The <scp>NIMH</scp> supports more comprehensive and inclusive genomic studies in psychiatry
Authors: Miri Gitik, Lora A. Bingaman, Laura M. Rowland, Andrea Horvath Marques
Journal: World Psychiatry (2024)

The inclusion of diverse populations in genomic studies is key to generate more comprehensive findings, as well as to ensure equitable research. However, most genomic studies have been conducted as yet on cohorts of European ancestry, with minimal representation of other populations worldwide1, 2. To address this historical gap, the US National Institute of Mental Health (NIMH) has established the Ancestral Populations Network (APN), through two funding opportunities3. The APN was formed with the overarching goals of: a) accelerating genetic discovery for psychiatric disorders in cohorts of non-European ancestry; b) advancing global mental health discovery and equity; c) facilitating measurement and data analytic harmonization efforts to enhance rigor and reproducibility; and d) generating a resource for network members and the scientific community. The APN also presents a distinctive global perspective toward reducing inequities and disparities in mental health research, by supporting strong in-country leadership representation, strengthening research capacity, and promoting the development of early-stage career researchers. Overall, the APN will collect and analyze data from 200,000 participants (cases, controls and families) from over 25 sites worldwide, through seven projects. The Populations Underrepresented in Mental Illness Association Studies (PUMAS) will use the newly developed blended genome exome (BGE) sequencing technology for genetic characterization of severe mental illnesses (SMI), including individuals with schizophrenia spectrum and bipolar disorder, in Africa, South America and the US. The project aims to create the largest to date phenotypic and genomic resource of people with non-European ancestry with SMI data. The Genomics of Schizophrenia in the South African Xhosa (SAXII) will characterize the genomic architecture of schizophrenia in the native Xhosa population of South Africa, using a combination of long-read and short-read whole genome sequencing (WGS) methods to identify new classes of damaging mutations. Using these innovative genomic technologies, the project will provide deeper insights into the genomic structure of individuals with schizophrenia and serve as a resource for other case-control comparison studies across ancestral populations. The Latin American Trans-Ancestry Initiative for OCD Genomics (LATINO) will identify genomic loci for obsessive-compulsive disorder (OCD) in the largest Latin American cohort to date. Genome-wide significant loci will be fine-mapped, and individual polygenic risk scores (PRS) will be calculated to determine genetic liability. The results of this study will provide meaningful insights into the pathophysiology of OCD, possibly leading to more effective treatments and clinical outcomes. The Identifying the Genetic Causes of Depression in a Deeply Phenotyped Population from South Korea (KOMOGEN-D) will identify genetic variation of a deeply phenotyped (including depression subtypes and environmental influences) cohort of South Korean women with severe recurrent depression. Data from this study will be further meta-analyzed with other cohorts of relevance to enhance the utility of this uniquely created resource. The Genetic Architecture of Early-Onset Psychosis in Mexicans (EPIMex) will use BGE sequencing to investigate the genetic architecture of early-onset psychosis in a deeply phenotyped (including social determinants of health and environmental exposure measures) pediatric sample in Mexico City, creating the largest resource to date of people with this condition. The project will enhance our understanding of risk factors, with a special focus on the Mexican population, currently underrepresented in psychiatric genetic studies. The Asian Bipolar Genetics Network (A-BIG-NET) will generate a large-scale genetics resource for the study of bipolar I disorder in East and South Asia populations. Participants from Taiwan, South Korea, India and Singapore will be deeply phenotyped and undergo BGE sequencing, to which data collected from a prior study in Pakistan will be added, to identify new genetic associations and putative causal variants. This resource will provide ways to examine and compare the genetic architecture of bipolar I disorder across other populations worldwide to accelerate efforts in gene discovery. The Genomics of Autism in Latinx Ancestries (GALA) will investigate the genetic risk of autism spectrum disorder in Hispanic/Latinx ancestry populations, conduct cross-ancestry genome-wide association studies (GWAS) to examine common genetic variation, perform fine-mapping and co-localization analyses of GWAS results, create PRS, and identify rare genetic variants. The APN provides a unique opportunity to develop areas of high relevance to large-scale genomic studies, including harmonization of clinical and cognitive phenotypes across different sociocultural settings worldwide, the role of social determinants of health, global human research ethics, local research capacity and leadership, and reciprocal knowledge transfer between global settings. Several workgroups have been established to collaborate in these areas, including: a) a workgroup on phenotype harmonization, aiming to shape the policies and practices for this harmonization, identifying opportunities for aligning phenotype measures across projects, adding new phenotypic measures, and standardizing methods; b) a workgroup on social determinants of health, facilitating discussion about the impact of social determinants of health on genomic research, promoting analyses on the dynamic interplay between genetics and societal factors across different APN projects, and establishing a standard and user-friendly protocol for collecting measures of social determinants; c) a workgroup on ethics, shaping and recommending best practices in community engagement, equity in global collaborations, informed consent and the decisional capacity process, and ethics committee mapping; d) a workgroup on capacity building, shaping the policies and practices that pertain to building human capital by assessing and defining needs, challenges and strengths of the projects in the APN, curating and developing training materials, and suggesting best practices as they relate to equitable collaborations; e) a workgroup on genomic data harmonization, aiming to harmonize ancestrally diverse genomic data to support high-quality data generation across the APN, developing easy-to-use and standardized analytical plans and computational plans across sites, and facilitating the integration of common and rare variant analyses for jointly harmonized genetic analyses; and f) a workgroup on genetic concepts, facilitating and coordinating testing of genetic hypotheses collaboratively across the APN. Through its collaborative efforts, the APN aims to create a unique resource for the field, with examples and recommendations on how to conduct equitable, global scientific genetic collaborations, as well as outline ethical considerations for establishing new recruitment sites, engaging local communities, and addressing stigma and research hesitancy as they relate to participating in psychiatric genetic research. Further, the APN will provide best practices on culturally adaptive phenotypic transdiagnostic harmonization efforts and integrating phenotypic and genomic data. It will also include recommendations on the collection of measures of social determinants of health and other environmental exposures in mental health genetic studies. In the genomic space, the APN aims to enhance gene discovery efforts by improving power for common and rare variant discovery, exploring population specific variation, and enhancing trans-ancestry fine-mapping efforts. These, in turn, can facilitate the refinement of PRS transferability between populations, address admixture-related issues, work toward more comprehensive population-specific reference maps, and examine the shared and distinct genetic architecture between different psychiatric disorders and symptoms. In the training and research capacity space, the APN is taking a psychiatric genetic-focused approach on developing and promoting the next generation of researchers across the world. By including a larger group of diverse populations from across the globe, the APN aims to enhance our understanding of mental illness, which would facilitate the development of new interventions to benefit people of all racial and ethnic groups.