Multiple Subsampling of Dense SNP Data Localizes Disease Genes with Increased Precision

Background/Aims: Current linkage studies detect and localize trait loci using genotypes sampled at hundreds of thousands of single nucleotide polymorphisms (SNPs). Such data should provide precise estimates of trait location once linkage has been established. However, correlations between nearby SNPs can distort the information about trait location. Traditionally, when faced with this dilemma, three approaches have been used: (1) ignore the correlation; (2) approximate the correlation; or, (3) analyze a single, approximately uncorrelated subset of the original dense data

Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants

RATIONALE: Idiopathic pulmonary fibrosis is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to non-genetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants genome-wide may contribute to the risk of IPF remains unknown.OBJECTIVES: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk.METHODS: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ≤0.01) within genes or regions. We also identified individual variants that are influential within genes and estimated the heritability of IPF based on rare and common variants.MEASUREMENTS AND MAIN RESULTS: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP-heritability of IPF was estimated to be 32% (s.e. 3%).CONCLUSIONS: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease

The <i>MUC5B</i> Variant Is Associated with Idiopathic Pulmonary Fibrosis but Not with Systemic Sclerosis Interstitial Lung Disease in the European Caucasian Population

<div><p>A polymorphism on the <i>MUC5B</i> promoter (rs35705950) has been associated with idiopathic pulmonary fibrosis (IPF) but not with systemic sclerosis (SSc) with interstitial lung disease (ILD). We genotyped the <i>MUC5B</i> promoter in the first 142 patients of the French national prospective cohort of IPF, in 981 French patients with SSc (346 ILD), 598 Italian patients with SSc (207 ILD), 1383 French controls and 494 Italian controls. A meta-analysis was performed including all American data available. The T risk allele was present in 41.9% of the IPF patients, 10.8% of the controls (P = 2×10^–44), OR 6.3 [4.6–8.7] for heterozygous patients and OR 21.7 [10.4–45.3] for homozygous patients. Prevalence of the T allele was not modified according to age, gender, smoking in IPF patients. However, none of the black patients with IPF presented the T allele. The prevalence of the T risk allele was similar between French (10%) and Italian (12%) cohorts of SSc whatever the presence of an ILD (11.1% and 13.5%, respectively). Meta-analysis confirmed the similarity between French, Italian and American cohorts of IPF or SSc-ILD. This study confirms 1) an association between the T allele risk and IPF, 2) an absence of association with SSc-ILD, suggesting different pathophysiology.</p></div

Meta-analysis of the <i>MUC5B</i> rs35705950 T allele risk in the three American cohorts and the French cohort of idiopathic pulmonary fibrosis (IPF).

<p>Forrest plots of the meta-analysis of the association of the <i>MUC5B</i> rs35705950 T polymorphism and IPF. Bars represent the 95% interval.</p

Meta-analysis of the <i>MUC5B</i> rs35705950 T allele risk in the two European (French and Italian) cohorts and the American cohort of systemic sclerosis (SSc).

<p>Forrest plots of the meta-analysis of the association of the <i>MUC5B</i> rs35705950 T polymorphism and (A) all SSc and (B) SSc with interstitial lung disease. Bars represent the 95% interval.</p