Whole Genome Sequencing Identifies Novel Functional Loci Associated With Lung Function in Puerto Rican Youth

Am J Respir Crit Care Med. 2020 May 27. doi: 10.1164/rccm.202002-0351OC. Online ahead of print.


Rationale: Puerto Ricans have the highest childhood asthma prevalence in the United States (23.6%), however, the etiology is uncertain.

Objective: In this study, we sought to uncover the genetic architecture of lung function in Puerto Rican youth with and without asthma who were recruited from the island (n=836).

Methods: We used admixture mapping and whole genome sequencing (WGS) data to discover genomic regions associated with lung function. Functional roles of the prioritized candidate SNPs were examined with chromatin immunoprecipitation sequencing (ChIP-seq), RNA-seq, and expression quantitative trait loci (eQTL) data.

Measurements and main results: We discovered a genomic region at 1q32 that was significantly associated with a 0.12 liter decrease in the lung volume of exhaled air [95%CI: -0.17 to -0.07, p-value=6.62×10-8] with each allele of African ancestry. Within this region, two SNPs were eQTLs of TMEM9 in nasal airway epithelial cells and MROH3P in esophagus mucosa. The minor alleles of these SNPs were associated with significantly decreased lung function and decreased TMEM9 gene expression. Another admixture mapping peak was observed on chromosome 5q35.1, indicating that each Native American ancestry allele was associated with 0.15 liter increase in lung function [95%CI: 0.08 to 0.21, p-value=5.03 ×10-6]. The region-based association tests identified 4 suggestive windows that harbored candidate rare variants associated with lung function.

Conclusions: We identified common and rare genetic variants that may play a critical role in lung function among Puerto Rican youth. We independently validated an inflammatory pathway that could potentially be used to develop more targeted treatments and interventions for patients with asthma.

Keywords: FEV1; RNA-seq; TMEM9; admixed; inflammatory.