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Bipolar disorder genetics

Bipolar disorder genetics


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My understanding is that bipolar disorder is polygenic.

1) Does one need to have all the genes for bipolar disorder in order to have the disease?

2) Is it possible for a person to have all the genes for bipolar disorder and still not have the disease?


Does one need to have all the genes for bipolar disorder in order to have the disease?

No. In genome-wide association studies (GWAS) of psychiatric conditions, it is a constant finding that the associated variants each influence the probability/risk. The effects of all known variants can then be summed up to a polygenic score (PGS). A person with higher PGS is more likely than someone with a low PGS. But some people with low PGS (i.e. people who don't have "all the genes") still get the condition, it is just not as frequent as people with high PGS.

Another reason why we can say 'no' to this question is through findings of quantitative genetics studies. These estimate the heritability of certain traits. For the answer to be 'yes', the heritability would have to be one ($h^2 = 1$). However, as far as I know, there are no known psychiatric conditions that have heritabilities of one. Some high (e.g. $h^2approx 0.8$), yes, but not one.

It's also worth mentioning that there is probably no sharp line between having bipolar disorder and not having it. It's a medical diagnosis that is useful but rough. Most likely, all of us have a little "bipolar" in us. I think it's probably most useful to view it as a spectrum.

Is it possible for a person to have all the genes for bipolar disorder and still not have the disease?

This is not known and it may not even be a well-defined question. We don't know all the variants that affect the risk of bipolar disorder (or most other polygenic disorders). So we cannot say for sure.

Some 'omnigenetic' hypotheses propose that all genetic variants have some effect on all traits. Some effects are just smaller and some larger. In this case, the expression 'all the genes for X' may be technically meaningless.


Genetics of bipolar disorder

Family and twin studies have consistently documented that bipolar disorder (BPD) is familial and heritable, but efforts to identify specific susceptibility genes have been complicated by the disorder's genetic and phenotypic complexity. Genetic linkage studies have implicated numerous chromosomal regions, but findings have been inconsistent. As with other complex disorders, it has become clear that linkage analysis lacks the power and precision to identify susceptibility loci for BPD. Candidate gene association studies have implicated several specific genes, but these studies have been limited by our incomplete understanding of the disorder's biology, and there have been few robustly replicated results. Within the past 2 years, a major advance in the genetics of complex disease has become feasible in the form of genome-wide association studies. Such studies, which require large sample sizes, have already proven successful in identifying susceptibility variants for a range of common medical disorders. Genome-wide association studies have begun to appear for BPD, and more are in progress. By providing an unbiased approach, this technology may reveal novel biological mechanisms underlying BPD.


Largest Genetic Study of Bipolar Disorder Identifies 64 Regions of the Genome That Increase Risk for the Condition

Niamh Mullins, PhD
Mount Sinai Health System

In the largest genetic study of bipolar disorder to date, researchers have identified 64 regions of the genome containing DNA variations that increase risk of bipolar disorder - more than double the number previously identified.

The research team also found overlap in the genetic bases of bipolar disorder and other psychiatric disorders. Furthermore, the study supports a role of sleep habits, alcohol, and substance usage in the development of bipolar disorder, although further research is needed to confirm these findings. The study results are published May 17 in Nature Genetics.

Bipolar disorder, a complex psychiatric disorder characterized by recurrent episodes of severely high and low mood, affects an estimated 40 to 50 million people worldwide. It typically begins in young adulthood, often takes a chronic course, and carries an increased risk of suicide, making it a major public health concern and cause of global disability.

To help elucidate the underlying biology of bipolar disorder, an international team of scientists from within the Psychiatric Genomics Consortium conducted a genome-wide association study. This means they scanned the DNA of lots of people, looking for genetic markers that were more common in those who had bipolar disorder. This involved scanning more than 7.5 million common variations in the DNA sequence of nearly 415,000 people, more than 40,000 of whom had bipolar disorder. The study identified 64 regions of the genome that contain DNA variations that increase risk of bipolar disorder.

&ldquoIt is well-established that bipolar disorder has a substantial genetic basis and identifying DNA variations that increase risk can yield insights into the condition&rsquos underlying biology,&rdquo says Niamh Mullins, PhD, Assistant Professor of Psychiatric Genomics at the Icahn School of Medicine at Mount Sinai and lead author of the paper. &ldquoOur study found DNA variations involved in brain cell communication and calcium signaling that increase risk of bipolar disorder.

The findings suggest that drugs, such as calcium channel blockers that are already used for the treatment of high blood pressure and other conditions of the circulatory system, could be investigated as potential treatments for bipolar disorder, yet it's important to note that future research to directly assess whether these medications are effective is essential.&rdquo

The study also found overlap in the genetic basis of bipolar disorder and that of other psychiatric disorders and confirmed the existence of partially genetically distinct subtypes of the disorder. Specifically, they found that bipolar I disorder shows a strong genetic similarity with schizophrenia and bipolar II disorder is more genetically similar to major depression.

&ldquoThis research would not have been possible without the collaborative efforts of scientists worldwide that enabled the study of hundreds of thousands of DNA sequences,&rdquo said Ole Andreassen, MD, PhD, Professor of Psychiatry, Institute of Clinical Medicine and Oslo University Hospital and senior author of the paper. &ldquoThrough this work, we prioritized some specific genes and DNA variations which can now be followed up in laboratory experiments to better understand the biological mechanisms through which they act to increase risk of bipolar disorder.&rdquo

The biological insights gained from this research could ultimately lead to the development of new and improved treatments or precision medicine approaches to stratify patients at high genetic risk who may benefit from targeted treatment or intervention strategies. Understanding causal risk could aid clinical decision-making in the prevention or management of the illness. Future genetic studies in larger and more diverse populations are now needed to pinpoint the genes relevant to risk of bipolar disorder in other areas of the genome.

The Psychiatric Genomics Consortium (PGC) is an international consortium of scientists dedicated to studying the genetic basis of psychiatric disorders and includes over 800 researchers, from more than 150 institutions from over 40 countries.


How genes influence bipolar disorder

Bipolar disorder can run in families, so many experts believe that genes play a role in its development.

The exact inheritance pattern of bipolar disorder is unclear, but variations in many genes likely combine to increase a person’s chance of developing it. Some environmental factors also play a role in triggering its symptoms.

The National Institute of Mental Health estimate that 2.8 percent of adults in the United States experience bipolar disorder in any given year. They also say that 4.4 percent of people will experience it at some point during their life.

In this article, we look at the genetic and nongenetic factors that may cause bipolar disorder, as well as some potential treatments for the condition.

Share on Pinterest A genetic predisposition to bipolar disorder may not be enough to trigger its development.

People are more likely to develop bipolar disorder if they have a close relative with the condition.

Individuals are also more likely to develop bipolar disorder if they have another mental health condition, such as depression or schizophrenia.

Some research suggests that the lifetime risk of bipolar disorder in relatives of someone with the condition is 5–10 percent for a close relative and 40–70 percent for a twin.

However, scientists do not fully understand the role that genes play in bipolar disorder.

According to the National Institutes of Health (NIH), some studies indicate that irregularities in many genes combine to increase a person’s chance of bipolar disorder. The exact way that this occurs remains unclear.

It is likely that just having a genetic predisposition to the disorder is not enough to trigger its development. Environmental factors may also be necessary to trigger symptoms in people with the relevant gene variations.

It is also important to note that just because someone has a greater chance of having bipolar disorder, it does not mean that they will go on to develop it.

Research suggests that the majority of people with a genetic predisposition are healthy, and most people with a relative who has bipolar disorder do not have the condition themselves.

Along with genetics, there are some environmental factors that appear to play a part in triggering bipolar disorder in susceptible people. These include:

  • Periods of high stress: Examples of stressful events that could trigger symptoms of bipolar disorder include a death in the family or being a survivor of rape, abuse, or another traumatic experience.
  • A traumatic head injury: Concussion or other types of brain injury may cause symptom onset.
  • Alcohol or drug misuse: Substance misuse is common among those with bipolar disorder, and the conditions may trigger each other in some cases. Drinking alcohol and using drugs can worsen symptoms of both mania and depression.
  • Childbirth: Some research suggests that childbirth has links to first-time psychiatric disorders, such as bipolar disorder, in new mothers.

There are four subtypes of bipolar disorder, each with similar symptoms.

However, the occurrence, duration, and intensity of the symptoms can determine which subtype a person has.

Types of bipolar disorder include:

  • Bipolar I disorder: This causes manic episodes lasting 1 week or more, or severe mania requiring hospitalization. If it occurs, a major depressive episode may last 2 weeks or more. A manic episode is all that is necessary for a doctor to diagnose bipolar I disorder, however.
  • Bipolar II disorder: This type is similar to bipolar I disorder but involves a less intense form of mania called hypomania. A person with bipolar II disorder must have a major depressive episode lasting 2 weeks or more preceding or following a hypomanic episode.
  • Cyclothymic disorder: This type causes symptoms of hypomania and depression for 2 years or more, but they do not fit the criteria for truly manic or depressive episodes.
  • Other types: These may involve bipolar disorder symptoms that do not fit into any of the other categories.

Symptoms of mania and hypomania

During manic episodes, which can cause extreme “highs” in mood, people may experience:

  • a lower need for sleep
  • a desire to engage in reckless behaviors such as using drugs or consuming alcohol
  • anger
  • difficulty concentrating or making decisions
  • irritability
  • high energy levels and restlessness
  • high self-esteem
  • intense enthusiasm
  • racing thoughts

Hypomania symptoms are similar to those of mania, but they are less intense.

Symptoms of depression

Depressive symptoms, lasting for 2 weeks or more, include:

  • changes in appetite and sleep habits and low energy
  • feelings of sadness or hopelessness
  • an inability to concentrate or make decisions
  • loss of interest in things the person once enjoyed
  • low self-esteem
  • oversleeping or not getting enough sleep or behaviors

Other symptoms

Around 50 percent of people with bipolar disorder also experience symptoms of psychosis, such as hallucinations and delusions. These cause people to imagine things that are not happening, or to maintain false beliefs.


Over 60 Genetic Links to Bipolar Disorder Identified in Largest Study to Date

Scientists have identified dozens of previously unidentified genetic indicators that increase risk for bipolar disorder, in what scientists say is the largest study of its kind to date.

In a genome-wide association study (GWAS) involving over 400,000 people – some 41,917 of whom had bipolar disorder – scientists compared variants in participants' DNA, looking for genetic markers that might be tied to the occurrence of the condition.

Bipolar disorder is a heritable mental disorder characterized by severe mood swings, typically ranging from mania or hypomania to depression it's estimated to affect about 45 million people across the globe.

While it has several subtypes, the condition is usually lifelong, and people with bipolar disorder also tend to have an increased risk of dying from suicide it's one of the reasons why a better understanding of the disease, including its genetic underpinnings, is a major public health concern.

"It is well-established that bipolar disorder has a substantial genetic basis and identifying DNA variations that increase risk can yield insights into the condition's underlying biology," says psychiatric geneticist Niamh Mullins from the Icahn School of Medicine at Mount Sinai in New York.

Previous GWAS investigations into the genetic origins of bipolar disorder have transformed our understanding of the condition by revealing numerous gene variants involved.

Despite these advancements, we're still very much at the beginning of this journey into figuring out how genes – including those shared by family members – affect people's chances of developing bipolar disorder, let alone appreciating how environmental factors may also contribute.

"Only a fraction of the genetic etiology of bipolar disorder has been identified, and the specific biological mechanisms underlying the development of the disorder are still unknown," Mullins and her co-authors explain in their new paper.

In the latest work, Mullins and her team more than doubled the existing count of known genetic markers for bipolar disorder, identifying 64 regions in the genome containing DNA variations that increase risk, 33 of which are new to science.

"Our study found DNA variations involved in brain cell communication and calcium signaling that increase risk of bipolar disorder," Mullins says.

Amongst the total 64 genomic loci associated with increased risk, 17 have previously been tied to the development of schizophrenia, while seven are linked to major depression – a coincidence that the researchers say represents "the first overlap of genome-wide significant loci between the mood disorders".

While there's still much we have yet to tease out in the data, the modeling here could suggest that some variants may put individuals at an increased risk of developing different kinds of depressive conditions.

"Across the entire genome, almost all variants influencing bipolar disorder also influence schizophrenia and major depression, albeit with variable effects," the team writes.

"Our results also corroborate previous genetic and clinical evidence of associations between bipolar and sleep disturbances, problematic alcohol use, and smoking."

In addition, the results appear to confirm previous indications that the two sub-types of bipolar (I and II) are genetically based, with BD I correlated with schizophrenia, while BD II has stronger genetic ties to major depression.

Ultimately, the researchers hope that the new and confirmed genetic correlations could help us to identify the most suitable candidate genes that could be targeted by future forms of medication.

That future is not here yet, but thanks to these scientists, we just took another stride towards it.


The Biologic Basis of Bipolar Disorder


Five mini-chapters on the brain chemistry of mania and depression
(updated 12/2014)

At this point, treatment of bipolar disorder is roughly equivalent to when diabetes was treated without insulin. We do not know the fundamental cause and cannot therefore target our treatments accordingly.

However, our understanding is growing very quickly. I used to hope that a Nobel prize would be awarded someday to someone who made the key discovery. But it now appears that the tapestry of manic symptoms is extremely complex. Many threads have been identified, and they are just beginning to come together. Even if no single researcher wins a Nobel, small breakthroughs seem to be coming more and more rapidly. This is a very exciting time in the history of bipolar understanding.

    : the genetic basis of bipolar disorder : Brain differences in bipolar disorder : The central role of the biological clock : The biologic basis of depression : There must be some evolutionary advantage?

Note that the biologic basis of depression is described in a separate section on this website.


Adoption studies

Only two adoption studies have used a modern concept of bipolar disorder. Mendlewicz and Rainer49 investigated the biological and adoptive parents of 29 bipolar and 22 normal adoptees and the biological parents of 31 bipolar non-adoptees and found significantly (p<0.05) greater risk of affective disorder (bipolar, schizoaffective, and unipolar) in the biological parents of bipolar adoptees (18% risk) compared with the adoptive parents (7% risk). This risk in biological relatives of bipolar adoptees was similar to that in the biological relatives of bipolar non-adoptees. The study of Wender et al 50 included only 10 bipolar probands but showed a similar (but non-significant) trend for biological relatives of probands to be at increased risk compared with adoptive relatives.


Genetic Findings

Given the high heritability of the disorder (79%–93%) (44), BD has long been known to have a strong genetic component. Nevertheless, understanding the nature of the genetic abnormalities in BD has proven to be quite difficult, and the precise genetic underpinnings of the disorder remain unknown. The evidence to date suggests that BD, like other neuropsychiatric disorders, is unlikely to be caused by one or even just a few genetic mutations. Rather, BD is likely to have a strong polygenic component (45) wherein the BD phenotype is the result of many genetic factors.

Evidence from several different methodologies suggests that the development of BD is under considerable genetic control. Twin studies demonstrate that monozygotic twins have a higher concordance rate (38.5%–43%) for BD than dizygotic twins (4.5%–5.6%) (46–48), and family studies show that adopted children with a biological parent with BD have a higher relative risk of developing the disorder themselves than adopted children whose biological parents do not have BD (4.3 versus 1.3) (49).

Several different methodologies are used to try to understand the genetics of BD, such as linkage analysis, candidate gene association studies, and genome-wide association studies (GWAS). In a linkage analysis study, genetic information is collected from pedigrees in an attempt to identify the chromosomal region wherein susceptibility genes may be located. Many markers spread across the genome are examined, with the goal of identifying genomic areas that appear to be inherited along with the disorder within each family. This methodology is particularly well suited, however, to identifying the genetic causes of disorders in which a small number of genes contribute to a large degree of risk for developing the disorder across families. As BD does not appear to be inherited in this way in the majority of cases, evidence from the many linkage analysis studies that have been carried out in BD has been largely inconclusive (44, 50, 51).

Genetic Association Studies

Candidate gene association studies are those in which a single or small number of a priori selected genes are examined in cases and controls. Results from these studies have generally been inconsistent a large meta-analysis of 487 candidate gene studies in BD did not find any genes that were significantly associated with the disorder after correction for multiple comparisons (52). However, the lack of any significant findings may be the result of methodological limitations such as insufficient sample sizes. Despite these negative results, it may be productive to examine candidate genes and their association with discrete phenotypic aspects of BD, rather than with the disorder as whole.

Genome-wide association studies (GWAS) are simultaneous investigations of hundreds of thousands of single-nucleotide polymorphisms (SNPs), with the goal of identifying SNPs that occur more or less often in one group compared with a control group. Approximately 12 GWAS have now been conducted in BD, and half of these have identified SNPs that are significantly associated with the disorder. The largest GWAS conducted to date in BD identified two SNPs that attained genome-wide statistical significance: CACNA1C, which encodes for the alpha subunit of the l -type calcium channel, and ODZ4, which is involved in cell surface signaling and neuronal pathfinding (53). CACNA1C was also identified in a previous GWAS (54), suggesting that this SNP is likely to be relevant to BD. ANK3 (encoding ankyrin 3) has also been identified in two BD GWAS (54, 55). Other SNPs that have been found to be significantly associated with BD include NCAN (encoding neurocan) (56), TRPC4AP (57), and TRANK3, PTGFR, and LMAN2L (55). Replication in larger samples will be required to confirm these results, as well as to discover additional SNPs that may be associated with BD. The specificity of these results to BD remains largely unknown however, recent work suggests that several genes appear to be associated with a range of disorders, rather than being specific to a single disorder. In a large-scale GWAS including samples from patients with unipolar depression, attention-deficit hyperactivity disorder, autism spectrum disorder, BD, and schizophrenia, three SNPs (located near CACNB2, AS3MT, and ITIH3, among others) were associated with all five disorders (58). In the same study, CACNA1B was associated with both BD and schizophrenia (58). These results suggest that there is likely to be considerable genetic overlap across disorders, as well as genetic findings that are specific to distinct disorders.

Pathway Analysis

The discovery of SNPs that appear to be associated with BD is critical and exciting nevertheless, the results are difficult to interpret, and the neurobiological significance of many of the identified SNPs is not well understood. Further work will undoubtedly clarify these findings and will hopefully lead to the elucidation of processes that are directly involved in the development or maintenance of BD. In the meantime, recent advances in genetic analysis allow for the examination of entire pathways of biologically related genes. For example, researchers can now investigate the particular genes that are known to be involved in specific biochemical functions. In BD, the results of the first pathway analysis study suggest that there is enrichment in three calcium channel subunits (CACNB3, CACNA1D, and CACNA1C) that are related to voltage-gated calcium channel activity (53). These findings are consistent with evidence that l -type calcium channel blockers are effective in treating BD, given that CACNA1C and CACNA1D encode for the major l -type alpha subunits in the brain. Enrichment of CACNA1C is also consistent with data from GWAS studies (53) and postmortem brain tissue gene expression studies (52). A recent meta-analysis investigated biological pathways contributing to the risk of BD using 4 published GWAS studies for a total of 5253 BD patients and 6874 controls. Based on this analysis, 17 significant canonical pathways were identified, of which 6 showed significant association with BD in both initial and replication data sets. The six pathways were driven by calcium channel genes, glutamate receptor genes, and genes involved in the second messenger system and in hormone regulation. Specifically, they were: corticotropin-releasing hormone (CRH) signaling, cardiac β-adrenergic signaling, phospholipase C (PLC) signaling, glutamate receptor signaling, endothelin 1 signaling, and cardiac hypertrophy signaling (59).

Alterations in Gene Expression

The examination of gene expression profiles within either postmortem brain tissue or peripheral tissue from living participants allows for additional investigation into the genetics of BD. In studies of gene expression, groups of genes are examined to identify shared mechanisms of regulation as well as commonalities in molecular, biological, or structural functions (60). One such study reported evidence for the downregulation of oligodenodrocyte-related genes (61) in BD compared with controls, which may be consistent with neuroimaging evidence of altered white matter in BD. In addition, gene expression studies in BD have reported an upregulation of genes related to inflammation and the immune response (60, 62–64) compared with controls. Finally, such studies have also provided evidence of a downregulation in genes involved in mitochondrial function and energy metabolism (60, 65–67). This last finding is consistent with evidence from multiple lines of investigation linking abnormal mitochondrial functioning and BD, such as magnetic resonance spectroscopy findings of lower pH in the frontal lobes of patients with BD compared with healthy controls (68, 69).

Structural Genetic Alterations

In addition to identifying differences in gene expression, it is also possible to investigate the genetics of BD by examining structural alterations in the genome. These alterations, such as copy number variations (CNVs), are likely to be rare but to have a larger effect on risk for developing BD compared with the common SNPs identified through GWAS. Although only a few studies of rare variation have been conducted in BD, the evidence suggests that there is an enrichment of rare CNVs in patients with BD compared with controls (70–72). However, the effects reported are small, and it appears that CNVs do not play as large of a role in the development of BD as they do in the development of schizophrenia or autism spectrum disorders (70), where structural variation appears to play a larger role. Studies that examine families, rather than individuals, can examine the rate of CNVs that are present in an individual but that are not present in either parent. These de novo CNVs appear to be increased in BD (4.3% rate of de novo CNVs in BD versus 0.9% for controls), particularly in patients with an early onset of BD (71). In fact, for individuals who had an early onset of BD, the rate of de novo CNVs was similar to that found in individuals with schizophrenia, a disorder known to have a higher burden of such structural variation (71).

Epigenetics

In addition to studying genes themselves, researchers have begun more recently to investigate epigenetics, or the regulation of gene expression this often involves a complex interaction between genes and environment. Much of the work in epigenetics has been carried out in nonhuman animals, although a few preliminary human studies have been conducted to examine several key epigenetic processes in BD. One of these processes, chromatin remodeling, refers to the ways in which gene transcription may be regulated through alterations within the chromatin, the complex of DNA and associated histone proteins. Several studies suggest that there are chromatin alterations in people with mood disorders (73, 74) compared with healthy controls. However, it is difficult to study chromatin remodeling in humans as such modifications are very sensitive to changes in experience and vary considerably across time. There is currently no way to directly assess chromatin modification in vivo in the brain in humans rather, studies have been carried out on postmortem brain tissue or on peripheral cells.

Several studies in BD have examined histone deacetylases (HDACs), enzymes that are integral to chromatin remodeling in that they tend to repress transcription (75–77). One such study found a reduction in the expression of several HDACs in patients with major depressive disorder or BD during a depressive episode and found no difference in these expression levels during a period of affective remission (73). A study of the expression of 11 different types of HDACs found that patients with BD demonstrated an increase in the expression of HDAC4 mRNA during a depressive episode and a decrease in the expression of HDAC6 and HDAC8 mRNA during both the depressive and remitted states (74). Although the particular downstream biological or behavioral significance of these HDAC alterations is currently unknown, there is evidence that abnormalities in HDAC expression are associated with a range of mood and cognitive phenotypes (78). Moreover, the mood stabilizer valproate, a first-line treatment for BD, appears to act as an HDAC inhibitor, further implicating epigenetic factors in the neurobiology of BD and suggesting that novel treatments may arise that target HDACs and other factors associated with chromatin remodeling (79).

HDACs are but one of many epigenetic factors that are likely to be critically important in the development and maintenance of mood disorder symptoms, and research in this area is relatively new. Epigenetic targets appear to be a promising avenue for the development of novel therapeutic agents and perhaps the application of personalized medicine in the treatment of BD.


Understanding the basic biology of bipolar disorder

Scientists know there is a strong genetic component to bipolar disorder, but they have had an extremely difficult time identifying the genes that cause it. So, in an effort to better understand the illness's genetic causes, researchers at UCLA tried a new approach.

Instead of only using a standard clinical interview to determine whether individuals met the criteria for a clinical diagnosis of bipolar disorder, the researchers combined the results from brain imaging, cognitive testing, and an array of temperament and behavior measures. Using the new method, UCLA investigators — working with collaborators from UC San Francisco, Colombia's University of Antioquia and the University of Costa Rica — identified about 50 brain and behavioral measures that are both under strong genetic control and associated with bipolar disorder. Their discoveries could be a major step toward identifying the specific genes that contribute to the illness.

The results are published in the Feb. 12 edition of the journal JAMA Psychiatry.

A severe mental illness that affects about 1 to 2 percent of the population, bipolar disorder causes unusual shifts in mood and energy, and it interferes with the ability to carry out everyday tasks. Those with the disorder can experience tremendous highs and extreme lows — to the point of not wanting to get out of bed when they're feeling down. The genetic causes of bipolar disorder are highly complex and likely involve many different genes, said Carrie Bearden, a senior author of the study and an associate professor of psychiatry and psychology at the UCLA Semel Institute for Neuroscience and Human Behavior.

"The field of psychiatric genetics has long struggled to find an effective approach to begin dissecting the genetic basis of bipolar disorder," Bearden said. "This is an innovative approach to identifying genetically influenced brain and behavioral measures that are more closely tied to the underlying biology of bipolar disorder than the clinical symptoms alone are."

The researchers assessed 738 adults, 181 of whom have severe bipolar disorder. They used high-resolution 3-D images of the brain, questionnaires evaluating temperament and personality traits of individuals diagnosed with bipolar disorder and their non-bipolar relatives, and an extensive battery of cognitive tests assessing long-term memory, attention, inhibitory control and other neurocognitive abilities.

Approximately 50 of these measures showed strong evidence of being influenced by genetics. Particularly interesting was the discovery that the thickness of the gray matter in the brain's temporal and prefrontal regions — the structures that are critical for language and for higher-order cognitive functions like self-control and problem-solving — were the most promising candidate traits for genetic mapping, based on both their strong genetic basis and association with the disease.

"These findings are really just the first step in getting us a little closer to the roots of bipolar disorder," Bearden said. "What was really exciting about this project was that we were able to collect the most extensive set of traits associated with bipolar disorder ever assessed within any study sample. These data will be a really valuable resource for the field."

The individuals assessed in this study are members of large families living in Costa Rica's central valley and Antioquia, Colombia. The families were founded by European and native Amerindian populations about 400 years ago and have a very high incidence of bipolar disorder. The groups were chosen because they have remained fairly isolated since their founding and their genetics are therefore simpler for scientists to study than those of general populations.

The fact that the findings aligned so closely with those of previous, smaller studies in other populations was surprising even to the scientists, given the subjects' unique genetic background and living environments.

"This suggests that even if the specific genetic variants we identify may be unique to this population, the biological pathways they disrupt are likely to also influence disease risk in other populations," Bearden said.

The researchers' next step is to use the genomic data they collected from the families — including full genome sequences and gene expression data— to begin identifying the specific genes that contribute to risk for bipolar disorder. The researchers also plan to extend their investigation into the children and teens in these families. They hypothesize that many of the bipolar-related brain and behavioral differences found in adults with bipolar disorder had their origins in adolescent neurodevelopment.

The study's other authors include Dr. Nelson Freimer, a UCLA professor of psychiatry and director of the UCLA Center for Neurobehavioral Genetics, and Scott Fears, assistant professor in the Center for Neurobehavioral Genetics. Please see the paper for a full list of co-authors. The research was supported by National Institute of Health grants R01MH075007, R01MH095454, P30NS062691, K23MH074644-01 and K08MH086786, and by Colciencias (Colombia's Administrative Department of Science, Technology and Innovation) and the Committee for the Development of Research (CODI) at Colombia's University of Antioquia.

The Semel Institute for Neuroscience and Human Behavior is an interdisciplinary research and education institute devoted to the understanding of complex human behavior, including the genetic, biological, behavioral and sociocultural underpinnings of normal behavior, and the causes and consequences of neuropsychiatric disorders. In addition to conducting fundamental research, the institute faculty seeks to develop effective strategies for prevention and treatment of neurological, psychiatric and behavioral disorder, including improvement in access to mental health services and the shaping of national health policy.


Largest Genetic Study of Bipolar Disorder Identifies 64 Regions of the Genome That Increase Risk for the Condition

In the largest genetic study of bipolar disorder to date, researchers have identified 64 regions of the genome containing DNA variations that increase the risk of bipolar disorder – more than double the number previously identified.

The research team also found overlap in the genetic bases of bipolar disorder and other psychiatric disorders. Furthermore, the study supports the role of sleep habits, alcohol, and substance usage in the development of bipolar disorder, although further research is needed to confirm these findings. The study results are published May 17 in Nature Genetics.

Bipolar disorder, a complex psychiatric disorder characterized by recurrent episodes of severely high and low mood, affects an estimated 40 to 50 million people worldwide. It typically begins in young adulthood, often takes a chronic course, and carries an increased risk of suicide, making it a major public health concern and cause of global disability.

To help elucidate the underlying biology of bipolar disorder, an international team of scientists from within the Psychiatric Genomics Consortium conducted a genome-wide association study. This means they scanned the DNA of lots of people, looking for genetic markers that were more common in those who had bipolar disorder. This involved scanning more than 7.5 million common variations in the DNA sequence of nearly 415,000 people, more than 40,000 of whom had bipolar disorder. The study identified 64 regions of the genome that contain DNA variations that increase the risk of bipolar disorder.

“It is well-established that bipolar disorder has a substantial genetic basis and identifying DNA variations that increase risk can yield insights into the condition’s underlying biology,” says Niamh Mullins, PhD, Assistant Professor of Psychiatric Genomics at the Icahn School of Medicine at Mount Sinai and lead author of the paper. “Our study found DNA variations involved in brain cell communication and calcium signaling that increase risk of bipolar disorder.

The findings suggest that drugs, such as calcium channel blockers that are already used for the treatment of high blood pressure and other conditions of the circulatory system, could be investigated as potential treatments for bipolar disorder, yet it’s important to note that future research to directly assess whether these medications are effective is essential.”

The study also found overlap in the genetic basis of bipolar disorder and that of other psychiatric disorders and confirmed the existence of partially genetically distinct subtypes of the disorder. Specifically, they found that bipolar I disorder shows a strong genetic similarity with schizophrenia and bipolar II disorder is more genetically similar to major depression.

“This research would not have been possible without the collaborative efforts of scientists worldwide that enabled the study of hundreds of thousands of DNA sequences,” said Ole Andreassen, MD, PhD, Professor of Psychiatry, Institute of Clinical Medicine, and Oslo University Hospital and senior author of the paper. “Through this work, we prioritized some specific genes and DNA variations which can now be followed up in laboratory experiments to better understand the biological mechanisms through which they act to increase risk of bipolar disorder.”

The biological insights gained from this research could ultimately lead to the development of new and improved treatments or precision medicine approaches to stratify patients at high genetic risk who may benefit from targeted treatment or intervention strategies. Understanding causal risk could aid clinical decision-making in the prevention or management of the illness. Future genetic studies in larger and more diverse populations are now needed to pinpoint the genes relevant to risk of bipolar disorder in other areas of the genome.

The Psychiatric Genomics Consortium (PGC) is an international consortium of scientists dedicated to studying the genetic basis of psychiatric disorders and includes over 800 researchers, from more than 150 institutions from over 40 countries.