ADVANCING DEPRESSION GENETICS IN AFRICA: INSIGHTS FROM HAALSI AND EMERGING AFRICAN COHORTS

Depression is a highly heritable and genetically complex disorder, contributing substantially to the global disease burden, yet its genetic underpinnings are not fully understood across diverse populations. Despite growing diversity in genome-wide association studies (GWAS) of major depressive disorder (MDD), continental African populations remain virtually unexplored. Addressing this gap is critical to ensuring that genetic discoveries can inform prevention, diagnosis, and treatment across all populations. This presentation highlights ongoing efforts to advance depression genetics in continental Africa. We present preliminary findings from the Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI), comprising approximately 2,438 participants. Depressive symptoms were assessed across three waves using the Center for Epidemiologic Studies Depression Scale (CES-D). Factor analysis was used to derive wave-specific scores, and a variance-based weighting approach was applied to generate composite longitudinal phenotypes for GWAS. Using this approach, we identified a genome-wide significant variant (rs80338306) in the CUB and Sushi Multiple Domains 1 (CSMD1) gene, which plays a key role in brain development and has been implicated in other psychiatric disorders. Notably, rs80338306 is a low-frequency variant in non-African populations. These findings demonstrate that leveraging longitudinal data through weighted factor scores can enhance statistical power in genetic studies of depression. Several other studies of continental African populations are underway. Recruitment is currently in progress for the Depression Genetics in Africa (DepGenAfrica) project, which will investigate genetic and environmental contributors to MDD on the continent. The study aims to enroll 12,000 participants across Nigeria, Ethiopia, and Malawi, including clinically diagnosed cases and matched controls. Diagnostic assessments employ the Schedules for Clinical Assessment in Neuropsychiatry (SCAN), complemented by symptom evaluation using the PHQ-9, alongside measures of psychosocial, behavioral, and cognitive factors. Genotyping will be conducted with an array enriched for common African variants, providing deeper insights into the genomic architecture of depression in African populations. Additional African-led initiatives will further contribute to psychiatric genomics, including studies in the Uganda General Population Cohort (GPC; n = 10,560) and NeuroGAP (n = 7,073). Together, these efforts, coordinated under the African arm of the Psychiatric Genomics Consortium (PGC), represent critical steps toward increasing global representation in depression genetics. Challenges remain, including data harmonisation, ethics, stigma, and limited infrastructure; addressing these through collaboration will advance depression genetics on the continent and support equitable global research.