Identification of rare variants for hypertension with incorporation of linkage information

We conducted linkage analysis using the genome-wide association study data on chromosome 3, and then assessed association between hypertension and rare variants of genes located in the regions showing evidence of linkage. The rare variants were collapsed if their minor allele frequencies were less than or equal to the thresholds: 0.01, 0.03, or 0.05. In the collapsing process, they were either unweighted or weighted by the nonparametric linkage log of odds scores in 2 different schemes: exponential weighting and cumulative weighting. Logistic regression models using the generalized estimating equations approach were used to assess association between the collapsed rare variants and hypertension adjusting for age and gender. Evidence of association from the weighted and unweighted collapsing schemes with minor allele frequencies ≤0.01, after accounting for multiple testing, was found for genes DOCK3 (p = 0.0090), ARMC8 (p = 1.29E-5), KCNAB1 (p = 5.8E-4), and MYRIP (p = 5.79E-6). DOCK3 and MYRIP are newly discovered. Incorporating linkage scores as weights was found to help identify rare causal variants with a large effect size.