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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.

ABSTRACT: Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

SUBMITTER: Soler Artigas M

PROVIDER: S-EPMC3267376 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.

Soler Artigas María M Loth Daan W DW Wain Louise V LV Gharib Sina A SA Obeidat Ma'en M Tang Wenbo W Zhai Guangju G Zhao Jing Hua JH Smith Albert Vernon AV Huffman Jennifer E JE Albrecht Eva E Jackson Catherine M CM Evans David M DM Cadby Gemma G Fornage Myriam M Manichaikul Ani A Lopez Lorna M LM Johnson Toby T Aldrich Melinda C MC Aspelund Thor T Barroso Inês I Campbell Harry H Cassano Patricia A PA Couper David J DJ Eiriksdottir Gudny G Franceschini Nora N Garcia Melissa M Gieger Christian C Gislason Gauti Kjartan GK Grkovic Ivica I Hammond Christopher J CJ Hancock Dana B DB Harris Tamara B TB Ramasamy Adaikalavan A Heckbert Susan R SR Heliövaara Markku M Homuth Georg G Hysi Pirro G PG James Alan L AL Jankovic Stipan S Joubert Bonnie R BR Karrasch Stefan S Klopp Norman N Koch Beate B Kritchevsky Stephen B SB Launer Lenore J LJ Liu Yongmei Y Loehr Laura R LR Lohman Kurt K Loos Ruth J F RJ Lumley Thomas T Al Balushi Khalid A KA Ang Wei Q WQ Barr R Graham RG Beilby John J Blakey John D JD Boban Mladen M Boraska Vesna V Brisman Jonas J Britton John R JR Brusselle Guy G GG Cooper Cyrus C Curjuric Ivan I Dahgam Santosh S Deary Ian J IJ Ebrahim Shah S Eijgelsheim Mark M Francks Clyde C Gaysina Darya D Granell Raquel R Gu Xiangjun X Hankinson John L JL Hardy Rebecca R Harris Sarah E SE Henderson John J Henry Amanda A Hingorani Aroon D AD Hofman Albert A Holt Patrick G PG Hui Jennie J Hunter Michael L ML Imboden Medea M Jameson Karen A KA Kerr Shona M SM Kolcic Ivana I Kronenberg Florian F Liu Jason Z JZ Marchini Jonathan J McKeever Tricia T Morris Andrew D AD Olin Anna-Carin AC Porteous David J DJ Postma Dirkje S DS Rich Stephen S SS Ring Susan M SM Rivadeneira Fernando F Rochat Thierry T Sayer Avan Aihie AA Sayers Ian I Sly Peter D PD Smith George Davey GD Sood Akshay A Starr John M JM Uitterlinden André G AG Vonk Judith M JM Wannamethee S Goya SG Whincup Peter H PH Wijmenga Cisca C Williams O Dale OD Wong Andrew A Mangino Massimo M Marciante Kristin D KD McArdle Wendy L WL Meibohm Bernd B Morrison Alanna C AC North Kari E KE Omenaas Ernst E Palmer Lyle J LJ Pietiläinen Kirsi H KH Pin Isabelle I Pola Sbreve Ek Ozren O Pouta Anneli A Psaty Bruce M BM Hartikainen Anna-Liisa AL Rantanen Taina T Ripatti Samuli S Rotter Jerome I JI Rudan Igor I Rudnicka Alicja R AR Schulz Holger H Shin So-Youn SY Spector Tim D TD Surakka Ida I Vitart Veronique V Völzke Henry H Wareham Nicholas J NJ Warrington Nicole M NM Wichmann H-Erich HE Wild Sarah H SH Wilk Jemma B JB Wjst Matthias M Wright Alan F AF Zgaga Lina L Zemunik Tatijana T Pennell Craig E CE Nyberg Fredrik F Kuh Diana D Holloway John W JW Boezen H Marike HM Lawlor Debbie A DA Morris Richard W RW Probst-Hensch Nicole N Kaprio Jaakko J Wilson James F JF Hayward Caroline C Kähönen Mika M Heinrich Joachim J Musk Arthur W AW Jarvis Deborah L DL Gläser Sven S Järvelin Marjo-Riitta MR Ch Stricker Bruno H BH Elliott Paul P O'Connor George T GT Strachan David P DP London Stephanie J SJ Hall Ian P IP Gudnason Vilmundur V Tobin Martin D MD

Nature genetics 20110925 11

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary functi ...[more]

PMID: 21946350

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Project description:Background & aimsGenome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.MethodsWe analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.ResultsA meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci.ConclusionsWe showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

Project description:BackgroundLung function is a heritable complex phenotype with obesity being one of its important risk factors. However, knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWASs in other populations are lacking.MethodsWe included 100 285 subjects from the China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS analyses were performed on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC in the CKB. We then performed genome-wide cross-trait analysis between lung function and obesity traits (body mass index (BMI), BMI-adjusted waist-to-hip ratio and BMI-adjusted waist circumference) to investigate the shared genetic effects in the CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in the CKB and their interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with the CKB using up to 457 756 subjects from the UK Biobank (UKB) for replication and investigation of ancestry-specific effects.ResultsWe identified nine genome-wide significant novel loci for FEV1, six for FVC and three for FEV1/FVC in the CKB. FEV1 and FVC showed significant negative genetic correlation with obesity traits in both the CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important biological pathways, including cell proliferation, embryo, skeletal and tissue development, and regulation of gene expression. Mendelian randomisation analysis suggested significant negative causal effects of BMI on FEV1 and on FVC in both the CKB and UKB. Lung function PRSs significantly modified the effect of change in BMI on change in lung function during an average follow-up of 8 years.ConclusionThis large-scale GWAS of lung function identified novel loci and shared genetic aetiology between lung function and obesity. Change in BMI might affect change in lung function differently according to a subject's polygenic background. These findings may open new avenues for the development of molecular-targeted therapies for obesity and lung function improvement.

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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.

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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.

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