Susceptibility gene hunting for recurrent unipolar depression using 400k genome-wide genotype data

Recurrent unipolar depression (RUD) is a complex disorder. Meta-analysis on phenotypes related to such disorders revealed genotype relative risk (GRR) for common genetic markers in the range of 1.15–1.5. We estimated to have 60% of power to detect an association for a common marker (MAF=0.5) with an GRR of 1.5 for a recessive genotypic model in our RUD case-control sample (223 cases, 370 controls, prevalence: 0.16, α=0.05). In respect of multiple testing in our genome-wide study the power to detect such an effect became near null. We hypothesised that risk factors for RUD might accelerate the disease process resulting in lower mean age at onset (AAO) of RUD. This potential relationship between risk factors and AAO might be useful to detect real positive associations under conditions of insufficient power. We performed genome-wide case-control and AAO of RUD association analysis. P-values for both phenotypes were ranked. SNPs with the smallest rang sum of tests for both phenotypes for which the disease risk genotype matches the one having the smallest AAO of RUD were selected. We identified 909 tests corresponding to 716 SNPs in 277 genes with nominal p-values <0.05 for both phenotypes. This number is about 3% higher as expected by chance giving 23 expected real positive hypotheses. The best-ranking tests with expected power of higher than 90% in our independent RUD case-control sample (1000 cases vs. 1029 controls) might be the most promising replication candidates.