Genome-wide association study identifies five loci associated with lung function

Repapi, Emmanouela; Sayers, Ian; Wain, Louise V.; Burton, Paul R.; Johnson, Toby; Obeidat, Ma’en; Zhao, Jing Hua; Ramasamy, Adaikalavan; Zhai, Guangju; Vitart, Véronique; Huffman, Jennifer E.; Igl, Wilmar; Albrecht, Eva; Deloukas, Panos; Henderson, John; Granell, Raquel; McArdle, Wendy L.; Rudnicka, Alicja R.; Barroso, Inês; Loos, Ruth J.F.; Wareham, Nicholas J.; Mustelin, Linda; Rantanen, Taina; Surakka, Ida; Imboden, Medea; Wichmann, H‐Erich; Grković, Ivica; Janković, Stipan; Zgaga, Lina; Al, Hartikainen; Peltonen, Leena; Gyllensten, Ulf; Johansson, Åsa; Zaboli, Ghazal; Campbell, Harry; Wild, Sarah H.; Wilson, James F.; Gläser, Sven; Homuth, Georg; Völzke, Henry; Mangino, Massimo; Soranzo, Nicole; Spector, Tim D.; Polašek, Ozren; Rudan, Igor; Wright, Alan F.; Heliövaara, Markku; Ripatti, Samuli; Pouta, Anneli; Naluai, Åsa Torinsson; Ac, Olin; Torén, Kjell; Cooper, Matthew N.; James, Alan; Palmer, Lyle J.; Hingorani, Aroon D.; Wannamethee, S. Goya; Whincup, Peter H.; Smith, George Davey; Ebrahim, Shah; McKeever, Tricia M.; Pavord, Ian D.; MacLeod, Andy; Morris, Andrew D.; Porteous, David J.; Cooper, Christopher S.; Dennison, Elaine; Shaheen, Seif O.; Karrasch, Stefan; Schnabel, Eva; Schulz, Holger; Grallert, Harald; Bouatia-Naji, Nabila; Delplanque, Jérôme; Froguel, Philippe; Blakey, John; Britton,; Morris, Richard; Holloway, John W.; Lawlor, Debbie A.; Hui, Jennie; Nyberg, Fredrik; Järvelin, Marjo‐Riitta; Jackson, Catherine; Kähönen, Mika; Kaprio, Jaakko; Probst‐Hensch, Nicole; Koch, Beate; Hayward, Caroline; Evans, David M.; Elliott, Paul; Strachan, David P.; Hall, Ian P.; Tobin, Martin D.

doi:10.1038/ng.501

Cited by 523 publications

(552 citation statements)

References 39 publications

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“…Furthermore, NDUFC2 may represent a novel oncogene involved in breast cancer and intestinal adenocarcinoma, predicting poor prognosis 39, 40. Notably, the pathological relevance of NDUFC2/rs11237379 has been also highlighted through genome‐wide association studies in pulmonary disease 41, 42…”

Section: Discussionmentioning

confidence: 99%

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease

Rubattu

Castro

Schulz

et al. 2016

JAHA

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BackgroundThe genetic basis of stroke susceptibility remains to be elucidated. STR1 quantitative trait locus (STR1/QTL) was identified on rat chromosome 1 of stroke‐prone spontaneously hypertensive rat (SHRSP) upon Japanese‐style stroke‐permissive diet (JD), and it contributes to 20% of the stroke phenotype variance.Methods and ResultsNine hundred eighty‐six probe sets mapping on STR1 were selected from the Rat RAE230A array and screened through a microarray differential expression analysis in brains of SHRSP and stroke‐resistant SHR (SHRSR) fed with either regular diet or JD. The gene encoding Ndufc2 (NADH dehydrogenase [ubiquinone] 1 subunit), mapping 8 Mb apart from STR1/QTL Lod score peak, was found significantly down‐regulated under JD in SHRSP compared to SHRSR. Ndufc2 disruption altered complex I assembly and activity, reduced mitochondrial membrane potential and ATP levels, and increased reactive oxygen species production and inflammation both in vitro and in vivo. SHRSR carrying heterozygous Ndufc2 deletion showed renal abnormalities and stroke occurrence under JD, similarly to SHRSP. In humans, T allele variant at NDUFC2/rs11237379 was associated with significant reduction in gene expression and with increased occurrence of early‐onset ischemic stroke by recessive mode of transmission (odds ratio [OR], 1.39; CI, 1.07–1.80; P=0.012). Subjects carrying TT/rs11237379 and A allele variant at NDUFC2/rs641836 had further increased risk of stroke (OR=1.56; CI, 1.14–2.13; P=0.006).ConclusionsA significant reduction of Ndufc2 expression causes complex I dysfunction and contributes to stroke susceptibility in SHRSP. Moreover, our current evidence may suggest that Ndufc2 can contribute to an increased occurrence of early‐onset ischemic stroke in humans.

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Section: Discussionmentioning

confidence: 99%

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease

Rubattu

Castro

Schulz

et al. 2016

JAHA

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“…However, the results of many small candidate gene studies have been inconsistent (9,10). Genomewide association studies (GWASs) of COPD (11)(12)(13) have, to date, identified three susceptibility loci that have been well replicated (14)(15)(16)(17)(18)(19)(20)(21). We report the results of a follow-up GWAS in four cohorts that identifiy a new COPD susceptibility locus.…”

Section: Introductionmentioning

confidence: 99%

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

Cho

Castaldi

Hersh

et al. 2011

A95. Cutting Edge Insights to the Pathobiology of Copd and Interstitial Lung Disease

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The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genomewide significant locus on chromosome 19q13 (rs7937, OR 5 0.74, P 5 2.9 3 10 29 ). Genotyping this single * Molecular Genetics, 2012, Vol. 21, No. 4 947-957 doi:10.1093/hmg/ddr524 Advance Access published on November 11, 2011nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P 5 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV 1 (P 5 0.08 and 0.04) and severe (GOLD 3&4) COPD (P 5 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.

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“…Even in normal healthy individuals there is variation in lung function. Meta-analysis of genome-wide studies (16 studies totaling >40,000 individuals) identified loci associated with natural variations in lung function of healthy volunteers (Hancock et al, 2010;Repapi et al, 2010). These loci included HHIP and PTCH1 which are both required for lung development in mice (Chuang et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The building blocks of mammalian lung development

Rawlins

2010

Developmental Dynamics

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Progress has recently been made in identifying progenitor cell populations in the embryonic lung. Some progenitor cell types have been definitively identified by lineage-tracing studies. However, others are not as well characterized and their existence is inferred on the basis of lung morphology, or mutant phenotypes. Here, I focus on lung development after the specification of the initial lung primordium. The evidence for various lung embryonic progenitor cell types is discussed and future experiments are suggested. The regulation of progenitor proliferation in the embryonic lung, and its coordinate control with morphogenesis, is also discussed. In addition, the relationship between embryonic and adult lung progenitors is considered. Developmental Dynamics 240:463-476,

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Genome-wide association study identifies five loci associated with lung function

Cited by 523 publications

References 39 publications

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

The building blocks of mammalian lung development

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