@article{26233ebc5be449f19a56a28c9a1bad3a,
title = "The Future of Genomic Studies Must Be Globally Representative: Perspectives from PAGE",
abstract = "The past decade has seen a technological revolution in human genetics that has empowered population-level investigations into genetic associations with phenotypes. Although these discoveries rely on genetic variation across individuals, association studies have overwhelmingly been performed in populations of European descent. In this review, we describe limitations faced by single-population studies and provide an overview of strategies to improve global representation in existing data sets and future human genomics research via diversity-focused, multiethnic studies. We highlight the successes of individual studies and meta-analysis consortia that have provided unique knowledge. Additionally, we outline the approach taken by the Population Architecture Using Genomics and Epidemiology (PAGE) study to develop best practices for performing genetic epidemiology in multiethnic contexts. Finally, we discuss how limiting investigations to single populations impairs findings in the clinical domain for both rare-variant identification and genetic risk prediction.",
keywords = "PAGE, diversity, fine mapping, genomics, multiethnic, transethnic",
author = "Bien, {Stephanie A.} and Wojcik, {Genevieve L.} and Hodonsky, {Chani J.} and Gignoux, {Christopher R.} and Iona Cheng and Matise, {Tara C.} and Ulrike Peters and Kenny, {Eimear E.} and North, {Kari E.}",
note = "Funding Information: The PAGE program is funded by the National Human Genome Research Institute with co-funding from the National Institute on Minority Health and Health Disparities. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The PAGE Consortium thanks the staff and participants of all PAGE studies for their important contributions. We thank Rasheeda Williams and Margaret Ginoza for providing assistance with program coordination. The complete list of PAGE members can be found at http://www.pagestudy.org. Funding Information: S.A.B and U.P. were supported by National Institutes of Health grant U01HG007376. K.E.N. was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant 1R01DK101855. C.J.H. was supported by National Heart, Lung, and Blood Institute training grant T32 HL007055. C.R.G. was supported by National Heart, Lung, and Blood Institute grant R01HL104608 and National Human Genome Research Institute grant U01HG009080. T.C.M. and G.L.W. were supported by National Institutes of Health grants U01HG007419 and R56HG010297. E.E.K. was supported by National Institutes of Health grant U01HG007417. I.C. was supported by National Institutes of Health grant U01 HG007397 and National Cancer Institute grant U01 CA164973. Funding Information: Combining results across ethnic groups can be challenging given genetic, environmental, sociocultural, and study-based heterogeneity. Therefore, the field must develop and test new tools specifically designed for these contexts. The Population Architecture Using Genomics and Epidemiology (PAGE; http://pagestudy.org) study was formed with the goal of developing best practices for transethnic studies. This study has been continuously funded by the National Institutes of Health since 2008 to study genomic variation in order to advance our understanding of the population architecture of genetic traits and disease in the presence of ancestral diversity. The first phase of the study, which ran from 2008 to 2013 and was funded by the National Human Genome Research Institute and the National Institute of Mental Health, examined putative causal genetic variants across approximately 100,000 African Americans, Asian Americans, Native Americans, Hispanics/Latinos, and Native Hawaiians from four centers representing nine large United States–based cohorts. Two genotyping approaches were employed: targeted genotyping of selected SNPs identified in GWASs of common disease, and a large-scale array-based effort using the Metabochip to facilitate transethnic fine mapping of several diseases of public health importance. The Metabochip array is a custom genotyping array designed for replication and fine mapping of cardiometabolic traits (121). Early PAGE work demonstrated that, while most risk loci identified from GWASs and populations of primarily European ancestry are shared across one or more ethnic groups, the underlying causal variants and their effects vary across populations (21). Funding Information: As demonstrated by the work of the PAGE study and other investigators, the inclusion of ancestrally diverse study populations in all aspects of genomic research and methods development is not only a scientific imperative but also essential for the equitable application of results (95). With support from the National Human Genome Research Institute and the National Institute on Minority Health and Health Disparities, PAGE has focused specifically on addressing the well-documented underrepresentation of US minority populations in genomic research by fostering productive collaboration with existing cohorts (56). The studies have attempted to address some of the noted historical biases throughout the research pipeline, including measurement and analysis of population-level genetic data. To address historical bias in genotyping platforms toward European variation, PAGE investigators and collaborators (the Consortium on Asthma Among African-Ancestry Populations in the Americas, Illumina, and other academic centers) designed a new array with comparable efficiencies in detecting genetic variation across all major continental populations, a tool that is now available to the scientific community (https://www.pagestudy.org/mega). The application of this platform to ancestrally diverse PAGE study participants has aided in the discovery of ancestry-specific disease-associated variation and improved understanding of the underlying biology of known genomic regions associated with risk. To date, PAGE has more than 80 published papers, many of which describe novel discoveries and fine mapping, generalization, and replication of previous findings for complex traits—for example, for lipids (35, 127), type 2 diabetes (53), adiposity (36, 38, 47), kidney function (40), coronary heart disease (125), blood pressure (39), electrocardiogram traits (4, 5), several cancers (28, 75, 92, 106), glucose and insulin levels (13, 37), inflammation (58, 71), and menopause/menarche (23, 111). PAGE has demonstrated the importance of multiethnic genomic studies in conjunction with careful consideration of recruitment, genotyping, and statistical methods development, leading to the discovery and refinement of disease-related loci and a better understanding of these complex traits in diverse populations. Publisher Copyright: {\textcopyright} Copyright 2019 by Annual Reviews. All rights reserved.",
year = "2019",
month = aug,
day = "31",
doi = "10.1146/annurev-genom-091416-035517",
language = "English (US)",
volume = "20",
pages = "181--200",
journal = "Annual Review of Genomics and Human Genetics",
issn = "1527-8204",
publisher = "Annual Reviews Inc.",
}