Bipolar disorder genetic component

Genetics of bipolar disorder - PMC

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Genetics of Bipolar Disorders - PsyAndNeuro.


Bipolar Spectrum Disorders (RBS) - cyclothymia, as well as bipolar affective disorder (BAD) of type I and II - polygenic diseases of a multifactorial nature, the development of which is influenced by both genetic factors and and environmental factors. RHD is manifested by disturbances in mood, thinking, and behavior that are characterized by bipolar phases—recurrent episodes of depression and mania in type I bipolar disorder or hypomania in type II bipolar disorder, but mixed episodes are also frequently observed. RHD has traditionally been classified either as part of the spectrum of psychoses or mood disorders (affective disorders). The lifetime prevalence is about 2.1% and does not differ between men (2.2%) and women (2.0%).

According to twin studies, the heritability of bipolar disorder is up to 85%, which indicates a high genetic influence on the risk of developing this disorder and its prognosis. At the same time, it is necessary to take into account environmental factors that also affect the manifestation and course of BAD. Examples of such factors include perinatal risk factors such as caesarean section, maternal influenza infection, maternal smoking during pregnancy, and late paternal age. Traumatic events in childhood are important, as is the use of psychoactive substances (PS) during adolescence, such as cannabis or other drugs, which can lead to an early onset of bipolar disorder and a more severe course. In addition, various somatic (endocrinological, immune or vascular) diseases can provoke a manifestation of bipolar disorder, as well as the use of drugs (antidepressants, corticosteroids, androgens, isoniazid and chloroquine) and electroconvulsive therapy.

Family studies attempt to answer the question - do disorders tend to aggregate (accumulate) in families? Family design typically compares the incidence of the disorder among first-degree relatives of an affected proband with the incidence of the disorder among relatives of unaffected probands and the general population. The higher frequency of the disorder among relatives of affected probands indicates that the disorder may run in families. However, this does not necessarily mean that only genes are involved in the etiology and pathogenesis of this disorder, as it can occur in families due to common environmental factors (for example, excessive stress, living in an ecologically unfavorable area, etc.).

According to family studies, first-degree relatives of affected individuals have a multiple increased risk of bipolar disorder. E.S. Gershon et al. reported a 19-fold increase in the risk of developing bipolar disorder and a 12.4-fold increase in the risk of developing recurrent depressive disorder (RDD). Twin studies (and to a lesser extent, studies with adopted children) have also provided evidence that genes contribute significantly to familial transmission of the disorder. Moreover, bipolar disorder manifesting in early childhood seems to be associated with increased family risk.

As mentioned earlier, although the presence of blood relatives with the same disorder in the family confirms the genetic influence on its development, family studies, unlike twin studies, do not allow us to more accurately quantify the contribution of genetic factors and separate their effects from possible environmental influences or mixed effects. Twin studies comparing groups of mono- and dizygotic pairs of twins can help analyze genetic and environmental contributions. Twin studies typically compare concordance scores for the disorder between monozygotic (MZ) twins (genetically identical) and dizygotic (DZ) twins (sharing half of the genes).

Assuming that the overall environmental influences on MZ twins are no different from environmental influences on DZ twins (equal-conditions assumption), the significantly higher levels of concordance in MZ twins reflect genetic influence itself. However, the level of agreement in MZ twins, which is less than 100%, means that environmental factors do influence the manifestation of a genetic influence - the phenotype of the disease. Twin studies can also be used to assess the contribution of genetic and environmental factors to the variance in susceptibility to the disorder. However, it should be understood that heritability demonstrates the strength of genetic influences for a population, but not for an individual, and estimates of heritability may vary depending on the population under study.

Despite differences in assessment and diagnosis methods, twin studies of bipolar disorder are generally consistent in observing greater agreement between MH twins than DZ twins. This provides strong evidence for the hypothesis that BAD is genetic in nature. Thus, studies have shown that estimates of the heritability of bipolar disorder are in the range of 60-85%, and there is little evidence that the general family environment plays a significant role. However, heritability estimates are less than 100%, indicating the influence of environmental factors

Overall, the available family studies support the findings that: 1) relatives of probands with BD have an increased risk of both BD and RDD; 2) relatives of probands with RDR are at increased risk of RDR, but probably do not have a significantly increased risk of BAD; 3) there is overlap between BAD with other disorders, especially schizophrenia spectrum disorders (In several studies, the risk of BAD among relatives of IAD probands was comparable to or higher than the risk among BAD probands. On the other hand, relatives of BAD probands did not a significantly increased risk of RAD was found).

It is also possible that the increased risk of RDR among relatives of probands with bipolar disorder may be overestimated if some relatives with unipolar depression are in fact latent cases of bipolar disorder.

Persons with a burdened history of bipolar disorder have an earlier onset (15 times more often than individuals without a family history of bipolar disorder), a more frequent presence of concomitant psychopathology (panic disorder, psychosis, substance dependence diseases and suicide), and also a more severe course of the underlying disease and a higher risk of hospitalization. In addition, individuals with a family history of bipolar disorder have a higher risk of developing fast cycle bipolar disorder, the most unfavorable subtype of this disorder.

A number of authors suggest that the level and characteristics of the therapeutic response to normothymic drugs, in particular lithium, can serve as a marker for identifying familial subtypes of bipolar disorder. Studies investigating the relationship between familial history of bipolar disorder and lithium response have produced mixed results, but some have found a better response among patients with a familial history, while others have not found a significant or even inverse relationship.

Modern molecular genetic research has achieved some success in studying the nature of BAD. To a greater extent, this is due to the use of the genome-wide association studies method (eng. genome-wide association studies , GWAS). Thus, studies using GWAS, in contrast to studies focused on candidate genes, considered a large number of common variants (single nucleotide polymorphisms) throughout the genome, which increased the chances of detecting genetic associations with BAD. To date, significant genetic associations based on GWAS results have been found in 19chromosomal loci, many of which have been replicated in other studies. BAR-associated genes determine the operation of calcium channels, cell division cycles, cytoskeleton formation, as well as various epigenetic processes, neuronal differentiation, building neuronal connections, regulation of neuronal growth, the operation of the hypothalamic-pituitary-adrenal axis, etc. Several genes, including TRANK1, CACNA1C, ANK3, ITIh4-ITIh5, ZNF804A, and NCAN, have also been associated with schizophrenia.

In addition to the common single nucleotide polymorphism (SNP) genetic polymorphisms found in GWAS, rare genetic variants may also be important for the development of RHD if they have high penetrance (a measure of the phenotypic expression of an allele in a population). ) and therefore may be associated with an increased risk of developing this disorder. Rare variants are classified according to their genomic size into single nucleotide variants, small insertions and deletions, and variants with a large number of copies, including copies of genes or their regions (Copy number variation, CNV; deletions or duplications of large sequences of deoxyribonucleic acid (DNA) in size from 1 thousand to several million base pairs). Thus, some studies have shown the accumulation of rare CNVs in patients with bipolar disorder, especially in patients with an early onset of the disease (from 5 to 18 years). However, these results have not always been replicated in other studies. The latest meta-analysis on this topic showed an association between three CNVs and BAR (duplications at 1q21.1 and 16p11.2 and deletions at 3q29), all of these variants have previously shown an association with schizophrenia.

However, despite the findings, genetic variants associated with RHD cannot currently be used to predict individual disease risk, its clinical course, or the effectiveness of medical treatment. Thus, the cumulative effect of common alleles with small effects explains only about 25–38% of the phenotypic variance for BAD. In addition, the polygenic nature of these disorders, as well as their heterogeneous phenotype and, as a result, the difficulties in generating truly clinically (phenotypically) homogeneous samples for genetic studies make it unlikely that such a prediction will be possible in the future. It is believed that such studies fail to detect the majority of causal variants that do not reach statistical significance, either due to small effect sizes or low allele frequencies.

A new solution could be an integrated approach using family design and next-generation sequencing methods. Studies with a similar methodology have been able to identify new genetic variants associated with BD that are involved in the development of the cerebral cortex, circadian rhythms, and glutamate neurotransmission processes.

Family-based design is one of the most popular in the field of medical genetic research and has many unique opportunities for studying the risk of developing a particular disease. With its help, it is possible to reduce genetic heterogeneity, and the study of family risks can be very informative for predicting the risk of human disease based on polygenic and common environmental components of genetic risk. Family design provides the maximum probability of detecting specific genetic markers associated not only with the phenotype, but also with potential familial forms of BD. However, despite these strengths, family design is rarely used in current clinical and basic research on psychiatric disorders due to the complexity of data collection and the difficulty in motivating patients and their families to participate in such research.

Obviously, given all the achievements of classical research with family design and the outstanding possibilities of modern genetic technologies, in particular, next generation whole exome sequencing, the most optimal approach may be the complex design of such studies. Each of the methods, taken separately, cannot give the expected result, but the correct combination of these methods provides good chances already at the study planning stage. Family design provides the maximum probability of detecting specific genetic markers associated not only with the nosological phenotype (diagnosis), but also with potential familial and hereditary forms of the disease, and modern genetic technologies make it possible to realize such a probability - to identify reliable and reproducible results.

Author: Kasyanov E.D.

Source: Kasyanov ED, Merculova TV, Kibitov AO, Mazo GE. Genetics of bipolar spectrum disorders: focus on family studies using whole exome sequencing // Genetica [Russian Journal of Genetics]. 2020. V. 56. No. 7. P. 762-782. doi: 10.31857/S001667582007005X

Gene expression profiles 'equate' schizophrenia and bipolar disorder

Researchers analyzed and compared Gene Expression Profiles in the Brain in Five Common Disorders psyche - autism, schizophrenia, depression, bipolar disorder and alcoholism. All diseases, except for alcoholism, turned out to be similar in varying degrees. expression profile, which is confirmed by the presence of common genetic markers. Article published at Science there you can also find an editorial note on the study.

Many mental illnesses have a significant hereditary component, and the same genetic markers often correlate with different diseases at the same time. This may mean that the development for example, schizophrenia, bipolar disorder and depression, goes through a similar mechanism. However, what kind of violations at the molecular level occur in the brain during the development of mental illness, is still unknown. There are no biochemical tests to diagnose patient for a particular disease.

To advance our understanding of the mechanisms mental illness at the molecular level, researchers from the University California (Los Angeles, USA) compared gene expression profiles in the cerebral cortex of 700 a person suffering from the five most common mental diseases. The work was carried out in collaboration with scientific groups commonmind, PsychENCODE and iPSYCH-BROAD, which analyze gene expression in brain tissues taken from patients postmortem.

The sample included 50 former patients with autism, 159 schizophrenia, 94 with bipolar disorder, 87 with major depression disorder and 17 patients with alcoholism. Two were taken as controls. samples - 293 "healthy" samples and 197 samples taken from patients with intestinal inflammation - a disease not associated with the nervous system. The researchers looked at how gene expression profiles patients change compared to controls, and the degree of correlation was determined changes among themselves for different disorders in pairs.

The profiles are most similar to each other expression in schizophrenia and bipolar disorder, diseases that little similar in manifestation, but have common genetic markers. According to experts, this is quite surprising, since the clinical symptoms of bipolar the disorder is usually grouped together with depression (disorders sentiments). However, the expression correlation coefficient for depression and bipolar disorder was three times lower than for schizophrenia and bipolar disorder. In second place in terms of the degree of correlation was the schizophrenia-autism pair. Despite the fact that twin studies have previously indicated the presence of a common hereditary component in depression and alcoholism, the analysis showed that gene expression alcoholism does not correlate with any other disease.

Changes in gene expression also indicated possible molecular mechanisms of disease development. For example, for autism, they found increased activity of genes associated with hyperactivation of microglia - immune cells central nervous system. This led the researchers to speculate that the inflammation is involved in the development of the disease. According to the editor of Science , one of the authors of the study organized a small clinical trial to see how the suppression of microglial activity would affect condition of patients with autism.

In general, the authors note that the similarity of gene expression profiles between various disorders is consistent with the presence of common genetic markers for these conditions, which, firstly, confirms the significant contribution of genetics to their development, and secondly, indicates the commonality of development mechanisms.

As scientists have previously shown, the development of schizophrenia is probably contributes one of the proteins of the immune system, which is also involved in maturation of synapses - contacts between neurons. About the history of schizophrenia research and how its genetic nature is studied can be read in our materials (1, 2, 3).

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