Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Madeline H Kowalski, Huijun Qian, Ziyi Hou, Jonathan D Rosen, Amanda L Tapia, Yue Shan, Deepti Jain, Maria Argos, Donna K Arnett, Christy Avery, Kathleen C Barnes, Lewis C Becker, Stephanie A Bien, Joshua C Bis, John Blangero, Eric Boerwinkle, Donald W Bowden, Steve Buyske, Jianwen Cai, Michael H Cho, Seung Hoan Choi, Hélène Choquet, L Adrienne Cupples, Mary Cushman, Michelle Daya, Paul S de Vries, Patrick T Ellinor, Nauder Faraday, Myriam Fornage, Stacey Gabriel, Santhi K Ganesh, Misa Graff, Namrata Gupta, Jiang He, Susan R Heckbert, Bertha Hidalgo, Chani J Hodonsky, Marguerite R Irvin, Andrew D Johnson, Eric Jorgenson, Robert Kaplan, Sharon L R Kardia, Tanika N Kelly, Charles Kooperberg, Jessica A Lasky-Su, Ruth J F Loos, Steven A Lubitz, Rasika A Mathias, Caitlin P McHugh, Courtney Montgomery, Jee-Young Moon, Alanna C Morrison, Nicholette D Palmer, Nathan Pankratz, George J Papanicolaou, Juan M Peralta, Patricia A Peyser, Stephen S Rich, Jerome I Rotter, Edwin K Silverman, Jennifer A Smith, Nicholas L Smith, Kent D Taylor, Timothy A Thornton, Hemant K Tiwari, Russell P Tracy, Tao Wang, Scott T Weiss, Lu-Chen Weng, Kerri L Wiggins, James G Wilson, Lisa R Yanek, Sebastian Zöllner, Kari E North, Paul L Auer, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group, Laura M Raffield, Alexander P Reiner, Yun Li
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2019
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/e2012563f33841c88441169fde0c6cd0
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:e2012563f33841c88441169fde0c6cd0
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Madeline H Kowalski Huijun Qian Ziyi Hou Jonathan D Rosen Amanda L Tapia Yue Shan Deepti Jain Maria Argos Donna K Arnett Christy Avery Kathleen C Barnes Lewis C Becker Stephanie A Bien Joshua C Bis John Blangero Eric Boerwinkle Donald W Bowden Steve Buyske Jianwen Cai Michael H Cho Seung Hoan Choi Hélène Choquet L Adrienne Cupples Mary Cushman Michelle Daya Paul S de Vries Patrick T Ellinor Nauder Faraday Myriam Fornage Stacey Gabriel Santhi K Ganesh Misa Graff Namrata Gupta Jiang He Susan R Heckbert Bertha Hidalgo Chani J Hodonsky Marguerite R Irvin Andrew D Johnson Eric Jorgenson Robert Kaplan Sharon L R Kardia Tanika N Kelly Charles Kooperberg Jessica A Lasky-Su Ruth J F Loos Steven A Lubitz Rasika A Mathias Caitlin P McHugh Courtney Montgomery Jee-Young Moon Alanna C Morrison Nicholette D Palmer Nathan Pankratz George J Papanicolaou Juan M Peralta Patricia A Peyser Stephen S Rich Jerome I Rotter Edwin K Silverman Jennifer A Smith Nicholas L Smith Kent D Taylor Timothy A Thornton Hemant K Tiwari Russell P Tracy Tao Wang Scott T Weiss Lu-Chen Weng Kerri L Wiggins James G Wilson Lisa R Yanek Sebastian Zöllner Kari E North Paul L Auer NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium TOPMed Hematology & Hemostasis Working Group Laura M Raffield Alexander P Reiner Yun Li Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.
description	Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.
format	article
author	Madeline H Kowalski Huijun Qian Ziyi Hou Jonathan D Rosen Amanda L Tapia Yue Shan Deepti Jain Maria Argos Donna K Arnett Christy Avery Kathleen C Barnes Lewis C Becker Stephanie A Bien Joshua C Bis John Blangero Eric Boerwinkle Donald W Bowden Steve Buyske Jianwen Cai Michael H Cho Seung Hoan Choi Hélène Choquet L Adrienne Cupples Mary Cushman Michelle Daya Paul S de Vries Patrick T Ellinor Nauder Faraday Myriam Fornage Stacey Gabriel Santhi K Ganesh Misa Graff Namrata Gupta Jiang He Susan R Heckbert Bertha Hidalgo Chani J Hodonsky Marguerite R Irvin Andrew D Johnson Eric Jorgenson Robert Kaplan Sharon L R Kardia Tanika N Kelly Charles Kooperberg Jessica A Lasky-Su Ruth J F Loos Steven A Lubitz Rasika A Mathias Caitlin P McHugh Courtney Montgomery Jee-Young Moon Alanna C Morrison Nicholette D Palmer Nathan Pankratz George J Papanicolaou Juan M Peralta Patricia A Peyser Stephen S Rich Jerome I Rotter Edwin K Silverman Jennifer A Smith Nicholas L Smith Kent D Taylor Timothy A Thornton Hemant K Tiwari Russell P Tracy Tao Wang Scott T Weiss Lu-Chen Weng Kerri L Wiggins James G Wilson Lisa R Yanek Sebastian Zöllner Kari E North Paul L Auer NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium TOPMed Hematology & Hemostasis Working Group Laura M Raffield Alexander P Reiner Yun Li
author_facet	Madeline H Kowalski Huijun Qian Ziyi Hou Jonathan D Rosen Amanda L Tapia Yue Shan Deepti Jain Maria Argos Donna K Arnett Christy Avery Kathleen C Barnes Lewis C Becker Stephanie A Bien Joshua C Bis John Blangero Eric Boerwinkle Donald W Bowden Steve Buyske Jianwen Cai Michael H Cho Seung Hoan Choi Hélène Choquet L Adrienne Cupples Mary Cushman Michelle Daya Paul S de Vries Patrick T Ellinor Nauder Faraday Myriam Fornage Stacey Gabriel Santhi K Ganesh Misa Graff Namrata Gupta Jiang He Susan R Heckbert Bertha Hidalgo Chani J Hodonsky Marguerite R Irvin Andrew D Johnson Eric Jorgenson Robert Kaplan Sharon L R Kardia Tanika N Kelly Charles Kooperberg Jessica A Lasky-Su Ruth J F Loos Steven A Lubitz Rasika A Mathias Caitlin P McHugh Courtney Montgomery Jee-Young Moon Alanna C Morrison Nicholette D Palmer Nathan Pankratz George J Papanicolaou Juan M Peralta Patricia A Peyser Stephen S Rich Jerome I Rotter Edwin K Silverman Jennifer A Smith Nicholas L Smith Kent D Taylor Timothy A Thornton Hemant K Tiwari Russell P Tracy Tao Wang Scott T Weiss Lu-Chen Weng Kerri L Wiggins James G Wilson Lisa R Yanek Sebastian Zöllner Kari E North Paul L Auer NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium TOPMed Hematology & Hemostasis Working Group Laura M Raffield Alexander P Reiner Yun Li
author_sort	Madeline H Kowalski
title	Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.
title_short	Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.
title_full	Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.
title_fullStr	Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.
title_full_unstemmed	Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.
title_sort	use of >100,000 nhlbi trans-omics for precision medicine (topmed) consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed african and hispanic/latino populations.
publisher	Public Library of Science (PLoS)
publishDate	2019
url	https://doaj.org/article/e2012563f33841c88441169fde0c6cd0
work_keys_str_mv	AT madelinehkowalski useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT huijunqian useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT ziyihou useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT jonathandrosen useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT amandaltapia useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT yueshan useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT deeptijain useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT mariaargos useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT donnakarnett useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT christyavery useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT kathleencbarnes useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT lewiscbecker useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT stephanieabien useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT joshuacbis useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT johnblangero useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT ericboerwinkle useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT donaldwbowden useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT stevebuyske useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT jianwencai useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT michaelhcho useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT seunghoanchoi useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT helenechoquet useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT ladriennecupples useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT marycushman useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT michelledaya useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT paulsdevries useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT patricktellinor useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT nauderfaraday useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT myriamfornage useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT staceygabriel useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT santhikganesh useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT misagraff useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT namratagupta useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT jianghe useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT susanrheckbert useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT berthahidalgo useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT chanijhodonsky useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT margueriterirvin useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT andrewdjohnson useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT ericjorgenson useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT robertkaplan useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT sharonlrkardia useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT tanikankelly useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT charleskooperberg useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT jessicaalaskysu useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT ruthjfloos useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT stevenalubitz useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT rasikaamathias useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT caitlinpmchugh useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT courtneymontgomery useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT jeeyoungmoon useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT alannacmorrison useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT nicholettedpalmer useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT nathanpankratz useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT georgejpapanicolaou useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT juanmperalta useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT patriciaapeyser useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT stephensrich useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT jeromeirotter useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT edwinksilverman useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT jenniferasmith useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT nicholaslsmith useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT kentdtaylor useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT timothyathornton useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT hemantktiwari useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT russellptracy useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT taowang useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT scotttweiss useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT luchenweng useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT kerrilwiggins useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT jamesgwilson useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT lisaryanek useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT sebastianzollner useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT karienorth useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT paullauer useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT nhlbitransomicsforprecisionmedicinetopmedconsortium useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT topmedhematologyhemostasisworkinggroup useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT lauramraffield useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT alexanderpreiner useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations AT yunli useof100000nhlbitransomicsforprecisionmedicinetopmedconsortiumwholegenomesequencesimprovesimputationqualityanddetectionofrarevariantassociationsinadmixedafricanandhispaniclatinopopulations
_version_	1718375693077708800
spelling	oai:doaj.org-article:e2012563f33841c88441169fde0c6cd02021-12-02T20:02:58ZUse of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.1553-73901553-740410.1371/journal.pgen.1008500https://doaj.org/article/e2012563f33841c88441169fde0c6cd02019-12-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1008500https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.Madeline H KowalskiHuijun QianZiyi HouJonathan D RosenAmanda L TapiaYue ShanDeepti JainMaria ArgosDonna K ArnettChristy AveryKathleen C BarnesLewis C BeckerStephanie A BienJoshua C BisJohn BlangeroEric BoerwinkleDonald W BowdenSteve BuyskeJianwen CaiMichael H ChoSeung Hoan ChoiHélène ChoquetL Adrienne CupplesMary CushmanMichelle DayaPaul S de VriesPatrick T EllinorNauder FaradayMyriam FornageStacey GabrielSanthi K GaneshMisa GraffNamrata GuptaJiang HeSusan R HeckbertBertha HidalgoChani J HodonskyMarguerite R IrvinAndrew D JohnsonEric JorgensonRobert KaplanSharon L R KardiaTanika N KellyCharles KooperbergJessica A Lasky-SuRuth J F LoosSteven A LubitzRasika A MathiasCaitlin P McHughCourtney MontgomeryJee-Young MoonAlanna C MorrisonNicholette D PalmerNathan PankratzGeorge J PapanicolaouJuan M PeraltaPatricia A PeyserStephen S RichJerome I RotterEdwin K SilvermanJennifer A SmithNicholas L SmithKent D TaylorTimothy A ThorntonHemant K TiwariRussell P TracyTao WangScott T WeissLu-Chen WengKerri L WigginsJames G WilsonLisa R YanekSebastian ZöllnerKari E NorthPaul L AuerNHLBI Trans-Omics for Precision Medicine (TOPMed) ConsortiumTOPMed Hematology & Hemostasis Working GroupLaura M RaffieldAlexander P ReinerYun LiPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 15, Iss 12, p e1008500 (2019)

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.

Ejemplares similares