PGC: Genetics of Bipolar Disorder - Brandon Coombes & Kevin O'Connell

Summary

In this presentation, Brandon Coombs discusses the genetics of bipolar disorder, emphasizing its high heritability (60-90%) and clinical complexity. He explains how bipolar disorder manifests differently across individuals and how it overlaps genetically with conditions like schizophrenia and depression. Despite advancements in GWAS (Genome-Wide Association Studies), the genetic underpinnings remain only partially understood, with 15-18% of the variance explained. The session covers challenges like misdiagnosis, rare genetic variations, and the need for larger sample sizes and diverse ancestries in future research. It concludes with potential clinical applications, particularly in pharmacogenomics, aiming to improve treatment responses and diagnostics.

Takeaways

• 😀 Bipolar disorder is characterized by shifts in mood, energy, and activity levels, with episodes of both depression and mania/hypomania.
• 😀 There are two main types of bipolar disorder: Type 1, which includes full manic episodes, and Type 2, which involves hypomania without full mania.
• 😀 The disorder shows high clinical heterogeneity, meaning its presentation can vary greatly from person to person, including factors like rapid cycling and psychosis.
• 😀 Bipolar disorder has a 1% lifetime prevalence globally, with onset typically occurring in the late teens or early adulthood, leading to poorer prognosis if diagnosed early.
• 😀 Misdiagnosis is common, as depressive symptoms may be mistaken for major depressive disorder (MDD), or early psychosis may be misdiagnosed as schizophrenia.
• 😀 Bipolar disorder is highly heritable, with a heritability estimate ranging from 60-90%, and a large genetic overlap with other psychiatric disorders like schizophrenia and depression.
• 😀 The first genome-wide association study (GWAS) for bipolar disorder in 2007 found no significant loci, but newer research with larger sample sizes has identified 64 significant loci.
• 😀 Despite significant genetic findings, only 15-18% of the genetic variance is explained, highlighting the problem of 'missing heritability' in bipolar disorder research.
• 😀 Potential causes of missing heritability include gene-environment interactions, rare genetic variations, and copy number variants (CNVs), but these remain underexplored due to the need for large, well-replicated studies.
• 😀 Pharmacogenomics in bipolar disorder is still in early stages, with lithium being a common treatment, but genetic research on predicting treatment response and adverse reactions is growing.
• 😀 Future research should focus on increasing sample sizes, including more diverse populations, and collecting deeper phenotypic data to better understand the heterogeneity of bipolar disorder and improve drug development.

Q & A

What is the definition of bipolar disorder?

Bipolar disorder is characterized by shifts in mood, energy, and activity levels. It typically involves episodes of depression and mania or hypomania, and these mood states can fluctuate over time, sometimes spanning months or years.

How is bipolar disorder classified, and what distinguishes type 1 from type 2?

Bipolar disorder is classified into type 1 and type 2. Type 1 involves full manic episodes, while type 2 is marked by hypomanic episodes that do not reach the full manic state. Type 2 is also more likely to feature depressive episodes.

What is rapid cycling in bipolar disorder?

Rapid cycling refers to the occurrence of four or more mood episodes (mania, hypomania, or depression) within a year. Some individuals with bipolar disorder experience rapid cycling, while others do not.

What is the estimated lifetime prevalence of bipolar disorder?

The lifetime prevalence of bipolar disorder is approximately 1% for both type 1 and type 2.

What is the significance of early age of onset for bipolar disorder?

An early onset of bipolar disorder, typically in adolescence, is associated with a poorer prognosis, higher comorbidity, and potential misdiagnosis. It can complicate the diagnosis, as early depressive symptoms may initially resemble major depressive disorder (MDD).

What genetic findings are associated with bipolar disorder?

Bipolar disorder has a heritability of 60-90%, with significant genetic overlap with other psychiatric disorders, particularly schizophrenia and depression. Genome-wide association studies (GWAS) have identified multiple loci associated with bipolar disorder, although they explain only 15-18% of its variance.

What challenges exist in understanding the genetics of bipolar disorder?

The major challenges in understanding the genetics of bipolar disorder include the missing heritability problem, where a large portion of the disorder's heritability is unexplained. Additionally, gene-environment and gene-gene interactions are understudied and require larger sample sizes for accurate identification.

What role do rare genetic variants play in bipolar disorder?

While rare genetic variants may contribute to the heritability of bipolar disorder, their impact is smaller than in other disorders like schizophrenia. Research into rare variants is ongoing, but current studies are limited due to the high costs of whole genome sequencing.

What is the current state of pharmacogenomics research in bipolar disorder?

Pharmacogenomic research in bipolar disorder is still limited. For lithium, a common mood stabilizer, studies have identified one significant genetic locus related to treatment response. Additionally, genetic risk for other conditions like schizophrenia and ADHD can influence lithium's effectiveness, though more research is needed.

What are polygenic risk scores (PRS) and how are they used in bipolar disorder research?

Polygenic risk scores (PRS) aggregate genetic data to predict disease risk or outcomes. In bipolar disorder, PRS are still in the early stages, with limited clinical utility for predicting case-control status. However, PRS have helped identify specific genetic risks associated with subtypes like rapid cycling and psychosis.

What are the future directions for research on bipolar disorder genetics?

Future directions include increasing ancestral diversity in research samples, expanding the size of GWAS studies, and improving phenotyping to better capture the heterogeneity of bipolar disorder. These efforts aim to enhance our understanding of the genetic underpinnings of the disorder and improve treatment strategies.