Genome-Wide Association Study in Patients with Pulmonary Mycobacterium Avium Complex Disease

2018 ◽  
Author(s):  
Ho Namkoong ◽  
Yosuke Omae ◽  
Takanori Asakura ◽  
Mitsunori Yoshida ◽  
Shoji Suzuki ◽  
...  
Keyword(s):  
Association Study ◽  
Mycobacterium Avium ◽  
Mycobacterium Avium Complex ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Mycobacterium Avium Complex Disease

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

2021 ◽  
pp. 1902269
Author(s):  
Ho Namkoong ◽  
Yosuke Omae ◽  
Takanori Asakura ◽  
Makoto Ishii ◽  
Shoji Suzuki ◽  
...  
Keyword(s):  
Association Study ◽  
Mycobacterium Avium ◽  
Odds Ratio ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Host Susceptibility ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Genome Wide

RationaleNontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear.ObjectivesWe aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen.MethodsThis 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.ResultsThe 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=1.64E−13, odds ratio=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. This SNP was also significantly associated with the disease in patients of Korean (p=2.18E−12, odds ratio=0.54) and European (p=5.12E−03, odds ratio=0.63) ancestry.ConclusionsWe identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

scholarly journals Clustering by phenotype and genome-wide association study in autism

2019 ◽  
Author(s):  
Akira Narita ◽  
Masato Nagai ◽  
Satoshi Mizuno ◽  
Soichi Ogishima ◽  
Gen Tamiya ◽  
...  
Keyword(s):  
Association Study ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Autism Spectrum ◽  
Genome Wide Association ◽  
Second Step ◽  
Cluster Number ◽  
Genome Wide ◽  
Preliminary Study ◽  
Chromosomal Loci

AbstractBackgroundAutism spectrum disorder (ASD) has phenotypically and genetically heterogeneous characteristics. A simulation study demonstrated that attempts to categorize patients with a complex disease into more homogeneous subgroups could have more power to elucidate hidden heritability.MethodsWe conducted cluster analyses using the k-means algorithm with a cluster number of 15 based on phenotypic variables from the Simons Simplex Collection (SSC). As a preliminary study, we conducted a conventional genome-wide association study (GWAS) with a dataset of 597 ASD cases and 370 controls. In the second step, we divided cases based on the clustering results and conducted GWAS in each of the subgroups vs controls (cluster-based GWAS). We also conducted cluster-based GWAS on another SSC dataset of 712 probands and 354 controls in the replication stage.ResultsIn the preliminary study, we observed no significant associations. In the second step of cluster-based GWASs, we identified 65 chromosomal loci, which included 30 intragenic loci located in 21 genes and 35 intergenic loci that satisfied the threshold of P<5.0×10−8. Some of these loci were located within or near previously reported candidate genes for ASD: CDH5, CNTN5, CNTNAP5, DNAH17, DPP10, DSCAM, FOXK1, GABBR2, GRIN2A5, ITPR1, NTM, SDK1, SNCA and SRRM4. Of these 65 significant chromosomal loci, rs11064685 located within the SRRM4 gene had a significantly different distribution in the cases vs. controls in the replication cohort.ConclusionsThese findings suggest that clustering may successfully identify subgroups with relatively homogeneous disease etiologies. Further cluster validation and replication studies are warranted in larger cohorts.

scholarly journals Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci

2021 ◽  
Author(s):  
Tarunveer S Ahluwalia ◽  
Bram P Prins ◽  
Mohammadreza Abdollahi ◽  
Nicola J Armstrong ◽  
Stella Aslibekyan ◽  
...  
Keyword(s):  
Association Study ◽  
Interleukin 6 ◽  
Fixed Effects ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Heritability Estimate ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide ◽  
Increased Risk

Abstract Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

scholarly journals A sex-stratified genome-wide association study of tuberculosis using a multi-ethnic genotyping array

2018 ◽  
Author(s):  
Haiko Schurz ◽  
Craig J Kinnear ◽  
Chris Gignoux ◽  
Genevieve Wojcik ◽  
Paul D van Helden ◽  
...  
Keyword(s):  
Association Study ◽  
X Chromosome ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Interaction Analysis ◽  
Genome Wide Association ◽  
Genotyping Array ◽  
Association Testing ◽  
Genome Wide ◽  
A Genome

AbstractTuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease with a known human genetic component. Males seem to be more affected than females and in most countries the TB notification rate is twice as high in males as in females. While socio-economic status, behaviour and sex hormones influence the male bias they do not fully account for it. Males have only one copy of the X chromosome, while diploid females are subject to X chromosome inactivation. In addition, the X chromosome codes for many immune-related genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sex-biased manner. We report the first TB susceptibility genome-wide association study (GWAS) with a specific focus on sex-stratified autosomal analysis and the X chromosome. Individuals from an admixed South African population were genotyped using the Illumina Multi Ethnic Genotyping Array, specifically designed as a suitable platform for diverse and admixed populations. Association testing was done on the autosome and X chromosome in a sex stratified and combined manner. SNP association testing was not statistically significant using a stringent cut-off for significance but revealed likely candidate genes that warrant further investigation. A genome wide interaction analysis detected 16 significant interactions. Finally, the results highlight the importance of sex-stratified analysis as strong sex-specific effects were identified on both the autosome and X chromosome.

scholarly journals Nonconserved Long Intergenic Noncoding RNAs Associate With Complex Cardiometabolic Disease Traits

2020 ◽  
Author(s):  
Andrea S. Foulkes ◽  
Caitlin Selvaggi ◽  
Tingyi Cao ◽  
Marcella E. O’Reilly ◽  
Esther Cynn ◽  
...  
Keyword(s):  
Association Study ◽  
Large Scale ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Noncoding Rnas ◽  
Transcriptome Profiling ◽  
Genome Wide Association ◽  
Genetic Associations ◽  
Genome Wide ◽  
Cardiometabolic Traits

Objective: Transcriptome profiling of human tissues has revealed thousands of long intergenic noncoding RNAs (lincRNAs) at loci identified through large-scale genome-wide studies for complex cardiometabolic traits. This raises the question of whether genetic variation at nonconserved lincRNAs has any systematic association with complex disease, and if so, how different this pattern is from conserved lincRNAs. We evaluated whether the associations between nonconserved lincRNAs and 8 complex cardiometabolic traits resemble or differ from the pattern of association for conserved lincRNAs. Approach and Results: Our investigation of over 7000 lincRNA annotations from GENCODE Release 33–GRCh38.p13 for complex trait genetic associations leveraged several large, established meta-analyses genome-wide association study summary data resources, including GIANT, UK Biobank, GLGC, Cardiogram, and DIAGRAM/DIAMANTE. These analyses revealed that (1) nonconserved lincRNAs associate with a range of cardiometabolic traits at a rate that is generally consistent with conserved lincRNAs; (2) these findings persist across different definitions of conservation; and (3) overall across all cardiometabolic traits, approximately one-third of genome-wide association study–associated lincRNAs are nonconserved, and this increases to about two-thirds using a more stringent definition of conservation. Conclusions: These findings suggest that the traditional notion of conservation driving prioritization for functional and translational follow-up of complex cardiometabolic genomic discoveries may need to be revised in the context of the abundance of nonconserved long noncoding RNAs in the human genome and their apparent predilection to associate with complex cardiometabolic traits.

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