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Genetic analyses of diverse populations improves discovery for complex traits

Author

Listed:
  • Genevieve L. Wojcik

    (Stanford University)

  • Mariaelisa Graff

    (University of North Carolina at Chapel Hill)

  • Katherine K. Nishimura

    (Fred Hutchinson Cancer Research Center)

  • Ran Tao

    (Vanderbilt University Medical Center
    Vanderbilt University Medical Center)

  • Jeffrey Haessler

    (Fred Hutchinson Cancer Research Center)

  • Christopher R. Gignoux

    (Stanford University
    University of Colorado Anschutz Medical Campus)

  • Heather M. Highland

    (University of North Carolina at Chapel Hill)

  • Yesha M. Patel

    (University of Southern California)

  • Elena P. Sorokin

    (Stanford University)

  • Christy L. Avery

    (University of North Carolina at Chapel Hill)

  • Gillian M. Belbin

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Stephanie A. Bien

    (Fred Hutchinson Cancer Research Center)

  • Iona Cheng

    (University of California San Francisco)

  • Sinead Cullina

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Chani J. Hodonsky

    (University of North Carolina at Chapel Hill)

  • Yao Hu

    (Fred Hutchinson Cancer Research Center)

  • Laura M. Huckins

    (Icahn School of Medicine at Mount Sinai)

  • Janina Jeff

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Anne E. Justice

    (University of North Carolina at Chapel Hill)

  • Jonathan M. Kocarnik

    (Fred Hutchinson Cancer Research Center)

  • Unhee Lim

    (University of Hawaii Cancer Center)

  • Bridget M. Lin

    (University of North Carolina at Chapel Hill)

  • Yingchang Lu

    (Icahn School of Medicine at Mount Sinai)

  • Sarah C. Nelson

    (University of Washington)

  • Sung-Shim L. Park

    (University of Southern California)

  • Hannah Poisner

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Michael H. Preuss

    (Icahn School of Medicine at Mount Sinai)

  • Melissa A. Richard

    (The University of Texas Health Science Center)

  • Claudia Schurmann

    (Icahn School of Medicine at Mount Sinai
    Digital Health Center
    Icahn School of Medicine at Mount Sinai)

  • Veronica W. Setiawan

    (University of Southern California)

  • Alexandra Sockell

    (Stanford University)

  • Karan Vahi

    (University of Southern California)

  • Marie Verbanck

    (Icahn School of Medicine at Mount Sinai)

  • Abhishek Vishnu

    (Icahn School of Medicine at Mount Sinai)

  • Ryan W. Walker

    (Icahn School of Medicine at Mount Sinai)

  • Kristin L. Young

    (University of North Carolina at Chapel Hill)

  • Niha Zubair

    (Fred Hutchinson Cancer Research Center)

  • Victor Acuña-Alonso

    (Escuela Nacional de Antropologia e Historia)

  • Jose Luis Ambite

    (University of Southern California)

  • Kathleen C. Barnes

    (University of Colorado Anschutz Medical Campus)

  • Eric Boerwinkle

    (The University of Texas Health Science Center)

  • Erwin P. Bottinger

    (Icahn School of Medicine at Mount Sinai
    Digital Health Center
    Icahn School of Medicine at Mount Sinai)

  • Carlos D. Bustamante

    (Stanford University)

  • Christian Caberto

    (University of Hawaii Cancer Center)

  • Samuel Canizales-Quinteros

    (Instituto Nacional de Medicina Genómica)

  • Matthew P. Conomos

    (University of Washington)

  • Ewa Deelman

    (University of Southern California)

  • Ron Do

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Kimberly Doheny

    (Johns Hopkins University)

  • Lindsay Fernández-Rhodes

    (University of North Carolina at Chapel Hill
    The Pennsylvania State University)

  • Myriam Fornage

    (The University of Texas Health Science Center)

  • Benyam Hailu

    (NIH National Institute on Minority Health and Health Disparities)

  • Gerardo Heiss

    (University of North Carolina at Chapel Hill)

  • Brenna M. Henn

    (University of California Davis)

  • Lucia A. Hindorff

    (NIH National Human Genome Research Institute)

  • Rebecca D. Jackson

    (Ohio State Medical Center)

  • Cecelia A. Laurie

    (University of Washington)

  • Cathy C. Laurie

    (University of Washington)

  • Yuqing Li

    (University of California San Francisco
    Cancer Prevention Institute of California)

  • Dan-Yu Lin

    (University of North Carolina at Chapel Hill)

  • Andres Moreno-Estrada

    (National Laboratory of Genomics for Biodiversity (UGA-LANGEBIO))

  • Girish Nadkarni

    (Icahn School of Medicine at Mount Sinai)

  • Paul J. Norman

    (University of Colorado Anschutz Medical Campus)

  • Loreall C. Pooler

    (University of Southern California)

  • Alexander P. Reiner

    (University of Washington)

  • Jane Romm

    (Johns Hopkins University)

  • Chiara Sabatti

    (Stanford University)

  • Karla Sandoval

    (National Laboratory of Genomics for Biodiversity (UGA-LANGEBIO))

  • Xin Sheng

    (University of Southern California)

  • Eli A. Stahl

    (Icahn School of Medicine at Mount Sinai)

  • Daniel O. Stram

    (University of Southern California)

  • Timothy A. Thornton

    (University of Washington)

  • Christina L. Wassel

    (University of Vermont)

  • Lynne R. Wilkens

    (University of Hawaii Cancer Center)

  • Cheryl A. Winkler

    (Frederick National Laboratory)

  • Sachi Yoneyama

    (University of North Carolina at Chapel Hill)

  • Steven Buyske

    (Rutgers University)

  • Christopher A. Haiman

    (University of Southern California)

  • Charles Kooperberg

    (Fred Hutchinson Cancer Research Center)

  • Loic Marchand

    (University of Hawaii Cancer Center)

  • Ruth J. F. Loos

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Tara C. Matise

    (Rutgers University)

  • Kari E. North

    (University of North Carolina at Chapel Hill)

  • Ulrike Peters

    (Fred Hutchinson Cancer Research Center)

  • Eimear E. Kenny

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Christopher S. Carlson

    (Fred Hutchinson Cancer Research Center)

Abstract

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1–3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4–10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States—where minority populations have a disproportionately higher burden of chronic conditions13—the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.

Suggested Citation

  • Genevieve L. Wojcik & Mariaelisa Graff & Katherine K. Nishimura & Ran Tao & Jeffrey Haessler & Christopher R. Gignoux & Heather M. Highland & Yesha M. Patel & Elena P. Sorokin & Christy L. Avery & Gil, 2019. "Genetic analyses of diverse populations improves discovery for complex traits," Nature, Nature, vol. 570(7762), pages 514-518, June.
  • Handle: RePEc:nat:nature:v:570:y:2019:i:7762:d:10.1038_s41586-019-1310-4
    DOI: 10.1038/s41586-019-1310-4
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    Cited by:

    1. Minta Thomas & Yu-Ru Su & Elisabeth A. Rosenthal & Lori C. Sakoda & Stephanie L. Schmit & Maria N. Timofeeva & Zhishan Chen & Ceres Fernandez-Rozadilla & Philip J. Law & Neil Murphy & Robert Carreras-, 2023. "Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Alexandra Barry & Michelle T. McNulty & Xiaoyuan Jia & Yask Gupta & Hanna Debiec & Yang Luo & China Nagano & Tomoko Horinouchi & Seulgi Jung & Manuela Colucci & Dina F. Ahram & Adele Mitrotti & Aditi , 2023. "Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Isabelle Austin-Zimmerman & Daniel F. Levey & Olga Giannakopoulou & Joseph D. Deak & Marco Galimberti & Keyrun Adhikari & Hang Zhou & Spiros Denaxas & Haritz Irizar & Karoline Kuchenbaecker & Andrew M, 2023. "Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Quan Sun & Bryce T. Rowland & Jiawen Chen & Anna V. Mikhaylova & Christy Avery & Ulrike Peters & Jessica Lundin & Tara Matise & Steve Buyske & Ran Tao & Rasika A. Mathias & Alexander P. Reiner & Paul , 2024. "Improving polygenic risk prediction in admixed populations by explicitly modeling ancestral-differential effects via GAUDI," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Jingning Zhang & Jianan Zhan & Jin Jin & Cheng Ma & Ruzhang Zhao & Jared O’Connell & Yunxuan Jiang & Bertram L. Koelsch & Haoyu Zhang & Nilanjan Chatterjee, 2024. "An ensemble penalized regression method for multi-ancestry polygenic risk prediction," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. Wei Fu & Shin-Yi Chou & Li-San Wang, 2022. "NIH Grant Expansion, Ancestral Diversity and Scientific Discovery in Genomics Research," NBER Working Papers 30155, National Bureau of Economic Research, Inc.
    7. Katrina G. Claw & Casey R. Dorr & Erica L. Woodahl, 2024. "Implementing community-engaged pharmacogenomics in Indigenous communities," Nature Communications, Nature, vol. 15(1), pages 1-5, December.
    8. Benjamin M. Jacobs & Daniel Stow & Sam Hodgson & Julia Zöllner & Miriam Samuel & Stavroula Kanoni & Saeed Bidi & Klaudia Walter & Claudia Langenberg & Ruth Dobson & Sarah Finer & Caroline Morton & Mon, 2024. "Genetic architecture of routinely acquired blood tests in a British South Asian cohort," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    9. Chen Wang & Tianying Wang & Krzysztof Kiryluk & Ying Wei & Hugues Aschard & Iuliana Ionita-Laza, 2024. "Genome-wide discovery for biomarkers using quantile regression at biobank scale," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    10. Dmitrii Usoltsev & Nikita Kolosov & Oxana Rotar & Alexander Loboda & Maria Boyarinova & Ekaterina Moguchaya & Ekaterina Kolesova & Anastasia Erina & Kristina Tolkunova & Valeriia Rezapova & Ivan Molot, 2024. "Complex trait susceptibilities and population diversity in a sample of 4,145 Russians," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    11. Ananyo Choudhury & Jean-Tristan Brandenburg & Tinashe Chikowore & Dhriti Sengupta & Palwende Romuald Boua & Nigel J. Crowther & Godfred Agongo & Gershim Asiki & F. Xavier Gómez-Olivé & Isaac Kisiangan, 2022. "Meta-analysis of sub-Saharan African studies provides insights into genetic architecture of lipid traits," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    12. Xinyuan Zhang & Anastasia M. Lucas & Yogasudha Veturi & Theodore G. Drivas & William P. Bone & Anurag Verma & Wendy K. Chung & David Crosslin & Joshua C. Denny & Scott Hebbring & Gail P. Jarvik & Ifti, 2022. "Large-scale genomic analyses reveal insights into pleiotropy across circulatory system diseases and nervous system disorders," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    13. Javier G. Serrano & Alejandra C. Ordóñez & Jonathan Santana & Elías Sánchez-Cañadillas & Matilde Arnay & Amelia Rodríguez-Rodríguez & Jacob Morales & Javier Velasco-Vázquez & Verónica Alberto-Barroso , 2023. "The genomic history of the indigenous people of the Canary Islands," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    14. Jiacheng Miao & Hanmin Guo & Gefei Song & Zijie Zhao & Lin Hou & Qiongshi Lu, 2023. "Quantifying portable genetic effects and improving cross-ancestry genetic prediction with GWAS summary statistics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    15. Shaan Khurshid & Julieta Lazarte & James P. Pirruccello & Lu-Chen Weng & Seung Hoan Choi & Amelia W. Hall & Xin Wang & Samuel F. Friedman & Victor Nauffal & Kiran J. Biddinger & Krishna G. Aragam & Pu, 2023. "Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    16. Michael G. Levin & Noah L. Tsao & Pankhuri Singhal & Chang Liu & Ha My T. Vy & Ishan Paranjpe & Joshua D. Backman & Tiffany R. Bellomo & William P. Bone & Kiran J. Biddinger & Qin Hui & Ozan Dikilitas, 2022. "Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    17. Surina Singh & Ananyo Choudhury & Scott Hazelhurst & Nigel J. Crowther & Palwendé R. Boua & Hermann Sorgho & Godfred Agongo & Engelbert A. Nonterah & Lisa K. Micklesfield & Shane A. Norris & Isaac Kis, 2023. "Genome-wide association study meta-analysis of blood pressure traits and hypertension in sub-Saharan African populations: an AWI-Gen study," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    18. Kimon Divaris & Gary D. Slade & Andrea G. Ferreira Zandona & John S. Preisser & Jeannie Ginnis & Miguel A. Simancas-Pallares & Cary S. Agler & Poojan Shrestha & Deepti S. Karhade & Apoena de Aguiar Ri, 2020. "Cohort Profile: ZOE 2.0—A Community-Based Genetic Epidemiologic Study of Early Childhood Oral Health," IJERPH, MDPI, vol. 17(21), pages 1-16, November.
    19. Alesha A. Hatton & Fei-Fei Cheng & Tian Lin & Ren-Juan Shen & Jie Chen & Zhili Zheng & Jia Qu & Fan Lyu & Sarah E. Harris & Simon R. Cox & Zi-Bing Jin & Nicholas G. Martin & Dongsheng Fan & Grant W. M, 2024. "Genetic control of DNA methylation is largely shared across European and East Asian populations," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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