Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Blood Pressure Working Group

Research output: Contribution to journalArticle

Abstract

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10 −4 ) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.

Original languageEnglish (US)
Pages (from-to)199-210
Number of pages12
JournalHuman genetics
Volume138
Issue number2
DOIs
StatePublished - Feb 8 2019

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Precision Medicine
Genome
Blood Pressure
Genes
Exome
National Heart, Lung, and Blood Institute (U.S.)
Atrial Appendage
RNA-Binding Proteins
Alternative Splicing
Hispanic Americans
Coronary Vessels
Chromosomes
Gene Expression
Brain

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data. / NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Blood Pressure Working Group.

In: Human genetics, Vol. 138, No. 2, 08.02.2019, p. 199-210.

Research output: Contribution to journalArticle

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Blood Pressure Working Group 2019, 'Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data', Human genetics, vol. 138, no. 2, pp. 199-210. https://doi.org/10.1007/s00439-019-01975-0
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Blood Pressure Working Group. / Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data. In: Human genetics. 2019 ; Vol. 138, No. 2. pp. 199-210.
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AU - He, Karen Y.

AU - Li, Xiaoyin

AU - Kelly, Tanika N.

AU - Liang, Jingjing

AU - Cade, Brian E.

AU - Assimes, Themistocles L.

AU - Becker, Lewis

AU - Beitelshees, Amber L.

AU - Bress, Adam P.

AU - Chang, Yen Pei Christy

AU - Chen, Yii Der Ida

AU - de Vries, Paul S.

AU - Fox, Ervin R.

AU - Franceschini, Nora

AU - Furniss, Anna

AU - Gao, Yan

AU - Guo, Xiuqing

AU - Haessler, Jeffrey

AU - Hwang, Shih Jen

AU - Irvin, Marguerite Ryan

AU - Kalyani, Rita R.

AU - Liu, Ching Ti

AU - Liu, Chunyu

AU - Martin, Lisa Warsinger

AU - Montasser, May E.

AU - Muntner, Paul M.

AU - Mwasongwe, Stanford

AU - Palmas, Walter

AU - Reiner, Alex P.

AU - Shimbo, Daichi

AU - Smith, Jennifer A.

AU - Snively, Beverly M.

AU - Yanek, Lisa

AU - Boerwinkle, Eric

AU - Correa, Adolfo

AU - Cupples, L. Adrienne

AU - He, Jiang

AU - Kardia, Sharon L.R.

AU - Kooperberg, Charles

AU - Mathias, Rasika

AU - Mitchell, Braxton D.

AU - Psaty, Bruce M.

AU - Vasan, Ramachandran S.

AU - Rao, D. C.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Wilson, James G.

AU - Chakravarti, Aravinda

AU - Morrison, Alanna C.

AU - Levy, Daniel

PY - 2019/2/8

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