Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma

Nat Commun. 2015 Jan 16;6:5965. doi: 10.1038/ncomms6965.

Abstract

Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1-5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case-parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10(-6); OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P=7.81 × 10(-8) and 4.09 × 10(-8), respectively) and MTHFR in the African ancestry sample (P=1.72 × 10(-6)). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the 'missing heritability' of asthma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asthma / genetics*
  • Carrier Proteins / genetics
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods*
  • Humans
  • Linkage Disequilibrium / genetics
  • Male
  • Membrane Proteins / genetics
  • Neoplasm Proteins / genetics

Substances

  • Carrier Proteins
  • GSDMB protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • tamalin protein, human