Genome-wide burden and association analyses implicate copy number variations in asthma risk among children and young adults from Latin America

Pablo Oliveira,Gustavo N O Costa,Fernanda S Kehdy,Rosemeire L Fiaccone,Fernando P Hartwig,George C G Barbosa,Alexandre Pereira,Andresa K A Damasceno,Laura C Rodrigues,Camila A Figueiredo,M Fernanda Lima-Costa,Eduardo Tarazona-Santos,Maurício L Barreto,Bernardo L Horta,Rita De C Ribeiro-Silva

doi:10.1038/s41598-018-32837-w

Abstract

The genetic architecture of asthma was relatively well explored. However, some work remains in the field to improve our understanding on asthma genetics, especially in non-Caucasian populations and with regards to commonly neglected genetic variants, such as Copy Number Variations (CNVs). In the present study, we investigated the contribution of CNVs on asthma risk among Latin Americans. CNVs were inferred from SNP genotyping data. Genome wide burden and association analyses were conducted to evaluate the impact of CNVs on asthma outcome. We found no significant difference in the numbers of CNVs between asthmatics and non-asthmatics. Nevertheless, we found that CNVs are larger in patients then in healthy controls and that CNVs from cases intersect significantly more genes and regulatory elements. We also found that a deletion at 6p22.1 is associated with asthma symptoms in children from Salvador (Brazil) and in young adults from Pelotas (Brazil). To support our results, we conducted an in silico functional analysis and found that this deletion spans several regulatory elements, including two promoter elements active in lung cells. In conclusion, we found robust evidence that CNVs could contribute for asthma susceptibility. These results uncover a new perspective on the influence of genetic factors modulating asthma risk.

Highlights

Asthma is a chronic inflammatory disorder of the airways characterized by reversible airflow obstruction
Copy number variations in the genome of admixed children from Salvador (Northeast Region of Brazil) (Table 1) were inferred from small nucleotide polymorphism (SNP) genotyping data (Illumina HumanOmni 2.5–8v1 panel) using two distinct algorithms implemented in PennCNV and QuantiSNP
To combine Copy Number Variations (CNVs) corresponding to the same event, deletions or duplications showing sequence overlap were grouped into a single copy number variation region (CNVR)

Summary

Introduction

Asthma is a chronic inflammatory disorder of the airways characterized by reversible airflow obstruction. Several large-scale studies, applying mainly small nucleotide polymorphism (SNP) microarrays and whole genome sequencing, have identified multiple short variants (rare and common) associated with asthma in different loci, including: 1q31.3 (DENND1B), 2q12.1 (IL1RL1/IL18R1), 5q12.1 (PDE4D), 5q22.1 (TSLP/WDR36), 5q31.1 (IL13), 6p21.32 (HLA-DR/DQ), 9p24.1 (IL33), 14q11.2 (DAD1/OXAL1L), 15q22.2 (FOXB1) and 17q21.1 (ORMDL3/GSDMB)[15,16,17,18,19,20] Due to all these efforts, the genetic architecture of asthma is relatively well known, with the genetic factors identified so far explaining a reasonable proportion of the heritability attributed to the disease (varying between 35% and 95%)[21]. We conducted a genome wide copy number variation study based in our previously published SNP genotyping data[19] to investigate the contribution of CNVs on asthma risk in Latin American admixed populations

Methods

Results

Conclusion