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Genome-wide association analysis identifies six new loci associated with forced vital capacity.

ABSTRACT: Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

SUBMITTER: Loth DW

PROVIDER: S-EPMC4140093 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Genome-wide association analysis identifies six new loci associated with forced vital capacity.

Loth Daan W DW Soler Artigas María M Gharib Sina A SA Wain Louise V LV Franceschini Nora N Koch Beate B Pottinger Tess D TD Smith Albert Vernon AV Duan Qing Q Oldmeadow Chris C Lee Mi Kyeong MK Strachan David P DP James Alan L AL Huffman Jennifer E JE Vitart Veronique V Ramasamy Adaikalavan A Wareham Nicholas J NJ Kaprio Jaakko J Wang Xin-Qun XQ Trochet Holly H Kähönen Mika M Flexeder Claudia C Albrecht Eva E Lopez Lorna M LM de Jong Kim K Thyagarajan Bharat B Alves Alexessander Couto AC Enroth Stefan S Omenaas Ernst E Joshi Peter K PK Fall Tove T Viñuela Ana A Launer Lenore J LJ Loehr Laura R LR Fornage Myriam M Li Guo G Wilk Jemma B JB Tang Wenbo W Manichaikul Ani A Lahousse Lies L Harris Tamara B TB North Kari E KE Rudnicka Alicja R AR Hui Jennie J Gu Xiangjun X Lumley Thomas T Wright Alan F AF Hastie Nicholas D ND Campbell Susan S Kumar Rajesh R Pin Isabelle I Scott Robert A RA Pietiläinen Kirsi H KH Surakka Ida I Liu Yongmei Y Holliday Elizabeth G EG Schulz Holger H Heinrich Joachim J Davies Gail G Vonk Judith M JM Wojczynski Mary M Pouta Anneli A Johansson Asa A Wild Sarah H SH Ingelsson Erik E Rivadeneira Fernando F Völzke Henry H Hysi Pirro G PG Eiriksdottir Gudny G Morrison Alanna C AC Rotter Jerome I JI Gao Wei W Postma Dirkje S DS White Wendy B WB Rich Stephen S SS Hofman Albert A Aspelund Thor T Couper David D Smith Lewis J LJ Psaty Bruce M BM Lohman Kurt K Burchard Esteban G EG Uitterlinden André G AG Garcia Melissa M Joubert Bonnie R BR McArdle Wendy L WL Musk A Bill AB Hansel Nadia N Heckbert Susan R SR Zgaga Lina L van Meurs Joyce B J JB Navarro Pau P Rudan Igor I Oh Yeon-Mok YM Redline Susan S Jarvis Deborah L DL Zhao Jing Hua JH Rantanen Taina T O'Connor George T GT Ripatti Samuli S Scott Rodney J RJ Karrasch Stefan S Grallert Harald H Gaddis Nathan C NC Starr John M JM Wijmenga Cisca C Minster Ryan L RL Lederer David J DJ Pekkanen Juha J Gyllensten Ulf U Campbell Harry H Morris Andrew P AP Gläser Sven S Hammond Christopher J CJ Burkart Kristin M KM Beilby John J Kritchevsky Stephen B SB Gudnason Vilmundur V Hancock Dana B DB Williams O Dale OD Polasek Ozren O Zemunik Tatijana T Kolcic Ivana I Petrini Marcy F MF Wjst Matthias M Kim Woo Jin WJ Porteous David J DJ Scotland Generation G Smith Blair H BH Viljanen Anne A Heliövaara Markku M Attia John R JR Sayers Ian I Hampel Regina R Gieger Christian C Deary Ian J IJ Boezen H Marike HM Newman Anne A Jarvelin Marjo-Riitta MR Wilson James F JF Lind Lars L Stricker Bruno H BH Teumer Alexander A Spector Timothy D TD Melén Erik E Peters Marjolein J MJ Lange Leslie A LA Barr R Graham RG Bracke Ken R KR Verhamme Fien M FM Sung Joohon J Hiemstra Pieter S PS Cassano Patricia A PA Sood Akshay A Hayward Caroline C Dupuis Josée J Hall Ian P IP Brusselle Guy G GG Tobin Martin D MD London Stephanie J SJ

Nature genetics 20140615 7

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Tw ...[more]

PMID: 24929828

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Project description:BACKGROUND:Genome-wide association studies of Single Nucleotide Polymorphisms (SNPs) have identified 55 SNPs associated with lung function. However, little is known about the effect of copy number variants (CNVs) on lung function, although CNVs represent a significant proportion of human genetic polymorphism. To assess the effect of CNVs on lung function quantitative traits, we measured copy number at 2788 previously characterised, common copy number variable regions in 6 independent cohorts (n?=?24,237) using intensity data from SNP genotyping experiments. We developed a pipeline for genome-wide association analysis and meta-analysis of CNV genotypes measured across multiple studies using SNP genotype array intensity data from different platform technologies. We then undertook cohort-level genome-wide association studies of CNV with lung function in a subset of 4 cohorts (n?<?=12,403) with lung function measurements and meta-analysed the results. Follow-up was undertaken for CNVs which were well tagged by SNPs, in up to 146,871 individuals. RESULTS:We generated robust copy number calls for 1962 out of 2788 (70 %) known CNV regions genome-wide, with 1103 measured with compatible class frequencies in at least 2 cohorts. We report a novel CNV association (discovery P?=?0.0007) with Forced Vital Capacity (FVC) downstream of BANP on chromosome 16 that shows evidence of replication by a tag SNP in two independent studies (replication P?=?0.004). In addition, we provide suggestive evidence (discovery P?=?0.0002) for a role of complex copy number variation at a previously reported lung function locus, containing the rootletin gene CROCC, that is not tagged by SNPs. CONCLUSIONS:We demonstrate how common CNV regions can be reliably and consistently called across cohorts, using an existing calling algorithm and rigorous quality control steps, using SNP genotyping array intensity data. Although many common biallelic CNV regions were well-tagged by common SNPs, we also identified associations with untagged mulitallelic CNV regions thereby illustrating the potential of our approach to identify some of the missing heritability of complex traits.

Dataset Information

Genome-wide association analysis identifies six new loci associated with forced vital capacity.

Publications

Genome-wide association analysis identifies six new loci associated with forced vital capacity.

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