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      Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease

      , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , the Nontuberculous Mycobacteriosis and Bronchiectasis – Japan Research Consortium (NTM-JRC)
      European Respiratory Journal
      European Respiratory Society (ERS)

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          Abstract

          Rationale

          Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear.

          Objectives

          We aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen.

          Methods

          This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping.

          Results

          The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64×10 −13, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 ( CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18×10 −12, OR 0.54) and European (p=5.12×10 −03, OR 0.63) ancestry.

          Conclusions

          We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

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          Most cited references31

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          Finding the missing heritability of complex diseases.

          Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
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            An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.

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              Is Open Access

              Annotation of functional variation in personal genomes using RegulomeDB

              As the sequencing of healthy and disease genomes becomes more commonplace, detailed annotation provides interpretation for individual variation responsible for normal and disease phenotypes. Current approaches focus on direct changes in protein coding genes, particularly nonsynonymous mutations that directly affect the gene product. However, most individual variation occurs outside of genes and, indeed, most markers generated from genome-wide association studies (GWAS) identify variants outside of coding segments. Identification of potential regulatory changes that perturb these sites will lead to a better localization of truly functional variants and interpretation of their effects. We have developed a novel approach and database, RegulomeDB, which guides interpretation of regulatory variants in the human genome. RegulomeDB includes high-throughput, experimental data sets from ENCODE and other sources, as well as computational predictions and manual annotations to identify putative regulatory potential and identify functional variants. These data sources are combined into a powerful tool that scores variants to help separate functional variants from a large pool and provides a small set of putative sites with testable hypotheses as to their function. We demonstrate the applicability of this tool to the annotation of noncoding variants from 69 full sequenced genomes as well as that of a personal genome, where thousands of functionally associated variants were identified. Moreover, we demonstrate a GWAS where the database is able to quickly identify the known associated functional variant and provide a hypothesis as to its function. Overall, we expect this approach and resource to be valuable for the annotation of human genome sequences.
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                Journal
                European Respiratory Journal
                Eur Respir J
                European Respiratory Society (ERS)
                0903-1936
                1399-3003
                August 12 2021
                August 2021
                August 2021
                February 04 2021
                : 58
                : 2
                : 1902269
                Article
                10.1183/13993003.02269-2019
                33542050
                82508137-e0a8-415a-938c-2f681bf3d6f5
                © 2021

                https://www.ersjournals.com/user-licence

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