Abstract
Background: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries. Results: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10− 7). Conclusions: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.
| Original language | English |
|---|---|
| Article number | 148 |
| Journal | BMC Genomics |
| Volume | 23 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2022 |
Bibliographical note
Publisher Copyright:© 2022, The Author(s).
Funding
GeneSTAR: GeneSTAR was supported by grants from the NIH/NHLBI (U01 HL72518, HL087698, HL49762, HL58625, HL071025, HL112064), the NIH/National Institute of Nursing Research (NR0224103), and by a grant from the NIH/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. CFS: CFS was supported by the NHLBI (R35HL135818, R01HL113338, R01HL098433, and R01HL46380). HCHS-SOL: The authors thank the staff and participants of HCHS/SOL for their important contributions. A complete list of HCHS/SOL staff and investigators can be found at http://www.cscc.unc.edu/hchs/ . The Hispanic Community Health Study/Study of Latinos is a collaborative study supported by contracts from the NHLBI to the University of North Carolina (HHSN268201300001I / N01-HC-65233), University of Miami (HHSN268201300004I / N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I / N01-HC-65235), University of Illinois at Chicago – HHSN268201300003I / N01-HC-65236 Northwestern Univ), and San Diego State University (HHSN268201300005I / N01-HC-65237). The following Institutes/Centers/Offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities (NIMHD), National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). WGS for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the HCHS/SOL” (phs001395) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201600033I). HyperGEN: We thank the HyperGEN Study participants and investigators for their significant contributions. HyperGEN is part of the NHLBI Family Blood Pressure Program; collection of the data represented here was supported by grants U01 HL054472, U01 HL054473, U01 HL054495, and U01 HL054509. The HyperGEN: Genetics of Left Ventricular Hypertrophy Study was supported by NHLBI grant R01 HL055673 with whole-genome sequencing made possible by supplement -18S1. THRV: THRV is supported by the NHLBI grant (R01HL111249). THRV is a collaborative study between Washington University in St. Louis, Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center, University of Texas in Houston, Taichung Veterans General Hospital, Taipei Veterans General Hospital, Tri-Service General Hospital, National Health Research Institutes, National Taiwan University, and Baylor University. THRV is based (substantially) on the parent SAPPHIRe study, along with additional population-based and hospital-based cohorts. SAPPHIRe was supported by NHLBI grants (U01HL54527, U01HL54498) and Taiwan funds, and the other cohorts were supported by Taiwan funds. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. The project described was also supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR002490 (Laura M. Raffield). MESA: WGS for the TOPMed program was supported by the NHLBI. WGS for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. 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 UL1TR001881, 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. 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, and by the National Center for Research Resources, Grant UL1RR033176. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, 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. FHS: Support for the FHS was provided by the NIH contract N01-HC-25195 (Boston University). We would also like to thank the FHS participants and families who participate in FHS research. In addition, we acknowledge the contributions of the research scientists and staffs of the Division of Intramural Research, NHLBI, NIH and Boston University. WHI investigator Nora Franceschini is funded by the NIH awards R01-MD012765, R01-DK117445-01A1 and R21-HL140385. GenSalt investigator, Tanika N. Kelly, is supported by NHLBI grant 5U01HL120393. GenSalt: GenSalt was supported by research grants (U01HL072507, R01HL087263, and R01HL090682) from the NHLBI and partially supported by the National Institute of General Medical Sciences of the NIH under Award Number P20GM109036 and the Collins C. Diboll Private Foundation, New Orleans, LA. SAFS: Collection of the San Antonio Family Study data was supported in part by National Institutes of Health (NIH) grants R01 HL045522, MH078143, MH078111 and MH083824; and whole genome sequencing of SAFS subjects was supported by U01 DK085524 and R01 HL113323. We are very grateful to the participants of the San Antonio Family Study for their continued involvement in our research programs. Samoan Study: The Samoan study is supported by NIH/NHLBI grants, R01HL093093 and R01HL133040. WGS for the TOPMed program was supported by the NHLBI. We acknowledge the support from the Samoan Ministry of Health and Ministry of Women, Community and Social Development, local village government officials, and the generosity of our research staff, and all participants. WHI: The WHI program is funded by the NHLBI through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The TOPMed component of WHI was funded by NIH award X01 HL139376. The authors would like to acknowledge contributions from WHI investigators: https://www-whi-org.s3.us-west-2.amazonaws.com/wp-content/uploads/WHI-Investigator-Short-List.pdf . KYH was partially supported by grant T32 HL007567 from the National Heart, Lung, and Blood Institute (NHLBI). This work was supported by HL086694 from NHLBI, HG003054 and HG011052 from the National Human Genome Research Institute. The funders do not have a role in this study. BioMe: The Mount Sinai BioMe Biobank has been supported by The Andrea and Charles Bronfman Philanthropies and in part by Federal funds from the NHLBI and NHGRI (U01HG00638001; U01HG007417; R56HG010297; R01DK110113; R01DK107786; X01HL134588). We thank all participants in the Mount Sinai Biobank. We also thank all our recruiters who have assisted and continue to assist in data collection and management and are grateful for the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. WGS for the Genome Sequencing Program (GSP) was funded by the National Human Genome Research Institute (NHGRI), the NHLBI, and the National Eye Institute (NEI). The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. The Centers for Common Disease Genomics (CCDG) program was supported by NHGRI and NHLBI, and WGS was performed at the Baylor College of Medicine Human Genome Sequencing Center (UM1 HG008898 and R01HL059367). CHS: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, HL105756 and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. GENOA: Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the National Heart, Lung and Blood Institute (U01 HL054457, U01 HL054464, U01 HL054481, R01 HL119443, and R01 HL087660) of the National Institutes of Health. DNA extraction for “NHLBI TOPMed: Genetic Epidemiology Network of Arteriopathy” (phs001345) was performed at the Mayo Clinic Genotyping Core, and WGS was performed at the DNA Sequencing and Gene Analysis Center at the University of Washington (3R01HL055673-18S1) and the Broad Institute (HHSN268201500014C). We would also like to thank the GENOA participants.
| Funders | Funder number |
|---|---|
| Baylor College of Medicine Human Genome Sequencing Center | UM1 HG008898 |
| Collins C. Diboll Private Foundation | |
| Johns Hopkins General Clinical Research Center | |
| Southern California Diabetes Endocrinology Research Center | |
| National Institutes of Health (NIH) | R01 HL045522, R21-HL140385, R01-MD012765, X01 HL139376, N01-HC-25195, U01 DK085524, R01 HL113323, MH083824, R01-DK117445-01A1, MH078111, MH078143 |
| National Institutes of Health (NIH) | |
| National Institute on Aging | |
| National Heart, Lung, and Blood Institute (NHLBI) | N02-HL-64278, R01HL133040, HL58625, U01 HL054464, R01HL098433, R01HL113338, U01 HL054509, R01HL059367, R01 HL055673, R01HL071051, R01HL071250, HL087698, R01HL071251, R01HL071205, R01HL090682, U01HL080295, U01 HL72518, R01HL087263, R01 HL119443, R01HL120393, U01 HL054481, HL071025, HG011052, U01HL130114, U01 HL054457, HL086694, HL49762, U01HL54527, R35HL135818, R01HL093093, HG003054, U01HL072507, R01HL111249, R01HL46380, HL112064, HL007567, R01HL071258, R01HL071259, R01 HL087660, U01 HL054472, U01 HL054473, U01 HL054495, HHSN268201600018C, U01HL54498 |
| National Heart, Lung, and Blood Institute (NHLBI) | |
| National Human Genome Research Institute | U01HG00638001, R56HG010297, U01HG007417, X01HL134588 |
| National Human Genome Research Institute | |
| National Eye Institute/National Institutes of Health | |
| National Institute of Health National Institute of Nursing Research | NR0224103 |
| National Institute of Health National Institute of Nursing Research | |
| National Institute of General Medical Sciences | P20GM109036 |
| National Institute of General Medical Sciences | |
| National Institute of Diabetes and Digestive and Kidney Diseases | R01DK110113, R01DK107786 |
| National Institute of Diabetes and Digestive and Kidney Diseases | |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | R01AG023629 |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | |
| National Institute of Dental and Craniofacial Research | MOD03 |
| National Institute of Dental and Craniofacial Research | |
| National Center for Research Resources | M01-RR000052, UL1RR033176 |
| National Center for Research Resources | |
| American the American Heart Association | 18CDA34110116 |
| American the American Heart Association | |
| National Center for Advancing Translational Sciences (NCATS) | UL1TR001881, KL2TR002490 |
| National Center for Advancing Translational Sciences (NCATS) | |
| Indiana Clinical and Translational Sciences Institute | |
| Boston University School of Public Health/Boston University Medical Campus | |
| Diabetes Research Connection | DK063491 |
| Diabetes Research Connection |
Keywords
- Blood pressure
- Rare variant analysis
- Whole genome sequencing
ASJC Scopus subject areas
- Biotechnology
- Genetics