First large genetic study of bipolar disorder in Asian populations launches

Nearly 60 percent of the world’s population resides in Asian countries, but only 10 percent of participants of genetic studies are of Asian descent. And that disparity is even greater in studies of psychiatric conditions, where participants are almost all of European ancestry, even though serious mental illness affects all human populations evenly. This lack of representation of the world’s population in genetic datasets leaves out a huge amount of genomic variation, limiting what scientists can learn about the biological basis of mental disorders. 

A global team of scientists is now trying to tackle this problem by launching a genetic study of bipolar disorder in people from India, Pakistan, Singapore, South Korea, and Taiwan. The study, called the Asian Bipolar Genetics Network (A-BIG-NET), will collect and analyze DNA and demographic, environmental, and medical information from 27,500 patients diagnosed with the psychiatric condition and 15,000 controls. 

The project is a collaboration between experts from the Broad Institute of MIT and Harvard (led by Hailiang Huang), Virginia Commonwealth University (led by Kenneth Kendler), Johns Hopkins University (led by Peter Zandi), National Institute of Mental Health and NeuroSciences in India (NIMHANS, led by Biju Viswanath), Indian Institute of Science (led by Bratati Kahali), Institute of Mental Health in Singapore (led by Jimmy Lee), Korea University College of Medicine (led by Heon-Jeong Lee), and National Taiwan University (led by Po-Hsiu Kuo). They will work together to recruit the participants, sequence the genomes, analyze the data, and build a network for rapid data-sharing. 

The team hopes to uncover genetic markers of bipolar disorder, which may point towards the biological causes and mechanisms underlying this condition that affects 1-2 percent of the world’s population. By focusing on Asian populations, the scientists aim to find markers that are more common in these groups than in others, which may highlight genetic roots of the disorder that are shared across other populations around the world. Better insight into the causes of bipolar disorder from this research could one day lead to new and better treatments.

“There haven’t been any sizable bipolar genetic studies from Asian populations,” said Hailiang Huang, the project’s leader, Director of the Stanley Global Asia Initiatives at the Stanley Center for Psychiatric Research at the Broad, and an Assistant Professor at Massachusetts General Hospital and Harvard Medical School. “If this were to continue, we risk the possibility that therapeutic innovations might exclude large segments of the global population which are under-represented in psychiatric genetics. This is a major unsolved challenge for everyone in the world, including people from South and East Asia.”

The new project extends Stanley Global, an initiative launched in 2014 by the Stanley Center to diversify genetic research and include underrepresented populations worldwide. One Stanley Global project, NeuroGAP-Psychosis, launched in 2018 to study the genetics of schizophrenia in four African countries, while another project, NeuroMex, is doing the same in Mexico. NeuroDev is studying neurodevelopmental differences in people in Kenya and South Africa.

“Studies like A-BIG-NET have potential to discover rare variant risk genes, which should have a big impact on the mechanistic understanding of bipolar disorder,  like the SCHEMA study did for schizophrenia. Because Asian populations have different genetic variants, their inclusion in A-BIG-NET will enhance the diversity and richness of gene discovery for bipolar,” said Morgan Sheng, co-director of the Stanley Center.

Global partnerships

A-BIG-NET was inspired by NeuroGAP-Psychosis and NeuroMex to expand this kind of genetics research to Asian countries. Though Stanley Global has sequenced genomic samples from East Asian populations before, A-BIG-NET expands that effort to include bipolar disorder and will study a much larger cohort. It will also be the first known large-scale study to explore the genetics of bipolar disorder in South Asian countries, and will build on recent discoveries from the Stanley Center including the first strong genetic signal for bipolar disorder.

“The most important finding I would hope would emerge from this project is to find the direct causal genes underlying bipolar disorder,” Huang said. “This study gives us the chance to actually identify the causal genes for bipolar disorder in the Asian population.”

“By taking a deep phenotyping approach, we will be collecting information which will allow us to explore a number of clinical subtypes of bipolar illness from a molecular genetic perspective to detect potential differences in their genetic substrate,” said Kendler, a Professor of Psychiatry and Human and Molecular Genetics at Virginia Commonwealth University and Co-Principal Investigator of the project. “Furthermore, studying a range of environmental risk factors will permit us to further clarify how genes and environment jointly act or interact to produce bipolar disorder.”

“This study will be an important step in increasing equity in research, especially in the area of psychiatric genetics, ” said Biju Viswanath, Professor of Psychiatry at NIMHANS in India and the lead on the Indian arm of the study. Viswanath has established the India Consortium on Mental Illness And Genetics In the Clinic (IC-MAGIC), which conducts large genetic studies on mental health. Participants from India will make up the largest cohort of the study. 

“The project will allow advanced training in psychiatric genetics, and engage more researchers and participants. This will allow greater community engagement and expand research capacity in the region. We will then be able to contribute both globally, and importantly, locally to understand these complex disorders,” said Sanjeev Jain, a NIMHANS Professor and senior co-investigator of the study.

About a third of A-BIG-NET’s genetic samples will be sequenced at the Broad by the Genomics Platform, with the rest being analyzed in their home countries. The scientists will use a recently developed sequencing technology called Blended Genome Exome (BGE), which deeply sequences the exome — the 2 percent of human DNA that translates into proteins — and more broadly decodes the rest of the genome. This approach was designed to increase the chances of finding new genetic variation from global samples in a cost-effective manner, allowing for a large number of samples to be sequenced. 

The team will publicly share A-BIG-NET data through the National Institute of Mental Health Data Archive (NDA) and the Bipolar Exomes Browser. They will also contribute their data to the Psychiatric Genomics Consortium Bipolar Workgroup and the Bipolar Sequencing Project, which will allow them to compare their results to those from other studies focused on European populations.

“This study puts together a strong team from Asia to work at understanding the biology of bipolar disorder,” said Jimmy Lee, a Senior Consultant at Singapore’s Institute of Mental Health, an associate professor at the Lee Kong Chian School of Medicine at Nanyang Technological University, and a co-senior investigator of the study. “Singapore is glad to be a part of this coordinated effort. I am confident the team will make important and impactful scientific discoveries, which will eventually translate into improved clinical care and recovery outcomes in people living with bipolar disorder. Additionally, I hope this effort will catalyze the growth of psychiatric genetics in Asia to address the gap in ethnic representation and knowledge.”

“Taiwan is often excluded from a number of major international organizations and actions. We’re very glad to be part of the global diversity initiative and to contribute to enhancing our understanding of a severe psychiatric disorder and reducing health inequity in the long run,” said the project’s co-lead, Po-Hsiu Kuo, Associate Dean of College of Public Health, and a Professor at Institute of Epidemiology and Preventive Medicine, National Taiwan University.

“In South Korea, no large-scale genomic study has been conducted on mental illness. Recently, however, psychiatric genetic researchers have reached a consensus on the need for large-scale collaborative genomic study on major mental illnesses, and formed the Korean Mood Disorder Genomics Consortium (KOMOGEN) with about 40 organizations to move the team to succeed in the project,” said the South Korea site leader, Heon-Jeong Lee, Professor of Psychiatry, Korea University College of Medicine.

Funding for this research is provided by the National Institute of Mental Health.