Bridging Gaps in Genomic Diversity to Advance Precision Medicine

Any two human beings are 99.9% identical—and the genetic differences between different populations are similarly minute. Yet, the 0.1% difference harbours significant gene-encoded protein diversity and expression differences, contributing to varying susceptibility to diseases and resistance to medications and has significant implications for research, healthcare and society. [1]This makes understanding the rich tapestry of genomic diversity across populations essential, for advancing precision medicine and developing more effective, tailored treatments.

Speakers at the PRECISE-IHCC Conference, jointly organised by Precision Health Research, Singapore (PRECISE) and the International Health Cohorts Consortium (IHCC) last August, highlighted various international and national initiatives undertaken by groups and countries to unlock genomic diversity across populations. 

Driving the World’s Largest Neuroimaging Genetics Initiative

One standout initiative was the ENIGMA Consortium and its scale. Engaging over 2,500 imaging genomics researchers across 47 countries, Professor Paul Thompson, Director of the ENIGMA Center for Worldwide Medicine, University of Southern California, explained the Consortium’s mission to uncover insights from brain imaging and genetic data to understand how the brain changes over one’s lifetime, and how diseases, treatments, and genes affect brain structure and function.

He shared that ENIGMA is leveraging neuroimages worldwide to answer important questions that have plagued us for a long time. For instance, are some brains more resilient to detrimental effects because of their genetics—and if so, can studying them lead us to potential new medications? These are the areas the working groups in development and ageing, genomics with a focus on evolution and gene-environment interactions, and neuroimaging and therapeutic interventions are looking to explore.

Since its founding in 2009, ENIGMA has grown to comprise over 50 working groups. With over 30 of them organised around brain diseases, it is evident that ENIGMA is not only looking to unlock the secrets of healthy brains, but also to gain a deeper understanding of brain diseases, including Alzheimer’s disease, Parkinson’s, bipolar disorder, schizophrenia, Tourette’s syndrome and autism. “Through neuroimaging, we can see how the brains of people with Alzheimer’s disease and depression are different from healthy people. Or which brain regions’ developments are disrupted in children with autism,” Professor Thompson elaborated.

Exploring Diversity in a Seemingly Homogenous Population

Over the years, the scale and inclusivity of its datasets spanning diverse populations and geographical areas—both rural and urban—have enabled the ENIGMA Consortium to make significant discoveries about specific genetic, and environmental features or neurobiological markers associated with brain disorder risk and treatment outcome. However, these achievements are not without challenges.

For example, the need to coordinate and create standardised metrics for accessing clinical symptoms of patients across multiple research sites is one that particularly resonated with Associate Professor Biju Viswanath from the National Institute of Mental Health and Neurosciences (NIMHANS). Also a key investigator at the Rohini Nilekani Centre for Brain and Mind at NIMHANS, A/Prof Viswanath led coordination efforts across multiple clinical sites in a consortium comprising 48 psychiatrists and a multidisciplinary team across the country.

Recognising that one in seven Indians is affected by a mental disorder—and that each affected individual lives with the condition for an average of 15 years with disability[2], A/Prof Viswanath and his research collaborators embarked on a longitudinal study to better understand the burden of mental disorders across Indian states. Working with 20,000 genomic samples, A/Prof Viswanath and team explored how genetics, environment and social stigma intersect to shape mental health outcomes.

While the strong stigma associated with mental disorders impeded the progress of recruitment and receptivity to the study in the beginning, the team’s perseverance and methodical approach eventually led to groundbreaking findings. In a largely homogeneous population with perceivably little ancestral diversity, the researchers were able to demonstrate the role of genetic predisposition in families with mental disorders, the impact of adverse childhood experiences on the onset of psychiatric illnesses, and identify genes and/or proteins that could cause atypical disease presentation or resistance to standard treatments. 

Reflecting on the significance of these insights, A/Prof Viswanath said, “We have a good momentum going at the moment. This is the first time a targeted study of this scale has been conducted for the South Asian population—and as we’ve come to realise, there’s actually so much diversity within India. Some specific clusters are emerging from our analyses. These findings are really exciting both from a research perspective and in shaping policies for more effective interventions.”

As a next step, A/Prof Viswanath’s team is looking not only to expand their datasets and build on their analyses, but also explore the portability of their findings to other parts of the world, including Europe and the Americas.

Uncovering the Role of Genetic Ancestry in Shaping Precision Medicine

Complementary to the work carried out by ENIGMA and A/Prof Viswanath’s work in mental health in India which revealed unexpected layers of diversity, similar revelations are emerging from Latin America. Professor Andrés Moreno-Estrada, Head of Genomic Services, Cinvestav-Mexico shared insights into the Mexican Biobank project—which he is leading.

In Mexico, a nationwide effort is underway to map the genotypes of over 6,000 Mexicans. Conducted across all 32 states of Mexico in both rural and urban areas from 898 local sites, the collected data is representative of the nationwide diversity. Touching on the significance of this effort, Prof Estrada said, “Latin America is a highly differentiated region—so we are not just different from other regions but also diverse within the region. With the Mexican Biobank project, we aim to not just step up on our genetic representation globally, but also gain deeper insights into the genetic characterisation within the region. For example, by tracing the genetic evolution of populations across different geographies, we can recover and reconstruct the historical trajectories of previous civilisations and their development over time.”

He emphasised that this knowledge can help to identify genetic predispositions in their population that stem from indigenous ancestry—insights that could ultimately help inform and address some of the current challenges in Mexico’s public health system.”

However, Prof Estrada concurred that these gains can only be sustained through successful recruitment of participants in both rural and urban communities—which calls for capacity building and resource sharing among researchers and institutions when it comes to data and knowledge. He rounded up, “Governments, organisations and populations from different parts of the world are warming up to the idea of precision medicine—but for it to truly realise its full potential, we need to work together, learn all we can about what sets us apart from one another, and create opportunities for populations to become healthier.”

A common theme emerges across these initiatives—despite their varied geographies, scopes and foci: meaningful precision medicine must be rooted in diverse data, shared resources and inclusive collaboration.

This is the last of a three-part PRECISE-IHCC conference series. Themed “From Cohorts to Clinics: The New Landscape of Global Healthcare”, the conference held from 21 to 23 August 2024 in Singapore covered 17 topics in precision medicine and sought to address challenges and opportunities in translating advances into tangible enhancements in patient care to reshape the landscape of modern healthcare.

For post-conference resources, visit here.

To catch up on the session recording, visit https://for.sg/genomic-diversity

[1] Ahmed Z, Zeeshan S, Mendhe D, Dong X. Human gene and disease associations for clinical-genomics and precision medicine research. Clin Transl Med. 2020 Jan;10(1):297-318. doi: 10.1002/ctm2.28. PMID: 32508008; PMCID: PMC7240856.

[2] The burden of mental disorders across the states of India: the Global Burden of Disease Study 1990–2017, Sagar, Rajesh et al. The Lancet Psychiatry, Volume 7, Issue 2, 148 - 161