Bipolar disorder is a common mental illness, estimated to affect around 1 to 4% of the population, but understanding the underlying genetics has proved a major challenge to researchers.
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Genome-wide association studies have been transformative in understanding the genetic basis of bipolar disorder, revealing the first specific genetic markers associated with the illness and helping to characterize a polygenic architecture that is also observed in other mental illnesses such as major depression and schizophrenia.
As researchers learn more about the genetic basis of bipolar disorder, it becomes more likely that the underlying neurobiological pathways may be identified, potentially leading to newly developed treatments. However, the inherited risk associated with bipolar remains largely unexplained and a lot of work remains ahead.
Now, in a comprehensive review of the progress so far, Francis Gordovez and Francis McMahon from the Department of Health and Human Services, National Institutes of Health, outline the major developments over recent years and ask some key questions about the future directions that genomics research should take.
The challenges researchers have faced
Starting with the phenotype of bipolar, the authors talk about the challenges presented by the subjective and varied nature of symptoms, which may be early or late-onset and frequent or infrequent, for example.
Previously, scientists would often focus only on people who had already received a diagnosis and/or who could be diagnosed easily by interview, which is unlikely to paint an accurate picture. Epidemiological studies focused on families demonstrated heritability and an increased risk of a mood disorder among first-degree relatives of those with bipolar.
However, a clear Mendelian pattern of inheritance could not be identified, suggesting that inheritance patterns were more complicated.
The advent of molecular genetics research
Since the advent of molecular genetics research, approaches have included searches for risk loci, candidate genes and genetic markers that span the genome (genetic-wide association studies).
Researchers generally used genetic linkage analysis to search for risk loci but the complex inheritance pattern of bipolar meant these failed to generate any replicable results.
Researchers trying to find candidate genes would focus on genetic markers located close to genes known to code for proteins of neurobiological significance. However, this strategy was generally unsuccessful, and studies were often limited by small sample sizes.
Studies that did generate more robust evidence were genome-wide association studies (GWASs), where researchers look for associations between large numbers of genetic markers spanning the genome and known bipolar traits, usually in large case-control cohorts. Since the first results using this approach were published in 2007, almost twenty more similar studies have been conducted.
The most recent one published involved 50,000 cases and identified 30 genome-wide loci, twenty of which were previously unknown.
However, many of the loci so far identified cannot be linked to single genes using the information currently available, meaning conclusions cannot be drawn about specific risk genes based on these studies.
Furthermore, polygenic risk scores that include the cumulative effects of up to thousands of risk alleles can better indicate genetic risk by including mutations that have not previously been detected.
Research studying copy number variants (CNVs) has found that these are involved in neurodevelopmental disorders and play a small role in bipolar. In large, case-control studies of the condition, researchers have identified at least two associated CNVs.
As WGS and other technologies come to the fore, we will doubtless ﬁnd very large numbers of smaller CNVs in the human genome. Many such smaller CNVs may also be associated with various neurodevelopmental and adult psychiatric disorders and may well be found to play an important role in BD [bipolar disorder]in the future,”
Promising future directions
After proceeding to discuss the genetic architecture of bipolar, etiology models and pharmacogenetic studies, Gordovez and McMahon introduce promising future directions including cellular phenotyping and reverse phenotyping.
Induced pluripotent stem cells (iPSCs) can be used for the in vitro assessment of phenotypes such as cellular function or morphology that could be associated with bipolar.
Larger-scale interactions that might be involved in brain circuitry alterations, for example, could be studied using 3D organoids. Initial results from some iPSC-based studies have so far indicated some neuronal changes in patients with bipolar.
As researchers continue to identify genes that influence risk, it may be helpful to study people who are at significant risk, but do not yet present with symptoms – a strategy referred to as reverse phenotyping. This approach has already generated findings in studies of CNVs associated with schizophrenia risk and in the future, it may uncover several phenotypes associated with known risk factors.
“Longitudinal studies of genetically high-risk individuals may also shed light on protective or resilience factors and could provide the basis for assessing the impact of primary prevention strategies,” say the reviewers.
Commenting on the ultimate aim of drug development, Gordovez and McMahon say the journey from the identification of risk alleles to the manufacture of new drugs for bipolar is a long and complicated one that will depend on whether the neurobiological pathways involved can be identified.
They think the iPSC technology could serve as a new platform for screening large numbers of potential new drugs, but that success will depend on whether robust cellular phenotypes can be identified that reﬂect at least some of the genetic risk factors that predispose to bipolar or related conditions. They also say that polygenic approaches will continue to be useful and may eventually find applications in certain clinical settings.
We have ﬁnally made it through the ﬁrst era of molecular genetics of BD, but the road to new methods of diagnosis and treatment may well remain long and uncertain,”
Gordovez F and McMahon F. The genetics of bipolar disorder. Molecular Psychiatry 2020. https://doi.org/10.1038/s41380-019-0634-7