Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations.

Journal: American journal of human genetics

Volume: 108

Issue: 4

Year of Publication: 2021

Affiliated Institutions:  Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA , USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA , USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA , USA. Electronic address: armartin@broadinstitute.org. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA , USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA , USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA , USA. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA , USA. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA , USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA , USA. Department of Microbiology, Immunology, and Parasitology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia. Department of Psychiatry, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda. Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia. Department of Immunology & Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda. Department of Mental Health, School of Medicine, Moi University College of Health Sciences, Eldoret, Kenya. Broad Genomics, Broad Institute of MIT and Harvard, Charles Street, Cambridge, MA , USA. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA , USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA , USA; Department of Neurology, Massachusetts General Hospital, Boston, MA , USA. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA , USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA , USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA , USA; Institute for Molecular Medicine Finland, Helsinki , Finland. Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; Centre for Innovative Drug Development & Therapeutic Trials for Africa, Addis Ababa University, Addis Ababa, Ethiopia. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA , USA. Department of Mental Health, Moi Teaching and Referral Hospital, Eldoret, Kenya. Department of Immunology, School of Medicine, Moi University College of Health Sciences, Eldoret, Kenya. Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa. Neurosciences Unit, Clinical Department, KEMRI-Wellcome Trust Research Programme-Coast, Kilifi, Kenya; Department of Psychiatry, University of Oxford, Oxford OX JX, UK. Department of Pharmacology and Toxicology, School of Medicine, Moi University College of Health Sciences, Eldoret, Kenya. Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa; SA MRC Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory , South Africa. Neurosciences Unit, Clinical Department, KEMRI-Wellcome Trust Research Programme-Coast, Kilifi, Kenya. Gencove, Inc., New York, NY , USA. SA MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa; SA MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town and Neuroscience Institute, Cape Town, South Africa. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA , USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA , USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA , USA; Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa. Department of Psychiatry and Human Behavioral Sciences, Walter Sisulu University, Mthatha, South Africa.

Abstract summary 

Genetic studies in underrepresented populations identify disproportionate numbers of novel associations. However, most genetic studies use genotyping arrays and sequenced reference panels that best capture variation most common in European ancestry populations. To compare data generation strategies best suited for underrepresented populations, we sequenced the whole genomes of 91 individuals to high coverage as part of the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study with participants from Ethiopia, Kenya, South Africa, and Uganda. We used a downsampling approach to evaluate the quality of two cost-effective data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those from deep whole-genome sequencing data. We show that low-coverage sequencing at a depth of ≥4× captures variants of all frequencies more accurately than all commonly used GWAS arrays investigated and at a comparable cost. Lower depths of sequencing (0.5-1×) performed comparably to commonly used low-density GWAS arrays. Low-coverage sequencing is also sensitive to novel variation; 4× sequencing detects 45% of singletons and 95% of common variants identified in high-coverage African whole genomes. Low-coverage sequencing approaches surmount the problems induced by the ascertainment of common genotyping arrays, effectively identify novel variation particularly in underrepresented populations, and present opportunities to enhance variant discovery at a cost similar to traditional approaches.

Authors & Co-authors:  Martin Atkinson Chapman Stevenson Stroud Abebe Akena Alemayehu Ashaba Atwoli Bowers Chibnik Daly DeSmet Dodge Fekadu Ferriera Gelaye Gichuru Injera James Kariuki Kigen Koenen Kwobah Kyebuzibwa Majara Musinguzi Mwema Neale Newman Newton Pickrell Ramesar Shiferaw Stein Teferra van der Merwe Zingela

Study Outcome 

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Citations :  Marchini J., Howie B. Genotype imputation for genome-wide association studies. Nat. Rev. Genet. 2010;11:499–511.
Authors :  40
Identifiers
Doi : 10.1016/j.ajhg.2021.03.012
SSN : 1537-6605
Study Population
Male,Female
Mesh Terms
Africa
Other Terms
Africa;GWAS;GWAS arrays;cost comparison;low-coverage sequencing;study design;whole-genome sequencing
Study Design
Study Approach
Country of Study
Uganda
Publication Country
United States