Genetics and Anxiety

Bradley Bush, ND

A lot of things get handed down from generation to generation. Some items, like antiques, are typically well received and cherished. Unfortunately, we are not always able to choose what gets handed down. Our genetic code is also passed along from generation to generation, both the good and the bad. Clinicians have a unique viewpoint that allows them to notice familial traits oftentimes overlooked by the casual acquaintance. We are trained to detect specific disease trends like hypertension, diabetes, and cancers, that often run in families. There is now more awareness about familial tendencies for mental illness, including the most common psychological disorder, anxiety. Our understanding of inherited susceptibilities is still in its infancy, but there are a handful of markers for single-nucleotide polymorphisms (SNPs) at your disposal to help screen and manage anxiety more effectively.

Familial Tendencies

Anxiety is the number one psychological disorder in the United States.¹ It is expressed differently between genders and is greatly impacted by familial tendencies. Researchers have found a 3-5-fold increased incidence among first-degree relatives affected with an anxiety disorder.² 

The results of a 20-year study published in January, 2005, in the journal Archives of General Psychiatry,³ revealed that the association of major depressive disorder (MDD) in parents and their children is moderated by the grandparents’ MDD status. This was also the case for anxiety in the children:

 “Anxiety disorders are an early sign of psychopathology in children from depressed families. Nearly 60% of the grandchildren (mean age, 12 years) with 2 generations of depression already had some psychiatric disorders. The increase in anxiety disorder in the grandchildren from high-risk grandparents was consistent with the findings from their parents when they were the same age as the grandchildren.”³

Not all mental disorders can be blamed on biological causes, since this would remove all environmental cofactors from the equation. But there are some findings that show that patients’ genetic makeup can play a vital role in determining whether they develop anxiety, as well as the type and level of anxiety they develop. There are several SNPs that show clinical promise and should be considered when screening for biological causes of anxiety.

Glutamic Decarboxylase 1 Gene (GAD1)

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. First-line treatment of anxiety disorders include benzodiazepines, whose anxiolytic effect is caused by their selective action on GABA-A receptors in the brain, increasing GABA receptor responsiveness. The glutamic acid decarboxylase (GAD) enzyme synthesizes GABA from glutamate. Genetic variations in this genes that encode for GAD have been associated with increased risk of panic attacks in women ⁴ and schizophrenia,⁵ and are suggested to play a role in anxiety/panic disorders.⁶

A study published in the August, 2006, issue of Molecular Psychiatry sampled 9270 adults from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders.⁷ It concluded that, “variations in the GAD1 gene may contribute to individual differences in [neuroticism] and predispose people across a range of anxiety disorders and major depression.”

Catechol-O-Methyltransferase (COMT)

The COMT gene provides instructions for making an enzyme called catechol-O-methyltransferase, which is involved in phase II (conjugative) metabolism of the catecholamine neurotransmitters (dopamine, epinephrine, and norepinephrine), catechol estrogens, and catechol flavonoids.⁸ COMT influences levels of neurotransmitters in the prefrontal cortex of the brain, personality, inhibition of behaviors, abstract thinking, and emotion.⁹ The COMT Val158Met polymorphism has been shown to be associated with phobic anxiety,¹⁰ neuroticism,¹¹ and panic disorder.¹²

Serotonin-transporter-linked Polymorphic Region (5-HTTLPR)

5-HTTLPR codes for the serotonin transporter (SERT). This is an important membrane protein that transports the neurotransmitter, serotonin, from the neural synaptic gap into a presynaptic neuron. Serotonin reuptake inhibitors (SSRIs) act predominately by targeting SERT.¹³ It has been reported that a 5-HTTLPR polymorphism may account for 4-5% of population variation of anxiety-related traits.¹⁴ Carriers of the “s,” or short allele, is associated with greater activity in the amygdala in the brain, responsible for anxiety, fear, and the panic response.^15,16 Furthermore, a 2004 meta-analysis of 26 studies and 5629 subjects found evidence for an association between the 5-HTTLPR short allele and increased anxiety-related personality scores. The investigators stated, “We conclude that there is a strong association between the serotonin transporter promoter variant and neuroticism as measured in the NEO personality inventory.”¹⁷

Conclusion

Although naturopathic doctors are not typically considered genetic specialists, our profession has been quietly pioneering the expansion of genetic screening in a general practice setting. Our drive to offer more personalized healthcare has elevated a number of SNPs to first or second-line laboratory testing, eg, celiac disease screening (HLA-DQ2 and HLA-DQ8), cytochrome P450 testing, and methylenetetrahydrofolate reductase (5-MTHFR). With the prevalence of anxiety disorders being so high, GAD1, COMT, and 5-HTTLPR offer further opportunities to address root causes in our patients and create more personalized treatment protocols.

Bradley Bush, ND received his ND degree from National College of Naturopathic Medicine in 2000. He is a co-author of the ND: Notes Science Board Review, and founder and past organizer of the annual Pharmaceutical Perspectives conference. Dr Bush currently sits on the board of the Naturopathic Education and Research Consortium (NERC).

References

1. Anxiety and Depression Association of America. Facts & Statistics. ADAA Web site. http://www.adaa.org/about-adaa/press-room/facts-statistics. Accessed November 15, 2013.
2. Kendler KS, Eaves LJ, Walters EE, et al. The identification and validation of distinct depressive syndromes in a population-based sample of female twins. Arch Gen Psychiatry. 1996;53(5):391-399.
3. Weissman MM, Wickramaratne P, Nomura Y, et al. Families at high and low risk for depression: a 3-generation study. Arch Gen Psychiatry. 2005;62(1):29-36.
4. Weber H, Scholz CJ, Domschke K, et al. Gender differences in associations of glutamate decarboxylase 1 gene (GAD1) variants with panic disorder. PLoS One. 2012;7(5):e37651.
5. Curley AA, Arion D, Volk DW, et al. Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features. Am J Psychiatry. 2011;168(9):921-929.
6. Domschke K, Tidow N, Schrempf M, et al. Epigenetic signature of panic disorder: a role of glutamate decarboxylase 1 (GAD1) DNA hypomethylation? Prog Neuropsychopharmacol Biol Psychiatry. 2013;46:189-196.
7. Hettema JM, An SS, Neale MC, et al. Association between glutamic acid decarboxylase genes and anxiety disorders,major depression, and neuroticism. Mol Psychiatry. 2006;11(8):752-762.
8. Yager JD. Catechol-O-methyltransferase: characteristics, polymorphisms and role in breast cancer. Drug Discov Today Dis Mech. 2012;9(1-2):e41-e46.
9. Domschke K, Ohrmann P, Braun M, et al. Influence of the catechol-O-methyltransferase val158met genotype on amygdala and prefrontal cortex emotional processing in panic disorder. Psychiatry Res. 2008;163(1):13-20.
10. McGrath M, Kawachi I, Ascherio A, et al. Association between catechol-O-methyltransferase and phobic anxiety. Am J Psychiatry. 2004;161(9):1703-1705.
11. Eley TC, Tahir E, Angleitner A, et al. Association analysis of MAOA and COMT with neuroticism assessed by peers. Am J Med Genet B Neuropsychiatr Genet. 2003;120B(1):90-96.
12. Domschke K, Freitag CM, Kuhlenbumer G, et al. Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. Int J Neuropsychopharmacol. 2004;7(2):183-188.
13. Stahl SM, Lee-Zimmerman C, Cartwright S, Morrissette DA. Serotonergic drugs for depression and beyond. Curr Drug Targets. 2013;14(5):578-585.
14. Heils A, Mössner R, Lesch KP. The human serotonin transporter gene polymorphism—basic research and clinical implications. J Neural Transm. 1997;104(10):1005-1014.
15. Andersson E, Rück C, Lavebratt C, et al. Genetic polymorphisms in monoamine systems and outcome of cognitive behavior therapy for social anxiety disorder. PLoS One. 2013;8(11):e79015.
16. Furmark T, Appel L, Henningsson S, et al. A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety. J Neurosci. 2008;28(49):13066-13074.
17. Sen S, Burmeister M, Ghosh D. Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am J Med Genet B Neuropsychiatr Genet. 2004;127B(1):85-89.