Heritability and genome-wide association study of diffusing capacity of the lung

Terzikhan, Natalie; Sun, Fangui; Verhamme, Fien; Adams, Hieab H.H.; Loth, Daan W.; Bracke, Ken R.; Stricker, Bruno H. Ch.; Lahousse, Lies; Dupuis, Josée; Brusselle, Guy; O'Conner, Greorge T

doi:10.1101/277343

Cited by 4 publications

(7 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These estimates may imply that there is a similar extent of genetic control to DL CO in our COPD-enriched populations and general population samples. However, these estimates from common SNPs in unrelated individuals were lower than estimated in related individuals from the Framingham Heart Study (49%; SE, 3%) or a twin study of females (39%; SE not reported) (36), as previously reported (14). Though the twin study previously showed sexual dimorphism of DL CO heritability (36), our heritability estimates in male and female subjects were similar.…”

Section: Discussionsupporting

confidence: 50%

“…Another study also found a significant association between a missense variant (p.Thr663Ala) in SCNN1A (sodium channel epithelial 1 a-subunit) and DL CO in response to exercise (38). Recently, a GWAS of DL CO and the carbon monoxide transfer coefficient (K CO ) in a general population sample identified association of the ADGRG6 locus with K CO but not for DL CO (14). The previously reported K CO -associated variant in ADGRG6 (rs17280293) is nominally significant in our study of DL CO (P = 0.03).…”

Section: Discussionmentioning

confidence: 98%

“…This approach has been applied to many respiratory diseases, including COPD (11), and quantitative traits such as emphysema (12) and spirometry (13). Recently, researchers in a genome-wide association study (GWAS) of DL CO reported a significant heritability estimate of DL CO in population-based cohorts, although no genome-wide significant associations for DL CO have been identified (14). We hypothesized that elucidating genetic determinants of DL CO in cohorts including larger proportions of COPD cases could lead to better understanding of the genetic architecture of COPD.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Genome-Wide Association Analysis of Single-Breath Dl_CO

Sakornsakolpat¹,

McCormack²,

Bakke

et al. 2019

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

DL CO is a widely used pulmonary function test in clinical practice and a particularly useful measure for assessing patients with chronic obstructive pulmonary disease (COPD). We hypothesized that elucidating genetic determinants of DL CO could lead to better understanding of the genetic architecture of COPD. We estimated the heritability of DL CO using common genetic variants and performed genome-wide association analyses in four cohorts enriched for subjects with COPD (COPDGene [Genetic Epidemiology of COPD], NETT [National Emphysema Treatment Trial], GenKOLS [Genetics of Chronic Obstructive Lung Disease study], and TESRA [Treatment of Emphysema With a Gamma-Selective Retinoid Agonist study]) using a combined European ancestry white dataset and a COPDGene African American dataset. We assessed our genome-wide significant and suggestive associations for DL CO in previously reported genomewide association studies of COPD and related traits. We also characterized associations of known COPD-associated variants and DL CO . We estimated the SNP-based heritability of DL CO in the European ancestry white population to be 22% (P = 0.0004). We identified three genome-wide significant associations with DL CO : variants near TGFB2, CHRNA3, and PDE11A loci (P , 5 3 10 28 ). In addition, 12 loci were suggestively associated with DL CO in European ancestry white (P , 1 3 10 25 in the combined analysis and P , 0.05 in both COPDGene and GenKOLS), including variants near NEGR1, CADM2, PCDH7, RETREG1, DACT2, NRG1, ANKRD18A, KRT86, NTN4, ARHGAP28, INSR, and PCBP3. Some DL CO -associated variants were also associated with COPD, emphysema, and/or spirometric values. Among 25 previously reported COPD loci, TGFB2, CHRNA3/CHRNA5, FAM13A, DSP, and CYP2A6 were associated with DL CO (P , 0.001). We identified several genetic loci that were significantly associated with DL CO and characterized effects of known COPD-associated loci on DL CO . These results could lead to better understanding of the heterogeneous nature of COPD.

show abstract

Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

See 1 more Smart Citation

Genome-Wide Association Analysis of Single-Breath Dl_CO

Sakornsakolpat¹,

McCormack²,

Bakke

et al. 2019

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…One of these variants, resulting in the missense mutation S123G, was also identified in Andean people living at altitude, suggesting it may be involved in the physiological adaptation to hypobaric hypoxia (Eichstaedt et al, 2017). A separate analysis of this variant found that expression of ADGRG6 in human lung tissue was decreased in COPD patients and in individuals with decreased pulmonary ventilatory function, suggesting this variant may also be functional (Terzikhan et al, 2018).…”

Section: Adgrg6 and Human Diseasementioning

confidence: 99%

The adhesion GPCR Adgrg6 (Gpr126): Insights from the zebrafish model

Baxendale

Asad

Shahidan

et al. 2021

Genesis

View full text Add to dashboard Cite

Summary Adhesion GPCRs are important regulators of conserved developmental processes and represent an untapped pool of potential targets for drug discovery. The adhesion GPCR Adgrg6 (Gpr126) has critical developmental roles in Schwann cell maturation and inner ear morphogenesis in the zebrafish embryo. Mutations in the human ADGRG6 gene can result in severe deficits in peripheral myelination, and variants have been associated with many other disease conditions. Here, we review work on the zebrafish Adgrg6 signaling pathway and its potential as a disease model. Recent advances have been made in the analysis of the structure of the Adgrg6 receptor, demonstrating alternative structural conformations and the presence of a conserved calcium‐binding site within the CUB domain of the extracellular region that is critical for receptor function. Homozygous zebrafish adgrg6 hypomorphic mutants have been used successfully as a whole‐animal screening platform, identifying candidate molecules that can influence signaling activity and rescue mutant phenotypes. These compounds offer promise for further development as small molecule modulators of Adgrg6 pathway activity.

show abstract

“…Additional studies have shown that this regulatory function of Gpr126 is conserved in mammals 41,42 and that Gpr126 also plays a role in myelin maintenance through communication with the cellular prion protein 43 . In humans, GPR126 mutations are linked to several cancers and other diseases 44,45,46,47,48 , including adolescent idiopathic scoliosis 49 and arthrogryposis multiplex congenita, a disorder characterized by multiple joint contractures 50 . Furthermore, Gpr126 is required for inner ear development in zebrafish 35 and GPR126 is required for heart development in mouse 37 , and it has been shown that the latter function is ECR-dependent and does not require the 7TM 30 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis for adhesion G protein-coupled receptor Gpr126 function

Leon

Cunningham

Riback

et al. 2019

Preprint

View full text Add to dashboard Cite

Many drugs target the extracellular regions (ECRs) of cell-surface receptors. The large and alternatively-spliced ECRs of adhesion G protein-coupled receptors (aGPCRs) have key functions in diverse biological processes including neurodevelopment, embryogenesis, and tumorigenesis. However, their structures and mechanisms of action remain unclear, hampering drug development. The aGPCR Gpr126/Adgrg6 regulates Schwann cell myelination, ear canal formation, and heart development; and GPR126 mutations cause myelination defects in human.Here, we determine the structure of the complete zebrafish Gpr126 ECR and reveal five domains including a previously-unknown domain. Strikingly, the Gpr126 ECR adopts a closed conformation that is stabilized by an alternatively spliced linker and a conserved calcium-binding site. Alternative splicing regulates ECR conformation and receptor signaling, while mutagenesis of the newly-characterized calcium-binding site abolishes Gpr126 function in vivo. These results demonstrate that Gpr126 ECR utilizes a multi-faceted dynamic approach to regulate receptor function and provide novel insights into ECR-targeted drug design.

show abstract

Heritability and genome-wide association study of diffusing capacity of the lung

Cited by 4 publications

References 25 publications

Genome-Wide Association Analysis of Single-Breath Dl_CO

Genome-Wide Association Analysis of Single-Breath Dl_CO

The adhesion GPCR Adgrg6 (Gpr126): Insights from the zebrafish model

Structural basis for adhesion G protein-coupled receptor Gpr126 function

Contact Info

Product

Resources

About

Heritability and genome-wide association study of diffusing capacity of the lung

Cited by 4 publications

References 25 publications

Genome-Wide Association Analysis of Single-Breath DlCO

Genome-Wide Association Analysis of Single-Breath DlCO

The adhesion GPCR Adgrg6 (Gpr126): Insights from the zebrafish model

Structural basis for adhesion G protein-coupled receptor Gpr126 function

Contact Info

Product

Resources

About

Genome-Wide Association Analysis of Single-Breath Dl_CO

Genome-Wide Association Analysis of Single-Breath Dl_CO