Background: Genome-wide association study (GWAS) has not been reported for persistent pulmonary hypertension of the newborn (PPHN). Previous studies proposed several genetic risks that may explain the small proportion of the genetic contribution for PPHN.
Objective: To identify genetic variants associated with PPHN using a GWAS.
Methods: This study was carried out in Thai subjects, including 45 PPHN patients and 294 normal subjects as a control group. Total of 659,184 SNPs were genotyped across the genome using Illumina Asian Screening Array-24 v1.0 BeadChip Array. We applied standard SNP quality control filters to exclude SNPs with a low call rate (<98%), a Hardy–Weinberg equilibrium (p-value<1x10-8) for controls. A principal component analysis was performed to exclude genetic outliers and confirm the absence of significant genetic stratification between cases and controls. After quality control, we obtained 498,160 autosomal SNPs for the GWAS analysis.
Results: In this study, the genomic inflation factor, lambda, was 1.008 and the Manhattan plots are presented in Figure 1. Two SNPs, rs140276032 (P=5.04x10-9) noted to be in the intergenic region in proximity to genes for the CDC14C gene and rs149768622 (P=3.40x10-8) located in the intron of WWC2 gene, achieved genome-wide significance (P<1x10-8). Other top-ten suggestive SNPs (P<1x10-5) were also identified. Of these, five (rs56074206, rs76080291, rs116280349, rs187729743, rs145552555) was located in the intron of five candidate genes (CIT, HDAC2, LOC100188947, LCORL, CYP39A1, respectively), and another 5 SNPs (rs375826735, rs143692554, rs140485153, rs141311709, rs10239513) was noted to be in intergenic regions. One SNPs (rs17034984) at the intron of the EPAS1 gene passed the Bonferroni threshold for significance was identified (P=0.00014)
Conclusions: This preliminary GWAS analysis showed that CDC14C and WWC2 might be associated with PPHN. In addition, our findings suggest that EPAS1 gene might be a key factor to contribute to the development of PPHN. However, with a larger sample size are necessary to validate this association.