADS-2 genes have "... showed that genetic variants of FADS1 and FADS2 influence blood lipid and breast milk essential fatty acids in pregnancy and lactation".(9) So delving a little deeper into how omega-fatty acids are synthesized may well be relevant for understanding some of the contributing factors to ADHD!

The formation of omega-3 fatty acids involves a conversion from alpha-linolenic acid (ALA) to eicosapentaenoic acid (EPA), and eventually docosahexaenoic acid (DHA), both of which are usually listed in the 'Supplement Facts' box on any bottle of fish or krill oil. These are the omega-3s that everyone is after when they take the nutritional supplements. This progression occurs through a series of steps which require enzymes such as delta-6 desaturase. Genes involved in fatty acid metabolism govern these enzymes; mutations or SNPs at these genes can therefore ultimately control the enzymes themselves. Fatty acid desaturases are key in determining both plasma and tissue fatty acid profiles and variations in fatty acid desaturase genes can modify whole-body lipid metabolism.(9) This is because two of these desaturase enzymes, namely delta-6 and delta-5, are necessary to convert the simplest omega-3 and omega-6 essential fatty acids to the special types of polyunsaturated fatty acids (PUFAs) that the brain requires. "...[T]he enzyme delta-6 desaturase, ... is important in the anabolism of PUFAs, linolic and linolenic acids that constitute neuronal membrane".(10) These special PUFAs have 20 or more carbon atoms and 3 or more double bonds are designated as 'highly unsaturated fatty acids' (HUFAs) and are what the brain needs. It is no surprise then that "... genetic inhibition of FADS2 drastically reduces the production of omega-6 HUFAs ..."(11) and a SNP in FADS2 has been significantly associated with ADHD, suggesting that the genetic profile of ADHD may have further effects on the overall metabolism of PUFAs.(7)

So what are the consequences of these enzymes for the production of HUFAs not functioning properly? If these enzymes don’t function at their highest level, dietary omega-3s aren’t adequately incorporated into the cell membrane structure.(12, 13) Genetic differences and the presence of external factors, such as alcohol or other types of fats, hinder the function of these enzymes, (14, 15) thereby interfering with the conversion process of these fatty acids and ultimately impacts omega-3 and omega-6 fatty acid uptake and incorporation into cell membranes.

So we see how examples of mutations in the production of omegas could have impacts on ADHD. And researchers have found associations to confirm that. But why does this happen at all? The answer goes back to real estate!

What is that famous expression in real estate?

"Location, location, location."

A number of these desaturase enzymes are all coded from a specific genetic region located on the 11th chromosome in humans, located at the 11q25 region. Coincidentally, this region is located near the 11q22 region, which has been linked to ADHD.(16) The closer two genetic regions are, the higher the chances they will be passed on together from parent to child. In other words, gene forms located near each other on a chromosome are more likely to be passed on together. That suggests that the 11q22 ADHD region may be influenced by some of the genes from the nearby 11q25 region and that was shown in research, which saw this association from their preliminary findings. (7)

Attempting to support these pathways through naturopathic treatments is a way our clinic helps patients. You can't change genes, but you can try to potentiate their desired outcome through nutrition, neurotransmitter nutraceuticals, homeopathics and more.

References:

1. National Institute of Health, National Institute of Mental Health. Attention Deficit/Hyperactivity Disorder (ADHD). https://www.nimh.nih.gov/health/statistics/attention-deficit-hyperactivity-disorder-adhd#part_2550. Accessed 09-18-2022.

2. Faraone, Stephen V, and Henrik Larsson. “Genetics of attention deficit hyperactivity disorder.” Molecular psychiatry vol. 24,4 (2019): 562-575. doi:10.1038/s41380-018-0070-0.

3. Gizer, Ian R et al. “Candidate gene studies of ADHD: a meta-analytic review.” Human genetics vol. 126,1 (2009): 51-90. doi:10.1007/s00439-009-0694-x.

4. Faraone SV, Mick E. Molecular genetics of attention deficit hyperactivity disorder. Psychiatr Clin North Am. 2010;33:159–80.

5. Franke, Barbara et al. “Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD.” Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology vol. 35,3 (2010): 656-64. doi:10.1038/npp.2009.170.

6. Demontis, Ditte et al. “Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.” Nature genetics vol. 51,1 (2019): 63-75. doi:10.1038/s41588-018-0269-7.

7. Brookes, Keeley J et al. “Association of fatty acid desaturase genes with attention-deficit/hyperactivity disorder.” Biological psychiatry vol. 60,10 (2006): 1053-61. doi:10.1016/j.biopsych.2006.04.025.

8. Blum, Kenneth et al. “Attention-deficit-hyperactivity disorder and reward deficiency syndrome.” Neuropsychiatric disease and treatment vol. 4,5 (2008): 893-918. doi:10.2147/ndt.s2627.

9. Xie, Lin, et al. “Genetic variants of the FADS1 FADS2 gene cluster are associated with altered (n-6) and (n-3) essential fatty acids in plasma and erythrocyte phospholipids in women during pregnancy and in breast milk during lactation.” The Journal of nutrition vol. 138,11 (2008): 2222-8. doi:10.3945/jn.108.096156.

10. Dodig-Curković, Katarina et al. “Uloga cinka u lijecenju hiperaktivnog poremećaja u djece” [The role of zinc in the treatment of hyperactivity disorder in children]. Acta medica Croatica : casopis Hravatske akademije medicinskih znanosti vol. 63,4 (2009): 307-13.

11. Ri, Keiken et al. “Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production.” Communications biology vol. 5,1 1001. 21 Sep. 2022, doi:10.1038/s42003-022-03972-y.

12. Nakada, T et al. “Membrane fatty acid composition shows delta-6-desaturase abnormalities in Alzheimer's disease.” Neuroreport vol. 1,2 (1990): 153-5. doi:10.1097/00001756-199010000-00018.

13. Monteiro, Jessica et al. “Menhaden oil, but not safflower or soybean oil, aids in restoring the polyunsaturated fatty acid profile in the novel delta-6-desaturase null mouse.” Lipids in health and disease vol. 11 60. 29 May. 2012, doi:10.1186/1476-511X-11-60.

14. Nakamura, M T et al. “Selective reduction of delta 6 and delta 5 desaturase activities but not delta 9 desaturase in micropigs chronically fed ethanol.” The Journal of clinical investigation vol. 93,1 (1994): 450-4. doi:10.1172/JCI116981.

15. Mahfouz, M. “Effect of dietary trans fatty acids on the delta 5, delta 6 and delta 9 desaturases of rat liver microsomes in vivo.” Acta biologica et medica Germanica vol. 40,12 (1981): 1699-1705.

16. Arcos-Burgos, Mauricio et al. “Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11.” American journal of human genetics vol. 75,6 (2004): 998-1014. doi:10.1086/426154.

The content and any recommendations in this article are for informational purposes only. They are not intended to replace the advice of the reader's own licensed healthcare professional or physician and are not intended to be taken as direct diagnostic or treatment directives. Any treatments described in this article may have known and unknown side effects and/or health hazards. Each reader is solely responsible for his or her own healthcare choices and decisions. The author advises the reader to discuss these ideas with a licensed naturopathic physician.