Interethnic analyses of blood pressure loci in populations of East Asian and European descent

Abstract

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.

Fig. 1

Interethnic heterogeneity of genetic impact of SBP. a Manhattan plot showing results for genome-wide scan of genetic impact heterogeneity. The genetic impact at transethnic SNPs were compared between two populations of different ancestries using GWAS data sets. b Regional plots on 12q24 and 10q21, where there were multiple SNPs with significant (P < 5×10^–8) evidence for interethnic heterogeneity (see Supplementary Data 6). Bordered circles represent SNPs with significant interethnic heterogeneity. Transethnic SNPs were plotted in two panels at each locus; genetic impacts of each SNP are denoted separately for Europeans (EUR, top panel) and East Asians (EAS, bottom panel) on 12q24 (left) and 10q21 (right) such that genetic impacts in Europeans are positive. In the individual regional plots, the correlation of ancestry-specific sentinel SNP to other SNPs at the locus is shown on a scale from minimal (blue) to maximal (red); the sentinel SNPs thus benchmarked are rs3184504 (EUR specific) and rs671 (EAS specific) on 12q24 and rs4590817 (EUR specific) and rs145193831 (EAS specific) on 10q21. The position of ancestry-specific sentinel SNP is indicated by an arrow head. c Phylogenetic relationships of ancestry-specific sentinel SNPs with transethnic haplotypes detectable in Europeans (top) and East Asians (bottom) on 12q24 (left) and 10q21 (right). Each node corresponds to a haplotype and the SNPs appear on the edges. The edge width reflects the haplotype frequency in the corresponding ethnic groups. At each locus, blood pressure increasing and decreasing haplotypes and derived, ancestry-specific alleles are colored in red and blue, respectively

Fig. 2

Transethnic genetic correlation and SNP-based heritability. SNP-based heritability of SBP, DBP and other complex disease and phenotype traits is shown separately for East Asians (EAS) and Europeans (EUR) by using the published GWAS summary statistics (Supplementary Table 6). The whiskers are 95% confidence intervals of each value

Fig. 3

Distribution of SNP effect-size in GWAS and power of GWAS. They are compared between East Asians and Europeans for DBP, low-density lipoprotein cholesterol (LDL-C), type 2 diabetes (T2D), body mass index (BMI) and height. a Distribution of SNP effect-size in actual GWAS conducted in East Asians (x-axis) and Europeans (y-axis). The effect-size of an SNP was standardized such that each of the trait and allele has a unit variance. The standardized effect-size equals the genetic impact. A positive effect-size indicates a higher trait value for the ALT allele compared to the REF allele of the 1000 Genomes (1000G) phase-3 data set. The horizontal and vertical bars to the bottom and right of the plots indicate the range of effect-sizes, in which genome-wide significant SNPs are localized. b The expected numbers of genome-wide significant loci detectable in a single GWAS and their interethnic overlap. The number of SNPs was scaled to 1000G SNPs even for GWAS in which HapMap-derived SNPs were assayed. SNPs located ≤500 kb were regarded to be at the same susceptibility locus. The numbers of loci were inferred from the heritability model shown in Supplementary Fig. 13, where true observable effect-sizes were computed based on 100 trials of random sampling under the assumed heritability parameters (see Methods)

Fig. 4

Interethnic compatibility of GWAS results for DBP, LDL-C, T2D, BMI, and height. Each point in the plots represents a sentinel SNP with genome-wide significance in the GWAS summary statistics (Supplementary Table 6), plotted with its standardized effect-size (in y-axis) against minor allele frequency (in x-axis) for East Asians (EAS in the left column) and Europeans (EUR in the right column). SNPs specific to either of the ethnic groups are colored in red; ancestry-specific association was defined such that the sentinel SNPs at the corresponding loci reached genome-wide significance (P < 5×10^–8) in one ethnic group but were non-polymorphic or rare (MAF < 0.05) in another ethnic group

Fig. 5

Examples of positive selection in East Asians. Selected haplotype forms are shown at five loci positively selected in East Asians. The five loci are near the following SNPs (or genes): a rs12748152 (ZDHHC18), b rs17031005 (THADA), c rs3868143 (KCTD19), d rs1548740 (TANC2) and e rs4253772 (PPARA). Selected haplotypes were identified by haploPS at five sentinel SNPs out of 63 ancestry-specific loci that were identified for complex traits. In the five chromosomal regions each containing the SNP (or locus) of interest, haploPS analyses were performed across a range of core haplotype frequencies from 5 to 95%, with a frequency step size of 5%, in East Asians (including JPT, MAS, CHB, CHS and CHD) as well as Europeans (CEU) and Nigerians in West Africa (YRI) of the HapMap Phase III populations. This yielded the longest haplotype exclusively in East Asians and provided an estimate for the selected allele in its respective population, as shown in the top of each panel. For each locus, haploPS additionally located on the haplotype form on which the advantageous allele is likely to reside; each nucleotide was colored differently, adenine in green, cytosine in blue, guanine in yellow and thymine in red. In each panel, the red vertical bar indicates the position of target SNP, and gene locations (green horizontal bars) are superimposed at the bottom. At two loci, proxy SNPs in complete LD (r² = 1.00 in EAS) with the sentinel SNPs were used for the analysis; rs3868143 and rs1548740 were used instead of rs11862222 and rs56174355, respectively, because of the genotype data unavailability