Genetic analyses of diverse populations improves discovery for complex traits

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, Gillian M. Belbin, Stephanie A. Bien, Iona Cheng, Sinead Cullina, Chani J. Hodonsky, Yao Hu, Laura M. Huckins, Janina Jeff, Anne E. Justice, Jonathan M. Kocarnik, Unhee Lim, Bridget M. Lin, Yingchang Lu, Sarah C. Nelson, Sung-Shim L. Park, Hannah Poisner, Michael H. Preuss, Melissa A. Richard, Claudia Schurmann, Veronica W. Setiawan, Alexandra Sockell, Karan Vahi, Marie Verbanck, Abhishek Vishnu, Ryan W. Walker, Kristin L. Young, Niha Zubair, Victor Acuña-Alonso, Jose Luis Ambite, Kathleen C. Barnes, Eric Boerwinkle, Erwin P. Bottinger, Carlos D. Bustamante, Christian Caberto, Samuel Canizales-Quinteros, Matthew P. Conomos, Ewa Deelman, Ron Do, Kimberly Doheny, Lindsay Fernández-Rhodes, Myriam Fornage, Benyam Hailu, Gerardo Heiss, Brenna M. Henn, Lucia A. Hindorff, Rebecca D. Jackson, Cecelia A. Laurie, Cathy C. Laurie, Yuqing Li, Dan-Yu Lin, Andres Moreno-Estrada, Girish Nadkarni, Paul J. Norman, Loreall C. Pooler, Alexander P. Reiner, Jane Romm, Chiara Sabatti, Karla Sandoval, Xin Sheng, Eli A. Stahl, Daniel O. Stram, Timothy A. Thornton, Christina L. Wassel, Lynne R. Wilkens, Cheryl A. Winkler, Sachi Yoneyama, Steven Buyske, Christopher A. Haiman, Charles Kooperberg, Loic Marchand, Ruth J. F. Loos, Tara C. Matise, Kari E. North, Ulrike Peters, Eimear E. Kenny () and Christopher S. Carlson ()
Additional contact information
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
Jeffrey Haessler: Fred Hutchinson Cancer Research Center
Christopher R. Gignoux: Stanford University
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
Stephanie A. Bien: Fred Hutchinson Cancer Research Center
Iona Cheng: University of California San Francisco
Sinead Cullina: 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
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
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
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
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
Kimberly Doheny: Johns Hopkins University
Lindsay Fernández-Rhodes: University of North Carolina at Chapel Hill
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
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
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
Christopher S. Carlson: Fred Hutchinson Cancer Research Center

Nature, 2019, vol. 570, issue 7762, 514-518

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1310-4

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