Genome-wide scan identifies CDH13 as a novel susceptibility locus contributing to blood pressure determination in two European populations

Abstract

Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel approach to search for genetic variants contributing to complex diseases. We conducted GWAS for three BP traits [systolic and diastolic blood pressure (SBP and DBP); hypertension (HYP)] in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort (n = 1644) recruited from general population in Southern Germany. GWAS with 395,912 single nucleotide polymorphisms (SNPs) identified an association between BP traits and a common variant rs11646213 (T/A) upstream of the CDH13 gene at 16q23.3. The initial associations with HYP and DBP were confirmed in two other European population-based cohorts: KORA S4 (Germans) and HYPEST (Estonians). The associations between rs11646213 and three BP traits were replicated in combined analyses (dominant model: DBP, P = 5.55 x 10(-5), effect -1.40 mmHg; SBP, P = 0.007, effect -1.56 mmHg; HYP, P = 5.30 x 10(-8), OR = 0.67). Carriers of the minor allele A had a decreased risk of hypertension. A non-significant trend for association was also detected with severe family based hypertension in the BRIGHT sample (British). The novel susceptibility locus, CDH13, encodes for an adhesion glycoprotein T-cadherin, a regulator of vascular wall remodeling and angiogenesis. Its function is compatible with the BP biology and may improve the understanding of the pathogenesis of hypertension.

Figure 1.

Quantile–quantile plots of the χ² statistic obtained from GWA analysis for SBP under the additive genetic model in the KORA S3 500K sample. The distribution of log₁₀(P) of association tests is shown before (black dots) and after (green dots) correction for population stratification performed by principal component analysis using the EIGENSOFT software (21). A genomic control analysis led to an inflation factor (λ) of 1.02.

Figure 2.

Genomic region of the rs11646213 associated with BP traits at 16q23.3. The upper part of the panel shows the chromosomal location of the SNP along with a flanking microsatellite D16S515 reported to be linked with BP traits (11,12). The middle part of the panel represents a plot of P-values from the genome-wide scan (654 SNPs) in KORA S3 with HYP (open triangle; logistic regression), SBP and DBP (open circle and open square, linear regression), and from the combined analysis of the population-based cohort samples KORA S3 (GWAS), KORA S4 and HYPEST under the dominant genetic model. The x-axis represents the genomic position (NCBI build 35) and the y-axis shows –log₁₀ (P-value). The lower part of the panel shows the gene content and linkage disequilibrium (LD) pattern (pairwise r²; KORA S3) of the genomic region. HYP, hypertension; SBP, systolic blood pressure; DBP, diastolic blood pressure; GWAS, genome-wide association study.

Figure 3.

Mean and SEM of SBP (A and C) and DBP (B and D) among minor allele carriers and non-carriers of rs11646213 in combined KORA S3 + S4 cohorts (total n = 2497) and HYPEST samples (total n = 1060) stratified by age. In KORA (A and B), the sample sizes in different age groups ranged from 351 to 739 for minor allele carriers (AA+AT) and from 189 to 367 for major allele homozygotes (TT). In HYPEST (C and D), the sample sizes in different age groups ranged from 58 to 455 for minor allele carriers (AA+AT) and from 53 to 297 for major allele homozygotes (TT).