Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 9, Issue 1, Pages 64-70Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.115.001215
Keywords
genetic variation; hypertension; genome-wide association study; exome; blood pressure
Funding
- National Heart, Lung, and Blood Institute (NHLBI) [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924]
- NHLBI [RC2 HL-102925, RC2 HL-102926, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268-201100009C, HHSN2682011000010C, HHSN2682011000011C, HHSN2682011000012C, R01HL087641, R01HL59367, R01HL086694, N01-HC-25195, HHSN268201200036C, HHSN268200800007C, N01HC55222N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393]
- National Institutes of Health through the American Recovery and Reinvestment Act [5RC2HL102419]
- Affymetrix, Inc [N02-HL-6-4278]
- National Institute on Aging [R01AG023629R01AG023629]
- National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268-201300050C]
- National Institute on Minority Health and Health Disparities
- MESA [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]
- National Center for Research Resources [UL1-TR-000040, UL1-RR-025005]
- National Center for Advancing Translational Sciences, CTSI grant [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center [DK063491]
- National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268-201100004C, HHSN271201100004C]
- European Commission FP6 STRP grant [018947 (LSHG-CT-2006-01947)]
- European Community's Seventh Framework Programme by the European Commission [HEALTH-F4-2007-201413, QLG2-CT-2002-01254]
- Netherlands Organization for Scientific Research
- Russian Foundation for Basic Research [NWO-RFBR 047.017.043]
- ZonMw [91111025]
- Hersenstichting Nederland [F2013[1]-28]
- Netherlands Organisation of Scientific Research Netherlands Organisation for Scientific Research (NWO) Investments [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly [014-93-015]
- Netherlands Genomics Initiative (NGI)/NWO [050-060-810]
- Netherlands Consortium for Healthy Ageing (NCHA)
- NGI/NWO [050-060-810]
- Genetic Laboratory of the Department of Internal Medicine, Erasmus MC
- complementation project of the Biobanking and Biomolecular Research Infrastructure Netherlands [CP2010-41]
- Erasmus Medical Center and Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
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Background- Rare genetic variants influence blood pressure (BP). Methods and Results- Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of approximate to 170 000 common variants (minor allele frequency, >= 1%; statistical significance, P <= 2.9x10(-7)) and gene-based tests of rare variants (minor allele frequency, < 1%; approximate to 17 000 genes; statistical significance, P <= 1.5x10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; beta=-3.20; P=4.1x10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (beta=-4.11; P=2.8x10(-4)), mean arterial pressure (beta=-3.50; P=8.9x10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; beta=-3.30; P=5.0x10(-7)). Conclusions- These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.
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