Low and differential polygenic score generalizability among African populations due largely to genetic diversity.

Journal: HGG advances

Volume: 4

Issue: 2

Year of Publication: 2023

Affiliated Institutions:  Global Initiative for Neuropsychiatric Genetics Education in Research (GINGER), Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, MA, USA. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA , USA. Department of Paediatrics and Child Health, Red Cross Children's Hospital and Medical Research Council Unit on Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa. Mental Health Project, Medical Research Council/Uganda Virus Research Institute (MRC/UVRI) & London School of Hygiene and Tropical Medicine (LSHTM), Uganda Research Unit, Entebbe, Uganda. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX , USA.

Abstract summary 

African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across groups. Differences in African ancestries contribute more to variability in PRS accuracy than other large cohort differences considered between individuals in the United Kingdom versus Uganda. We computed PRS in African ancestry populations using existing European-only versus ancestrally diverse genetic studies; the increased diversity produced the largest accuracy gains for hemoglobin concentration and white blood cell count, reflecting large-effect ancestry-enriched variants in genes known to influence sickle cell anemia and the allergic response, respectively. Differences in PRS accuracy across African ancestries originating from diverse regions are as large as across out-of-Africa continental ancestries, requiring commensurate nuance.

Authors & Co-authors:  Majara Lerato L Kalungi Allan A Koen Nastassja N Tsuo Kristin K Wang Ying Y Gupta Rahul R Nkambule Lethukuthula L LL Zar Heather H Stein Dan J DJ Kinyanda Eugene E Atkinson Elizabeth G EG Martin Alicia R AR

Study Outcome 

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Statistics
Citations :  Visscher P.M., Wray N.R., Zhang Q., Sklar P., McCarthy M.I., Brown M.A., Yang J. 10 Years of GWAS discovery: biology, function, and translation. Am. J. Hum. Genet. 2017;101:5–22.
Authors :  12
Identifiers
Doi : 100184
SSN : 2666-2477
Study Population
Male,Female
Mesh Terms
Humans
Other Terms
Africa;GWAS;global health;health disparities;polygenic scores;population genetics
Study Design
Cohort Study,Cross Sectional Study
Study Approach
Systemic Review
Country of Study
Uganda
Publication Country
United States