A genome-wide association study (GWAS) for bronchopulmonary dysplasia

Abstract

Objective: Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD.

Methods: The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip.

Results: Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative.

Conclusions: We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

Keywords: chronic lung disease; genetic predisposition to disease; genome-wide association study (GWAS); premature; very low birth weight infant.

FIGURE 1

Race/ethnicity of study population. A, PC analysis for population stratification. In the left panel, the first PC (PC1) is plotted against the second; in the right panel, the first PC is plotted against the third PC (PC2 and PC3). Each point represents an infant sample, and clusters of PCs represent population substructures. Colors represent self-reported race/ethnicities. Texts in plots indicate directions of genetic ancestries. AA, African American; ASI, Asian; CAU, Caucasian; HISP, Hispanic; NAT, North American Native; NON-HISP, Non-Hispanic; PI, Pacific Islander. B, Estimated proportions of genetic ancestries defined by SNP-typing for our study population. Colors represent ancestries. Each vertical line represents an individual infant, and the vertical spread of a specific color indicates the percentage of a specific ancestry in that individual. The self-reported race/ethnicity is aligned on top of the estimated genetic ancestries. The estimated genetic ancestry has discrepancies with self-reported race/ethnicity and displays a high level of population mixture. The small numbers of “Other” infants (see Table 1) are not illustrated. AA, African American; AFR, African; ASI, Asian; CAU, Caucasian; HISP, Hispanic; NAT, North American Native; PI, Pacific Islander.

FIGURE 2

Manhattan plot of GWAS discovery results. Measured SNPs are represented with triangles, and imputed SNPs are represented with circles. Results are plotted on negative log 10 scale. SNPs in Table 2 are labeled with their gene symbols or chromosomal regions.