Combined linkage and association analysis identifies rare and low frequency variants for blood pressure at 1q31

Heming Wang, Priyanka Nandakumar, Fasil Tekola-Ayele, Bamidele O. Tayo, Erin B. Ware, C. Charles Gu, Yingchang Lu, Jie Yao, Wei Zhao, Jennifer A. Smith, Jacklyn N. Hellwege, Xiuqing Guo, Todd L. Edwards, Ruth J.F. Loos, Donna K. Arnett, Myriam Fornage, Charles Rotimi, Sharon L.R. Kardia, Richard S. Cooper, D. C. RaoGeorg Ehret, Aravinda Chakravarti, Xiaofeng Zhu

Research output: Contribution to journalArticle

Abstract

High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and is more prevalent in African Americans as compared to other US groups. Although large, population-based genome-wide association studies (GWAS) have identified over 300 common polymorphisms modulating inter-individual BP variation, largely in European ancestry subjects, most of them do not localize to regions previously identified through family-based linkage studies. This discrepancy has remained unexplained despite the statistical power differences between current GWAS and prior linkage studies. To address this issue, we performed genome-wide linkage analysis of BP traits in African-American families from the Family Blood Pressure Program (FBPP) and genotyped on the Illumina Human Exome BeadChip v1.1. We identified a genomic region on chromosome 1q31 with LOD score 3.8 for pulse pressure (PP), a region we previously implicated in DBP studies of European ancestry families. Although no reported GWAS variants map to this region, combined linkage and association analysis of PP identified 81 rare and low frequency exonic variants accounting for the linkage evidence. Replication analysis in eight independent African ancestry cohorts (N = 16,968) supports this specific association with PP (P = 0.0509). Additional association and network analyses identified multiple potential candidate genes in this region expressed in multiple tissues and with a strong biological support for a role in BP. In conclusion, multiple genes and rare variants on 1q31 contribute to PP variation. Beyond producing new insights into PP, we demonstrate how family-based linkage and association studies can implicate specific rare and low frequency variants for complex traits.

Original languageEnglish (US)
JournalEuropean Journal of Human Genetics
DOIs
StateAccepted/In press - Jan 1 2018

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Wang, H., Nandakumar, P., Tekola-Ayele, F., Tayo, B. O., Ware, E. B., Gu, C. C., Lu, Y., Yao, J., Zhao, W., Smith, J. A., Hellwege, J. N., Guo, X., Edwards, T. L., Loos, R. J. F., Arnett, D. K., Fornage, M., Rotimi, C., Kardia, S. L. R., Cooper, R. S., ... Zhu, X. (Accepted/In press). Combined linkage and association analysis identifies rare and low frequency variants for blood pressure at 1q31. European Journal of Human Genetics. https://doi.org/10.1038/s41431-018-0277-1