Asthma Genetics in the Post-GWAS Era.

Genome-wide association studies (GWAS) of asthma have yielded exciting results and identified novel risk alleles and loci. But, like other common complex diseases, asthma-associated alleles have small effect sizes and account for little of the prevalence of asthma. In this review, I discuss the limitations of GWAS approaches and the major challenges facing geneticists in the post-GWAS era and propose alternative strategies to address these challenges. In particular, I propose that focusing on genetic variations that influences gene expression and using cell models of gene-environment interactions in cell types that are relevant to asthma will allow us to more completely characterize the genetic architecture of asthma.

[1]  D. Nicolae,et al.  Genome-Wide Methylation Study Identifies an IL-13-induced Epigenetic Signature in Asthmatic Airways. , 2016, American journal of respiratory and critical care medicine.

[2]  M. Obeidat,et al.  Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases. , 2016, American journal of respiratory cell and molecular biology.

[3]  K. Bønnelykke,et al.  Association between respiratory infections in early life and later asthma is independent of virus type , 2015, Journal of Allergy and Clinical Immunology.

[4]  Daniel J. Jackson,et al.  Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication , 2015, Proceedings of the National Academy of Sciences.

[5]  Samuel W. Baker,et al.  Host Genetic Variation Influences Gene Expression Response to Rhinovirus Infection , 2015, PLoS genetics.

[6]  Scott T. Weiss,et al.  Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma , 2015, Nature Communications.

[7]  B. Frey,et al.  The human splicing code reveals new insights into the genetic determinants of disease , 2015, Science.

[8]  S. Rosset,et al.  Measuring missing heritability: Inferring the contribution of common variants , 2014, Proceedings of the National Academy of Sciences.

[9]  Adan Valladares-Salgado,et al.  Cross-tissue and tissue-specific eQTLs: partitioning the heritability of a complex trait. , 2014, American journal of human genetics.

[10]  Han Xu,et al.  Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. , 2014, American journal of human genetics.

[11]  C J Lodge,et al.  CD14 polymorphisms, microbial exposure and allergic diseases: a systematic review of gene–environment interactions , 2014, Allergy.

[12]  Chun Jimmie Ye,et al.  Intersection of population variation and autoimmunity genetics in human T cell activation , 2014, Science.

[13]  John D. Blischak,et al.  Methylation QTLs Are Associated with Coordinated Changes in Transcription Factor Binding, Histone Modifications, and Gene Expression Levels , 2014, bioRxiv.

[14]  Manuel A. R. Ferreira,et al.  Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype. , 2014, The Journal of allergy and clinical immunology.

[15]  Peggy Hall,et al.  The NHGRI GWAS Catalog, a curated resource of SNP-trait associations , 2013, Nucleic Acids Res..

[16]  Joseph K. Pickrell Joint analysis of functional genomic data and genome-wide association studies of 18 human traits , 2013, bioRxiv.

[17]  Thomas Blicher,et al.  A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations , 2013, Nature Genetics.

[18]  Jonathan K. Pritchard,et al.  Identification of Genetic Variants That Affect Histone Modifications in Human Cells , 2013, Science.

[19]  Kari Stefansson,et al.  Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization , 2013, Nature Genetics.

[20]  Hans Bisgaard,et al.  Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. , 2013, The New England journal of medicine.

[21]  M. Love,et al.  Airway epithelial miRNA expression is altered in asthma. , 2012, American journal of respiratory and critical care medicine.

[22]  David C. Nickle,et al.  Lung eQTLs to Help Reveal the Molecular Underpinnings of Asthma , 2012, PLoS genetics.

[23]  Manuel A. R. Ferreira,et al.  Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA , 2012, PloS one.

[24]  Shane J. Neph,et al.  Systematic Localization of Common Disease-Associated Variation in Regulatory DNA , 2012, Science.

[25]  A. Hofman,et al.  Interaction of a 17q12 variant with both fetal and infant smoke exposure in the development of childhood asthma‐like symptoms , 2012, Allergy.

[26]  L. Wain,et al.  Genome-wide association study to identify genetic determinants of severe asthma , 2011, Thorax.

[27]  John C. Marioni,et al.  Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection , 2012, Proceedings of the National Academy of Sciences.

[28]  E. Lander,et al.  The mystery of missing heritability: Genetic interactions create phantom heritability , 2012, Proceedings of the National Academy of Sciences.

[29]  Ryan D. Hernandez,et al.  Meta-analysis of Genome-wide Association Studies of Asthma In Ethnically Diverse North American Populations , 2011, Nature Genetics.

[30]  P. Visscher,et al.  Estimating missing heritability for disease from genome-wide association studies. , 2011, American journal of human genetics.

[31]  Carole Ober,et al.  Gene-environment interactions in human disease: nuisance or opportunity? , 2011, Trends in genetics : TIG.

[32]  Runze Li,et al.  A dynamic model for genome-wide association studies , 2011, Human Genetics.

[33]  Florence Demenais,et al.  A large-scale, consortium-based genomewide association study of asthma. , 2010, The New England journal of medicine.

[34]  D. Duffy,et al.  Genetic influence on the age at onset of asthma: a twin study. , 2010, The Journal of allergy and clinical immunology.

[35]  G. Gibson Hints of hidden heritability in GWAS , 2010, Nature Genetics.

[36]  Jason H. Moore,et al.  Missing heritability and strategies for finding the underlying causes of complex disease , 2010, Nature Reviews Genetics.

[37]  D. Postma,et al.  A sequence variant on 17q21 is associated with age at onset and severity of asthma , 2010, European Journal of Human Genetics.

[38]  N. Cox,et al.  Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS , 2010, PLoS genetics.

[39]  David N Cooper,et al.  GWAS: heritability missing in action? , 2010, European Journal of Human Genetics.

[40]  Aiqing He,et al.  Systems genetics analysis of gene-by-environment interactions in human cells. , 2010, American journal of human genetics.

[41]  A. Simpson,et al.  The role of lipopolysaccharide in the development of atopy in humans , 2010, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[42]  F Kauffmann,et al.  17q21 variants modify the association between early respiratory infections and asthma , 2009, European Respiratory Journal.

[43]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[44]  Joseph T. Glessner,et al.  17q12-21 variants interact with smoke exposure as a risk factor for pediatric asthma but are equally associated with early-onset versus late-onset asthma in North Americans of European ancestry. , 2009, The Journal of allergy and clinical immunology.

[45]  F. Collins,et al.  Potential etiologic and functional implications of genome-wide association loci for human diseases and traits , 2009, Proceedings of the National Academy of Sciences.

[46]  Florence Demenais,et al.  CD14 and toll-like receptor gene polymorphisms, country living, and asthma in adults. , 2009, American journal of respiratory and critical care medicine.

[47]  Cecilia Kim,et al.  Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. , 2009, American journal of respiratory and critical care medicine.

[48]  J. Bousquet,et al.  Effect of 17q21 variants and smoking exposure in early-onset asthma. , 2008, The New England journal of medicine.

[49]  Wai-ming Lee,et al.  Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. , 2008, American journal of respiratory and critical care medicine.

[50]  D. Postma,et al.  Interleukin 13, CD14, pet and tobacco smoke influence atopy in three Dutch cohorts: the allergenic study , 2008, European Respiratory Journal.

[51]  W. G. Hill,et al.  Heritability in the genomics era — concepts and misconceptions , 2008, Nature Reviews Genetics.

[52]  T Sigsgaard,et al.  Atopy and new‐onset asthma in young Danish farmers and CD14, TLR2, and TLR4 genetic polymorphisms: a nested case‐control study , 2007, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[53]  Yee Hwa Yang,et al.  Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids , 2007, Proceedings of the National Academy of Sciences.

[54]  B. Brunekreef,et al.  Not all farming environments protect against the development of asthma and wheeze in children. , 2007, The Journal of allergy and clinical immunology.

[55]  I. Pin,et al.  Association between farm exposure and atopy, according to the CD14 C-159T polymorphism. , 2006, The Journal of allergy and clinical immunology.

[56]  A. Woodcock,et al.  Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment. , 2006, American journal of respiratory and critical care medicine.

[57]  D. Nowak,et al.  Opposite effects of CD 14/-260 on serum IgE levels in children raised in different environments. , 2005, The Journal of allergy and clinical immunology.

[58]  D. Nicolae,et al.  Effects of dog ownership and genotype on immune development and atopy in infancy. , 2004, The Journal of allergy and clinical immunology.

[59]  R. Vainionpää,et al.  Rhinovirus-induced wheezing in infancy—the first sign of childhood asthma?☆☆☆ , 2003, Journal of Allergy and Clinical Immunology.

[60]  R. Lemanske The Childhood Origins of Asthma (COAST) study , 2002, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[61]  J. Bach,et al.  The effect of infections on susceptibility to autoimmune and allergic diseases. , 2002, The New England journal of medicine.

[62]  R. Beasley,et al.  The burden of asthma with specific reference to the United States. , 2002, The Journal of allergy and clinical immunology.

[63]  Dennis Nowak,et al.  Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey , 2001, The Lancet.

[64]  B. Kjellman,et al.  Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. , 2000, American journal of respiratory and critical care medicine.

[65]  E. Mutius,et al.  Reduced risk of hay fever and asthma among children of farmers , 2000, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[66]  W. Eder,et al.  Austrian children living on a farm have less hay fever, asthma and allergic sensitization , 2000, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[67]  D. Sherrill,et al.  Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years , 1999, The Lancet.

[68]  P. Holt,et al.  A Polymorphism* in the 5' flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. , 1999, American journal of respiratory cell and molecular biology.

[69]  B. Wüthrich,et al.  Prevalence of hay fever and allergic sensitization in farmer's children and their peers living in the same rural community , 1999, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[70]  J. Kaprio,et al.  A population-based study of bronchial asthma in adult twin pairs. , 1991, Chest.

[71]  D. Duffy,et al.  Genetics of asthma and hay fever in Australian twins. , 1990, The American review of respiratory disease.

[72]  B. Butland,et al.  Changes in asthma prevalence: two surveys 15 years apart. , 1989, Archives of disease in childhood.