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

• Published in: Human genetics Vol. 138; no. 2; pp. 199 - 210
• Main Authors: He, Karen Y., Li, Xiaoyin, Kelly, Tanika N., Liang, Jingjing, Cade, Brian E., Assimes, Themistocles L., Becker, Lewis C., Beitelshees, Amber L., Bress, Adam P., Chang, Yen-Pei Christy, Chen, Yii-Der Ida, de Vries, Paul S., Fox, Ervin R., Franceschini, Nora, Furniss, Anna, Gao, Yan, Guo, Xiuqing, Haessler, Jeffrey, Hwang, Shih-Jen, Irvin, Marguerite Ryan, Kalyani, Rita R., Liu, Ching-Ti, Liu, Chunyu, Martin, Lisa Warsinger, Montasser, May E., Muntner, Paul M., Mwasongwe, Stanford, Palmas, Walter, Reiner, Alex P., Shimbo, Daichi, Smith, Jennifer A., Snively, Beverly M., Yanek, Lisa R., Boerwinkle, Eric, Correa, Adolfo, Cupples, L. Adrienne, He, Jiang, Kardia, Sharon L. R., Kooperberg, Charles, Mathias, Rasika A., Mitchell, Braxton D., Psaty, Bruce M., Vasan, Ramachandran S., Rao, D. C., Rich, Stephen S., Rotter, Jerome I., Wilson, James G., Chakravarti, Aravinda, Morrison, Alanna C., Levy, Daniel, Arnett, Donna K., Redline, Susan, Zhu, Xiaofeng
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-02-2019; Springer; Springer Nature B.V
• Subjects: Alternative splicing; Alternative Splicing - genetics; Biomedical and Life Sciences; Biomedicine; Blood pressure; Blood Pressure - genetics; Chromosome 16; Chromosomes, Human, Pair 16 - genetics; Coronary artery; Data processing; DNA sequencing; Exome; Female; Follow-Up Studies; Gene expression; Gene Function; Genes; Genetic aspects; Genetic Linkage; Genetic Variation; Genome, Human; Genome-Wide Association Study; Genomes; Genomics; High-Throughput Nucleotide Sequencing; Human Genetics; Humans; Linkage analysis; Male; Metabolic Diseases; Molecular Medicine; Non-coding RNA; Original Investigation; Precision medicine; Protein binding; Recombinases - genetics; Ribonucleic acid; RNA; RNA Splicing Factors - genetics; RNA-binding protein
• ISSN: 0340-6717; 1432-1203; 1432-1203
• DOI: 10.1007/s00439-019-01975-0

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.