Genome–Environment Interactions and Psychiatric Disorders

Genome–Environment Interactions and Psychiatric Disorders: Comparison

Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Jacob Peedicayil.

Environmental factors are known to interact with the genome by altering epigenetic mechanisms regulating gene expression and contributing to the pathogenesis of psychiatric disorders.

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1. Introduction

Psychiatric disorders include the following ^[1]: schizophrenia (SZ) and other primary psychotic disorders; mood disorders such as bipolar disorder (BD) and major depressive disorder (MDD); anxiety and fear-related disorders; obsessive -compulsive and related disorders; and personality disorders. It has been well established from family, twin, and adoption studies that the psychosis SZ, the mood disorders BD and MDD, and anxiety disorder (AD) have a genetic basis. These are common, chronic disorders whose inheritance patterns involve several genes, possibly hundreds, or even thousands.

Environmental factors are well known to interact with the genome and influence the pathogenesis of psychiatric disorders ^[2]. This purpose of this article is tto present a narrative review of the genome–environment interactions underlying common psychiatric disorders such as SZ, BD, MDD, and AD whose pathogeneses continue to be unclear, and which continue to cause much suffering to affected patients, despite a large amount of research into finding better treatments. The guidelines of Murphy ^[3] were followed while writing the review. It was thought that a proper understanding of how the genome and the environment interact in these disorders may help in the development of biomarkers for these disorders and improve the treatment of these disorders. The cited articles were obtained from PubMed and Google Scholar and the period of review chosen was from 1 January 2000 to 31 December 2022. The search terms used were as follows: gene or genetic; genome; environment; mental or psychiatric disorder; epigenetic; and interaction. Both preclinical and clinical studies were included. Both original studies and review articles were included. Case reports and letters to the editor were excluded. If there were multiple papers dealing with the relevant topic, the paper or papers that best described the genome–environment interactions involved were chosen. Non-English, and non-peer-reviewed papers were excluded.

2. Genetic Basis of Psychiatric Disorders

It has been estimated that about 70 to 80% of the approximately 25,000 genes of the human genome are expressed in the brain, and because most genes encode more than one protein, there may be 100,000 different proteins in the brain ^[4]. Of these, about 10,000 are known proteins and 100 or less of these are targets for currently used psychotropic drugs ^[4]. The study of families using population genetics methods over the last 50 years has consistently supported a genetic and heritable component to psychiatric disorders. More recently, molecular genetic techniques have shown that specific regions on chromosomes are associated with specific diagnoses. Many genes, including those encoding proteins involved in synaptic transmission, have been found to correlate with psychiatric disorders ^[4]. However, much more work is needed to determine precisely how these genes predispose individuals to psychiatric disease states.

3. Epigenetic Mechanisms and Environmental Factors

The environment cannot interact with the genome by altering the DNA sequence easily. However, the environment can relatively easily change expression of the genome by affecting epigenetic mechanisms regulating gene expression [16,17,18]^[5][6][7]. Different epigenetic mechanisms can transmit the effects of the environment on the genome. For instance, in rats it was shown that the chemical vinclozilin methoxychlor reduces sperm count and motility by changing methylation of DNA in the testes [18]^[7]. It has been demonstrated that air pollution can change histones to cause changes in blood leukocytes [18]^[7]. The roundworm Caenorhabditis elegans has to differentiate deleterious from useful bacterial foods among the many bacteria it is exposed to in the surroundings. Kaletsky et al. [19]^[8] demonstrated that one exposure to purified small RNAs obtained from Pseudomonas Aeuginosa (PA14) is adequate to cause pathogen avoidance, both in the treated organisms as well as in four later generations of offspring. One Pseudomonas aeruginosa ncRNA, P11, is both needed and sufficient to convey learned avoidance of PA14, and its Caenorhabditis elegans target, maco-1, is necessary for avoidance.

4. Environmental Factors and Psychiatric Disorders

The common, chronic psychiatric disorders such as SZ, BD, and MDD have been described as suffering from the “curse of polygenicity” [20]^[9]. Indeed, there is evidence that such disorders may be “omnigenic”, that is, affecting all genes in the genome [21,22]^[10][11]. Why do common, chronic disorders such as these psychiatric disorders tend to be polygenic, or even omnigenic? The answer could be that in order to account for extensive environmental involvement, hundreds, or even thousands, of genes need to be involved [23]^[12].

5. Environmental Factors Acting Epigenetically in Psychiatric Disorders

Given below is evidence for several environmental factors altering epigenetic mechanisms of gene expression and leading to the development of psychiatric disorders (Table 1).

Table 1.

Environmental factors interacting epigenetically with the genome in the pathogenesis of psychiatric disorders.

Social determinants of mental health including early life adversity and early life stress

Maternal prenatal stress

Poverty

Migration

Urban dwelling

Pregnancy and birth complications

Alcohol use

Substance use other than alcohol

Microbiota

Prenatal and postnatal infections

6. Reversal of Genome–Environment Interactions in the Treatment of Psychiatric Disorders

As is clear from the preceding sections, epigenetic mechanisms of gene expression are dysregulated in psychiatric disorders, and thereby could be contributing to the pathogenesis of these disorders. Many, if not all, treatment modalities used in the treatment of psychiatric disorders at least partly, if not entirely, act by altering epigenetic mechanisms of gene expression. Thus, it is possible that these treatments undo what the disease process has done to patients. In the broad sense, the epigenetic effects of these treatments can be considered to be environmental factors interacting with the genome in patients with psychiatric disorders in a reverse manner and thereby alleviating symptoms of the disorders. Given below is how such factors can modify the epigenetic mechanisms of gene expression in the treatment of psychiatric disorders (Table 2).

Table 2. Environmental factors interacting epigenetically with the genome to reverse psychiatric disorders.

Psychotropic drugs

Psychotherapy

Electroconvulsive therapy

Physical exercise

References

World Health Organization. The ICD-11 Classification Of Mental And Behavioural Disorders: Diagnostic Criteria for Research; World Health Organization: Geneva, Switzerland, 2018.
Assary, E.; Vincent, J.P.; Keers, R.; Pluess, M. Gene-environment interaction and psychiatric disorders: Review and future directions. Semin. Cell Dev.Biol. 2018, 77, 133–143.
Murphy, C.M. Writing an effective review article. J. Med. Toxicol. 2012, 8, 89–90.
Boland, R.; Verduin, M.L.; Ruiz, P. Kaplan & Sadock’s Synopsis of Psychiatry, 12th ed.; Wolters Kluwer: Philadelphia, PA, USA, 2022.
Feil, R.; Fraga, M.F. Epigenetics and the environment: Emerging patterns and implications. Nat. Rev. Genet. 2012, 13, 97–109.
Feinberg, A.P.; Fallin, M.D. Epigenetics at the crossroads of genes and the environment. JAMA 2015, 314, 1129–1130.
Norouzitallab, P.; Baruah, K.; Vanrompay, D.; Bossier, P. Can epigenetics translate environmental cues into phenotypes? Sci. Total Environ. 2019, 647, 1281–1293.
Kaletsky, R.; Moore, R.S.; Vrla, G.D.; Parsons, L.R.; Gitai, Z.; Murphy, C.T. C. elegans interprets bacterial non-coding RNAs to learn pathogenic avoidance. Nature 2020, 586, 445–451.
Kendler, K.S. Incremental advances in psychiatric molecular genetics and nosology. World Psychiatry 2022, 21, 415–416.
Peedicayil, J.; Grayson, D.R. An epigenetic basis for an omnigenic model of psychiatric disorders. J. Theor. Biol. 2018, 443, 52–55.
Peedicayil, J.; Grayson, D.R. Some implications of an epigenetic-based omnigenic model of psychiatric disorders. J. Theor. Biol. 2018, 452, 81–84.
van Os, J.; Rutten, B.P.F.; Poulton, R. Gene-environment interactions in schizophrenia: Review of epidemiological findings and future directions. Schizophr. Bull. 2008, 34, 1066–1082.