Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner

BMC Genetics

Bernard D Keavney⁴  Mauro Santibáñez Koref⁵  Bongani M Mayosi¹  Michael S Cunnington³  W Andrew Owens²  Ruairidh I R Martin⁵ 

[1] Department of Medicine, University of Cape Town, Cape Town, South Africa;Division of Cardiothoracic Services, The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UK;Hull and East Yorkshire NHS Trust, Hull, UK;Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK;Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK

关键词: Genome-wide association study;    Atrial fibrillation;    Trans-ethnic mapping;    Expression QTL mapping;   

Others  :  1121347
DOI  :  10.1186/s12863-014-0136-1

 received in 2014-02-03, accepted in 2014-11-24,  发布年份 2014

【 摘 要 】

Background

The ZFHX3 gene, located in Chromosome 16q22.3, codes for a transcription factor which is widely expressed in human tissues. Genome-wide studies have identified associations between variants within the gene and Kawasaki disease and atrial fibrillation. ZFHX3 has two main transcripts that utilise different transcription start sites. We examined the association between genetic variants in the 16q22.3 region and expression of ZFHX3 to identify variants that regulate gene expression.

Results

We genotyped 65 single-nucleotide polymorphisms to tag genetic variation at the ZFHX3 locus in two cohorts, 451 British individuals recruited in the North East of England and 310 mixed-ancestry individuals recruited in South Africa. Allelic expression analysis revealed that the minor (A) allele of rs8060701, a variant in the first intron of ZFHX3, was associated with a 1.16-fold decrease in allelic expression of both transcripts together, (p = 4.87e-06). The minor (C) allele of a transcribed variant, rs10852515, in the second exon of ZFHX3 isoform A was independently associated with a 1.36-fold decrease in allelic expression of ZFHX3 A (p = 7.06e-31), but not overall ZFHX3 expression. However, analysis of total gene expression of ZFHX3 failed to detect an association with genotype at any variant. Differences in linkage disequilibrium between the two populations allowed fine-mapping of the locus to a 7 kb region overlapping exon 2 of ZFHX3 A. We did not find any association between ZFHX3 expression and any of the variants identified by genome wide association studies.

Conclusions

ZFHX3 transcription is regulated in a transcript-specific fashion by independent cis-acting transcribed polymorphisms. Our results demonstrate the power of allelic expression analysis and trans-ethnic fine mapping to identify transcript-specific cis-acting regulatory elements.

【 授权许可】

   
2014 Martin et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Benjamin EJ, Rice KM, Arking DE, Pfeufer A, van Noord C, Smith AV, Schnabel RB, Bis JC, Boerwinkle E, Sinner MF, Dehghan A, Lubitz SA, D'Agostino RB Sr, Lumley T, Ehret GB, Heeringa J, Aspelund T, Newton-Cheh C, Larson MG, Marciante KD, Soliman EZ, Rivadeneira F, Wang TJ, Eiríksdottir G, Levy D, Psaty BM, Li M, Chamberlain AM, Hofman A, Vasan RS, et al.: Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet 2009, 41(8):879-881.
• [2]Gudbjartsson DF, Holm H, Gretarsdottir S, Thorleifsson G, Walters GB, Thorgeirsson G, Gulcher J, Mathiesen EB, Njolstad I, Nyrnes A, Njølstad I, Nyrnes A, Wilsgaard T, Hald EM, Hveem K, Stoltenberg C, Kucera G, Stubblefield T, Carter S, Roden D, Ng MC, Baum L, So WY, Wong KS, Chan JC, Gieger C, Wichmann HE, Gschwendtner A, Dichgans M, Kuhlenbäumer G, et al.: A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 2009, 41(8):876-878.
• [3]Ellinor PT, Lunetta KL, Albert CM, Glazer NL, Ritchie MD, Smith AV, Arking DE, Müller-Nurasyid M, Krijthe BP, Lubitz SA, Bis JC, Chung MK, Dörr M, Ozaki K, Roberts JD, Smith JG, Pfeufer A, Sinner MF, Lohman K, Ding J, Smith NL, Smith JD, Rienstra M, Rice KM, Van Wagoner DR, Magnani JW, Wakili R, Clauss S, Rotter JI, Steinbeck G, et al.: Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012, 44(6):670-675.
• [4]Burgner D, Davila S, Breunis WB, Ng SB, Li Y, Bonnard C, Ling L, Wright VJ, Thalamuthu A, Odam M, Shimizu C, Burns JC, Levin M, Kuijpers TW, Hibberd ML: International Kawasaki Disease Genetics Consortium: A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease. PLoS Genet 2009, 5(1):e1000319.
• [5]Traylor M, Farrall M, Holliday EG, Sudlow C, Hopewell JC, Cheng YC, Fornage M, Ikram MA, Malik R, Bevan S, Thorsteinsdottir U, Nalls MA, Longstreth W, Wiggins KL, Yadav S, Parati EA, Destefano AL, Worrall BB, Kittner SJ, Khan MS, Reiner AP, Helgadottir A, Achterberg S, Fernandez-Cadenas I, Abboud S, Schmidt R, Walters M, Chen WM, Ringelstein EB, O'Donnell M, et al.: Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol 2012, 11(11):951-962.
• [6]Flicek P, Ahmed I, Amode MR, Barrell D, Beal K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fairley S, Fitzgerald S, Gil L, García-Girón C, Gordon L, Hourlier T, Hunt S, Juettemann T, Kähäri AK, Keenan S, Komorowska M, Kulesha E, Longden I, Maurel T, McLaren WM, Muffato M, Nag R, Overduin B, Pignatelli M, Pritchard B, Pritchard E, et al.: Ensembl 2013. Nucleic Acids Res 2013, 41(Database issue):D48-D55.
• [7]Miura Y, Tam T, Ido A, Morinaga T, Miki T, Hashimoto T, Tamaoki T: Cloning and characterization of an ATBF1 isoform that expresses in a neuronal differentiation-dependent manner. J Biol Chem 1995, 270(45):26840-26848.
• [8]Cho YG, Song JH, Kim CJ, Lee YS, Kim SY, Nam SW, Lee JY, Park WS: Genetic alterations of the ATBF1 gene in gastric cancer. Clin Cancer Res 2007, 13(15 Pt 1):4355-4359.
• [9]Kim CJ, Song JH, Cho YG, Cao Z, Lee YS, Nam SW, Lee JY, Park WS: Down-regulation of ATBF1 is a major inactivating mechanism in hepatocellular carcinoma. Histopathology 2008, 52(5):552-559.
• [10]Zhang Z, Yamashita H, Toyama T, Sugiura H, Ando Y, Mita K, Hamaguchi M, Kawaguchi M, Miura Y, Iwase H: ATBF1-a messenger RNA expression is correlated with better prognosis in breast cancer. Clin Cancer Res 2005, 11(1):193-198.
• [11]Sun X, Frierson HF, Chen C, Li C, Ran Q, Otto KB, Cantarel BL, Vessella RL, Gao AC, Petros J, Miura Y, Simons JW, Dong JT: Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer. Nat Genet 2005, 37(4):407-412.
• [12]Cunnington MS, Santibanez Koref M, Mayosi BM, Burn J, Keavney B: Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with ANRIL expression. PLoS Genet 2010, 6(4):e1000899.
• [13]Verlaan DJ, Ge B, Grundberg E, Hoberman R, Lam KC, Koka V, Dias J, Gurd S, Martin NW, Mallmin H, Nilsson O, Harmsen E, Dewar K, Kwan T, Pastinen T: Targeted screening of cis-regulatory variation in human haplotypes. Genome Res 2009, 19(1):118-127.
• [14]Campino S, Forton J, Raj S, Mohr B, Auburn S, Fry A, Mangano VD, Vandiedonck C, Richardson A, Rockett K, Clark TG, Kwiatkowski DP: Validating discovered Cis-acting regulatory genetic variants: application of an allele specific expression approach to HapMap populations. PLoS One 2008, 3(12):e4105.
• [15]Stranger BE, Montgomery SB, Dimas AS, Parts L, Stegle O, Ingle CE, Sekowska M, Smith GD, Evans D, Gutierrez-Arcelus M, Price A, Raj T, Nisbett J, Nica AC, Beazley C, Durbin R, Deloukas P, Dermitzakis ET: Patterns of cis regulatory variation in diverse human populations. PLoS Genet 2012, 8(4):e1002639.
• [16]Grundberg E, Small KS, Hedman ÅK, Nica AC, Buil A, Keildson S, Bell JT, Yang TP, Meduri E, Barrett A, Nisbett J, Sekowska M, Wilk A, Shin SY, Glass D, Travers M, Min JL, Ring S, Ho K, Thorleifsson G, Kong A, Thorsteindottir U, Ainali C, Dimas AS, Hassanali N, Ingle C, Knowles D, Krestyaninova M, Lowe CE, Di Meglio P, et al.: Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet 2012, 44(10):1084-1089.
• [17]Dimas AS, Deutsch S, Stranger BE, Montgomery SB, Borel C, Attar-Cohen H, Ingle C, Beazley C, Gutierrez Arcelus M, Sekowska M, Gagnebin M, Nisbett J, Deloukas P, Dermitzakis ET, Antonarakis SE: Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 2009, 325(5945):1246-1250.
• [18]Diekhans M, Dreszer TR, Giardine BM, Harte RA, Hillman-Jackson J, Hsu F, Kirkup V, Kuhn RM, Learned K, Li CH, Meyer LR, Pohl A, Raney BJ, Rosenbloom KR, Smith KE, Haussler D, Kent WJ: The UCSC Genome Browser database: update 2011. Nucleic Acids Res 2011, 39(Database issue):D876-D882.
• [19]The UCSC Genome Browser. (genome.ucsc.edu)
• [20]Lettre G, Palmer CD, Young T, Ejebe KG, Allayee H, Benjamin EJ, Bennett F, Bowden DW, Chakravarti A, Dreisbach A, Farlow DN, Folsom AR, Fornage M, Forrester T, Fox E, Haiman CA, Hartiala J, Harris TB, Hazen SL, Heckbert SR, Henderson BE, Hirschhorn JN, Keating BJ, Kritchevsky SB, Larkin E, Li M, Rudock ME, McKenzie CA, Meigs JB, Meng YA, et al.: Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project. PLoS Genet 2011, 7(2):e1001300.
• [21]Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT: The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009, 55(4):611-622.
• [22]Browning SR, Browning BL: Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am J Hum Genet 2007, 81(5):1084-1097.
• [23]Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005, 21(2):263-265.
• [24]Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D: The structure of haplotype blocks in the human genome. Science 2002, 296(5576):2225-2229.
• [25]Holm S: A simple sequentially rejective multiple test procedure. Scand J Stat 1979, 6(2):65-70.
• [26]Kim TS, Kawaguchi M, Suzuki M, Jung CG, Asai K, Shibamoto Y, Lavin MF, Khanna KK, Miura Y: The ZFHX3 (ATBF1) transcription factor induces PDGFRB, which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress. Dis Model Mech 2010, 3(11–12):752-762.
• [27]The Gene Expression Atlas. [http://www.ebi.ac.uk/gxa/]
• [28]Yang TP, Beazley C, Montgomery SB, Dimas AS, Gutierrez-Arcelus M, Stranger BE, Deloukas P, Dermitzakis ET: Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies. Bioinformatics 2010, 26(19):2474-2476.
• [29]Berry FB, Miura Y, Mihara K, Kaspar P, Sakata N, Hashimoto-Tamaoki T, Tamaoki T: Positive and negative regulation of myogenic differentiation of C2C12 cells by isoforms of the multiple homeodomain zinc finger transcription factor ATBF1. J Biol Chem 2001, 276(27):25057-25065.
• [30]Tao R, Li C, Newburn EN, Ye T, Lipska BK, Herman MM, Weinberger DR, Kleinman JE, Hyde TM: Transcript-specific associations of SLC12A5 (KCC2) in human prefrontal cortex with development, schizophrenia, and affective disorders. J Neurosci 2012, 32(15):5216-5222.
• [31]Huang Q, Lin B, Liu H, Ma X, Mo F, Yu W, Li L, Li H, Tian T, Wu D, Shen F, Xing J, Chen ZN: RNA-Seq analyses generate comprehensive transcriptomic landscape and reveal complex transcript patterns in hepatocellular carcinoma. PLoS One 2011, 6(10):e26168.