Posted: April 30th, 2022

The role of genetics in bipolar disorder

The role of genetics in bipolar disorder

Bipolar disorder (BP) is a mental health condition that affects the mood, energy, and behavior of individuals. It is characterized by episodes of mania, hypomania, depression, or mixed states, which can last from hours to weeks. BP is a complex disorder, which pathogenesis is influenced by a number of genetic and environmental factors. The aim of this paper is to review the current evidence on the role of genetics in BP, and to discuss the implications for diagnosis, treatment, and prevention.

Genetic factors are estimated to account for 60-85% of the variance in BP susceptibility, according to twin studies . However, the genetic architecture of BP is not well understood, as no single gene or variant can explain the disorder. Rather, BP is likely caused by the cumulative effect of multiple common and rare variants across the genome, each with small effect size . Genome-wide association studies (GWAS) have identified several loci associated with BP risk, such as ANK3, CACNA1C, ODZ4, SYNE1, and TRANK1 . However, these loci explain only a small fraction of the heritability (~20%) , suggesting that many more variants remain to be discovered.

One way to increase the power of genetic studies is to use polygenic risk scores (PRS), which are measures of the overall genetic liability for a trait based on the sum of weighted risk alleles from GWAS . PRS can be used to estimate the genetic overlap between BP and other traits, such as schizophrenia, major depression, anxiety disorders, substance use disorders, personality traits, and cognitive abilities . These analyses have revealed that BP shares a substantial proportion of genetic risk with schizophrenia and major depression, reflecting the clinical and biological similarities between these disorders . Moreover, PRS can be used to predict BP risk in individuals or populations, and to identify subgroups of patients with different clinical features or treatment outcomes .

Another way to improve the detection of genetic variants involved in BP is to use next-generation sequencing (NGS), which allows the analysis of the whole genome or exome at high resolution . NGS can identify rare variants with large effect sizes that may have been missed by GWAS. For example, NGS studies have found rare copy number variants (CNVs) and single nucleotide variants (SNVs) in genes related to synaptic function, calcium signaling, neurodevelopment, and immune system in BP patients . However, NGS studies also face challenges such as high costs, low sample sizes, heterogeneity of phenotypes and sequencing platforms, and difficulties in interpreting the functional consequences of rare variants .

The identification of genetic factors involved in BP has important implications for understanding the biological mechanisms underlying the disorder. Genetic variants can affect the expression or function of genes that are involved in neurotransmission, neuroplasticity, circadian rhythms, inflammation, and other pathways relevant for mood regulation . Moreover, genetic factors can interact with environmental factors, such as stress, trauma, infection, or medication use, to modulate the onset and course of BP . Therefore, studying the gene-environment interactions in BP can provide insights into the etiology and pathophysiology of the disorder.

The knowledge of genetic factors involved in BP can also have implications for diagnosis, treatment, and prevention. Genetic testing can help to improve the accuracy and timeliness of diagnosis by distinguishing BP from other psychiatric disorders or subtypes of BP . Genetic testing can also help to predict the response or adverse effects of pharmacological or psychological treatments by identifying genetic markers of drug metabolism or target engagement . Furthermore, genetic testing can help to identify individuals at high risk of developing BP who may benefit from early intervention or prevention strategies .

In conclusion, genetics plays a major role in BP susceptibility and expression. However, BP is a complex disorder that involves multiple genes and environmental factors. Therefore, more research is needed to elucidate the specific genetic variants and pathways involved in BP and their interaction with environmental factors. This will help to improve the understanding of the biological basis of BP and to develop more effective and personalized interventions for this condition.

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