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

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.

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Funding

This work was supported in part by NIH grants HL086694 to AC and HG003054 to XZ. TLE was supported by NIH/NHLBI grant HL121429, JNH was supported by T32CA160056,  RJFL was support by NIH grants DK107786, DK110113, and U01HG007417. The GenNet study is funded by NIH grants HL086694. The Genetic Epidemiology Network of Arteriopathy (GENOA) was supported by the National Heart, Lung and Blood Institute (HL054464, HL054457, HL054481, HL087660, HL086694, HL119443) of the National Institutes of Health. Genotyping was performed at the Center for Inherited Disease Research (CIDR). The HyperGEN cohort study is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, and 2 R01 HL55673-12. The study involves: University of Utah (Network Coordinating Center, Field Center, and Molecular Genetics Lab); University of Alabama at Birmingham (Field Center and Echo Coordinating and Analysis Center); Medical College of Wisconsin (Echo Genotyping Lab); Boston University (Field Center); University of Minnesota (Field Center and Biochemistry Lab); University of North Carolina (Field Center); Washington University (Data Coordinating Center); Weil Cornell Medical College (Echo Reading Center); National Heart, Lung, & Blood Institute. For a complete list of HyperGEN Investigators: http://www.biostat.wustl.edu/hypergen/Acknowledge.html. The Supports for replication cohorts are shown in Supplementary.

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Correspondence to Aravinda Chakravarti or Xiaofeng Zhu.

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

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