Genetic research in psychobiology and psychiatry has radically changed the epidemiological approach to anxiety disorders. The main studies are family studies, looking into the same family: siblings, ascendants, descendants, cousin hood, the presence of the same disorder. Another technique is the search for common disorders in true twins who have the same genetic heritage in comparison with false twins who are individuals as different as two brothers or sisters, born in a spaced manner in time. This approach is notnew, we find it in the psychiatry textbooks of the beginning of the 20th century, in particular that of Henri Ey.
The rapid development of molecular biology applied to genetics in the past fifteen years has made it possible to highlight the genetic factors of schizophrenia, bipolar disorder and even Alzheimer’s disease. As far as anxiety disorders are concerned, the current conclusions are much less solid. This is certainly explained by the role of the environment which seems to be a more important factor than in the aforementioned diseases. In addition, anxiety disorders come in the form of different diseases: generalized anxiety,social anxiety, panic disorder, post-traumatic stress, phobias,and obsessive-compulsive disorder. Regarding generalised anxiety, there are few studies based on the technique of family aggregation, that is to say the transmission of the disease in the first degree of descendants. The problem of the genetic transmission of an anxiety disorder and particularly that of generalized anxiety is not easy to solve. It’s more about understanding what the risk factors are than genetics in the strict sense. If we take the case of the subject having apparent with an anxiety disorder, what is the nature of the risk of becoming himself anxious?
Presumably, like a sponge, the child will pump up the parent’s anxiety more than the possible transmission of the disorder’s genes. Recent knowledge of the human genome is not sufficient to understand the rules for the transmission of a disease, unless the latter is linked to one gene and only one. Unfortunately, this is not the case with mental illnesses and particularly anxiety. Genetic exploration of the various anxiety disorders has been carried out through studies of the ascendants and descendants. By investigating the possible mode of transmission for which the prevalence of a particular phenotype has been particularly observed in subjects without anxiety, in comparison with members of the same family exhibiting a form of anxiety.
Heritability estimates were also evaluated in studies in twins in which a comparison was made between the concordancerates in monozygotic twins and dizygotic twins. In the past decade, genetic analyzes of anxiety disorders have often been performed by association studies or surveys of the co-occurrence of a specific phenotype or genetic variants.
Currently, association studies are carried out in two ways:-
- a priori, on the basis of analyzes of hypotheses of candidate genes
- by means of whole genome association studies during which markers are evaluated in order to evaluate the genetic variation across the whole genome. While genomic studies on anxiety disorders are slowly emerging, much of the evidence from candidate gene association studies has not yet been carried out.
Considering the substantial evidence for a genetic component(partly crossed) in the pathophysiology of generalized anxiety (GAD) and other anxiety-related traits, molecular genetic studies such that linkage and association studies have been continued to identify chromosomal risk loci and TAG sensitivity genes.
Genes linked to serotonergic neurotransmission have been at the center of investigations on GAD based on their relevance to the pathophysiology of anxiety disorders and depression. Patients with GAD have a higher frequency of a repeat allele of the serotonin transporter gene. GAD has also been associated with the S allele of the promoter region of the serotonin transporter gene (5-HTTLPR). Other genetic studies in GAD have focused on the monoamine oxidase A (MAO-A) gene. A polymorphism of the MAO-A gene characterized by 3 alleles was found more often in women diagnosed with GAD compared to non-anxious controls.
Other genetic analyzes of TAG (and other anxiety disorders) will provide better knowledge of candidate genes that are linked to a major depressive disorder. There is indeed a continuum between depression and particularly bipolar illness and anxiety (we can also say comorbidity).These genes include those involved in the production of the brain derivated neurotrophic factor (BDNF), as well as enzymes such as COMT which is an enzyme in the metabolism of both dopamine and L-Dopa. DAT (active dopamine transporter), FKBP5 is a protein that, in humans, is encoded by the FKBP5 gene. Finally, a major mediator of the stress response, the corticotropin releasing hormone receptor 1 (CRHR1) has proven to be an important contributor to the pathogenesis of major depressive disorder and GAD.
Recent research has shown that children of parents presenting with PTSD, have a significant risk factor for presenting themselves with PTSD. For example, the diagnosis of PTSD was more common in the adult offspring of Holocaust survivors with PTSD compared to descendants of Holocaust survivors without PTSD. Analyzes of the offspring of parents exposed to the Holocaust with PTSD revealed a decrease in salivary cortisol levels and an increase in the inhibition of plasma cortisol after the administration of a low dose of dexamethasone compared to children of survivors without PTSD. Likewise, the offspring of mothers with PTSD, who were pregnant at the time of the September 11, 2001 terrorist attacks, also have lower cortisol levels. The negative correlation between the cortisol levels of the offspring and maternal PTSD suggests that epigenetics contributes to the intergenerational transmission of the risk of post-traumatic stress. Studies in twins have shown that exposure to trauma and PTSD itself are moderately hereditary and moderately genetically correlated. To date, the molecular genetics of PTSD remains largely unknown.
The studies focused mainly on a subset of genes involved in serotonergic, dopaminergic and neuroendocrine function with resolutely mixed results. Twin studies have shown that social anxiety has an inherited basis, but genetic studies have yet to demonstrate robust risk variants. Genome-wide association analysis (GWAS) of subjects was performed to determine the heritability of social anxiety. GWAS were carried out in ancestral groups (European, African, Latin American) using linear regression models for each of the three component studies, then meta-analyzed in all studies. The heritability based for social anxiety was significant. A meta-analytically significant locus at the genome level was observed in each of the groups.
Finally, despite their importance to mental health and their documented heritability, genetic research aimed at identifying the genetic contributions of anxiety disorders has little success, in particular in relation to recent advances in the genetics of other psychiatric illnesses. This slow progress is due to the lack of well-documented genomic studies. Thus, the genetic basis of anxiety disorders remains a largely unknown area. The strategies implemented are genome-wide variant association studies, exome sequencing, genetic prediction of the response to treatment, the genetic epidemiology of anxiety disorders and the prospects for dissection of anxiety. Overall, these various studies already published, highlight the genetic and phenotypic complexity of anxiety pathologies and especially the need for other better constructed studies in order to progress in the knowledge of the genesis of anxiety disorders.