TY - JOUR
T1 - Variant discovery and fine mapping of genetic loci associated with blood pressure traits in Hispanics and African Americans
AU - Franceschini, Nora
AU - Carty, Cara L.
AU - Lu, Yingchang
AU - Tao, Ran
AU - Sung, Yun Ju
AU - Manichaikul, Ani
AU - Haessler, Jeff
AU - Fornage, Myriam
AU - Schwander, Karen
AU - Zubair, Niha
AU - Bien, Stephanie
AU - Hindorff, Lucia A.
AU - Guo, Xiuqing
AU - Bielinski, Suzette J.
AU - Ehret, Georg
AU - Kaufman, Joel D.
AU - Rich, Stephen S.
AU - Carlson, Christopher S.
AU - Bottinger, Erwin P.
AU - North, Kari E.
AU - Rao, D. C.
AU - Chakravarti, Aravinda
AU - Barrett, Paula Q.
AU - Loos, Ruth J.F.
AU - Buyske, Steven
AU - Kooperberg, Charles
N1 - Funding Information:
This work was supported by the Population Architecture Using Genomics and Epidemiology (PAGE) program which is funded by the National Human Genome Research Institute (NHGRI) [U01HG004803 (to the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) program, U01HG004798 (to the Epidemiologic Architecture of Genes Linked to Environment (EAGLE)), U01HG004802 (to the Multi-Ethnic Cohort (MEC)), U01HG004790 (to the Women's Health Initiative (WHI)), and U01HG004801 (to the PAGE Coordinating Center), and their respective NHGRI ARRA supplements. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy.org. The data and materials included in this report result from a collaboration between the following studies. Funding support for the "Epidemiology of putative genetic variants: The Women's Health Initiative" study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Funding support for the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) program is provided through the NHGRI PAGE program [U01HG004803 and its NHGRI ARRA supplement]. The following CALiCo studies contributed to this manuscript and are funded by the following agencies: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; NHGRI contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center [U01HG004801-01 and its NHGRI ARRA supplement]. The National Institutes of Mental Health also contributes to the support for the PAGE Coordinating Center. Additional support for this work was provided by the NHGRI through [R01 HG006124]. CLC received support from UL1TR000075 from the NIH National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences or the NIH. NF receives support from R21HL123677. PQB receives support from NHLBI grant R01 HL089717. Metabochip genotyping for the HyperGen and GenNet studies was supported by 5 R01 HL086694. MESA was conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01- HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, and UL1-TR-000040. MESA Family is conducted and supported by the NHLBI in collaboration with MESA investigators. Support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071258, R01HL071259, by the National Center for Research Resources, Grant UL1RR033176, and the National Center for Advancing Translational Sciences, Grant UL1TR000124. This publication was developed under a STAR research assistance agreement, No. RD831697 (MESA Air), awarded by the U.S Environmental protection Agency (EPA). It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. Metabochip genotyping data was supported in part by grants and contracts R01HL98077, N02-HL-64278, HL071205, UL1TR000124, DK063491, RD831697, and P50 ES015915. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Mount Sinai BioMe Biobank is supported by The Andrea and Charles Bronfman Philanthropies. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions. The authors thank the staff and participants of the ARIC study for their important contributions. Additionally, the authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf. The Mount Sinai BioMe Biobank is supported by The Andrea and Charles Bronfman Philanthropies.
PY - 2016/10
Y1 - 2016/10
N2 - Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African Americans and Hispanics. Fourteen variants in three loci (KCNK3, FGF5, ATXN2-SH2B3) were significantly associated with blood pressure in Hispanics. The most significant diastolic blood pressure variant identified in our analysis, rs2586886/KCNK3 (P = 5.2 × 10-9), also replicated in independent Hispanic and European-descent samples. African American and trans-ethnic meta-analysis data identified novel variants in the FGF5, ULK4 and HOXA-EVX1 loci, which have not been previously associated with blood pressure traits. Our identification and independent replication of variants in KCNK3, a gene implicated in primary hyperaldosteronism, as well as a variant in HOTTIP (HOXA-EVX1) suggest that further work to clarify the roles of these genes may be warranted. Overall, our findings suggest that loci identified in European descent populations also contribute to blood pressure variation in diverse populations including Hispanics and African Americans - populations that are understudied for hypertension genetic risk factors.
AB - Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African Americans and Hispanics. Fourteen variants in three loci (KCNK3, FGF5, ATXN2-SH2B3) were significantly associated with blood pressure in Hispanics. The most significant diastolic blood pressure variant identified in our analysis, rs2586886/KCNK3 (P = 5.2 × 10-9), also replicated in independent Hispanic and European-descent samples. African American and trans-ethnic meta-analysis data identified novel variants in the FGF5, ULK4 and HOXA-EVX1 loci, which have not been previously associated with blood pressure traits. Our identification and independent replication of variants in KCNK3, a gene implicated in primary hyperaldosteronism, as well as a variant in HOTTIP (HOXA-EVX1) suggest that further work to clarify the roles of these genes may be warranted. Overall, our findings suggest that loci identified in European descent populations also contribute to blood pressure variation in diverse populations including Hispanics and African Americans - populations that are understudied for hypertension genetic risk factors.
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U2 - 10.1371/journal.pone.0164132
DO - 10.1371/journal.pone.0164132
M3 - Article
C2 - 27736895
AN - SCOPUS:84991336343
VL - 11
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 10
M1 - e0164132
ER -