A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20

被引：29

作者：

Hanchard, Neil A. ^{[1
,2
]}

Swaminathan, Shanker ^{[1
,2
]}

Bucasas, Kristine ^{[1
,3
]}

Furthner, Dieter ^{[6
]}

Fernbach, Susan ^{[1
]}

Azamian, Mahshid S. ^{[1
]}

Wang, Xueqing ^{[1
]}

Lewin, Mark ^{[7
]}

Towbin, Jeffrey A. ^{[8
]}

D'Alessandro, Lisa C. A. ^{[4
]}

Morris, Shaine A. ^{[4
]}

Dreyer, William ^{[4
]}

Denfield, Susan ^{[4
]}

Ayres, Nancy A. ^{[4
]}

Franklin, Wayne J. ^{[4
]}

Justino, Henri ^{[4
]}

Lantin-Hermoso, M. Regina ^{[4
]}

Ocampo, Elena C. ^{[4
]}

Santos, Alexia B. ^{[4
]}

Parekh, Dhaval ^{[4
]}

Moodie, Douglas ^{[4
]}

Jeewa, Aamir ^{[4
]}

Lawrence, Emily ^{[4
]}

Allen, Hugh D. ^{[4
]}

Penny, Daniel J. ^{[4
]}

Fraser, Charles D. ^{[5
]}

Lupski, James R. ^{[1
,2
]}

Popoola, Mojisola ^{[2
]}

Wadhwa, Lalita ^{[5
]}

Brook, J. David ^{[9
]}

Bu'Lock, Frances A. ^{[10
]}

Bhattacharya, Shoumo ^{[11
]}

Lalani, Seema R. ^{[1
]}

Zender, Gloria A. ^{[14
]}

Fitzgerald-Butt, Sara M. ^{[12
,14
,15
]}

Bowman, Jessica ^{[12
,15
]}

Corsmeier, Don ^{[12
,16
]}

White, Peter ^{[12
,16
]}

Lecerf, Kelsey ^{[13
]}

Zapata, Gladys ^{[1
,2
]}

Hernandez, Patricia ^{[1
,2
]}

Goodship, Judith A. ^{[17
]}

Garg, Vidu ^{[12
,14
,15
]}

Keavney, Bernard D. ^{[18
]}

Leal, Suzanne M. ^{[1
,3
]}

Cordell, Heather J. ^{[17
]}

Belmont, John W. ^{[1
,2
]}

McBride, Kim L. ^{[12
,14
]}

机构：

[1] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[2] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[3] Baylor Coll Med, Ctr Stat Genet, Houston, TX 77030 USA

[4] Baylor Coll Med, Dept Pediat, Div Cardiol, Houston, TX 77030 USA

[5] Baylor Coll Med, Dept Surg, Houston, TX 77030 USA

[6] Childrens Hosp, Dept Paediat, Linz, Austria

[7] Seattle Childrens Hosp, Div Cardiol, Seattle, WA USA

[8] Univ Tennessee, Hlth Sci Ctr, Pediat Cardiol, Memphis, TN USA

[9] Univ Nottingham, Sch Life Sci, Nottingham, England

[10] Glenfield Hosp, East Midlands Congenital Heart Ctr, Leicester, Leics, England

[11] Univ Oxford, Radcliffe Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England

[12] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA

[13] Ohio State Univ, Coll Med, Columbus, OH 43210 USA

[14] Nationwide Childrens Hosp, Ctr Cardiovasc & Pulm Res, Columbus, OH USA

[15] Nationwide Childrens Hosp, Ctr Heart, Columbus, OH USA

[16] Nationwide Childrens Hosp, Ctr Microbial Pathogenesis, Columbus, OH USA

[17] Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England

[18] Univ Manchester, Inst Cardiovasc Sci, Manchester, Lancs, England

来源：

HUMAN MOLECULAR GENETICS | 2016年 / 25卷 / 11期

基金：

美国国家卫生研究院;

关键词：

LEFT-HEART SYNDROME; TRACT OBSTRUCTION MALFORMATIONS; AORTIC-VALVE STENOSIS; COPY-NUMBER VARIANTS; GENERAL-POPULATION; CATHEPSIN-K; RISK LOCI; DISEASE; EXPRESSION; DEFECTS;

D O I：

10.1093/hmg/ddw071

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 x 10(-8) for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 x 10(-9), odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 x 10(-5), OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 x 10(-9) for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 x 10(-7) for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high h range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.

引用

页码：2331 / 2341

页数：11

共 77 条

[1] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[2] Blocking expression of AHR2 and ARNT1 in zebrafish larvae protects against cardiac toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin [J].

Antkiewicz, Dagmara S. ;

Peterson, Richard E. ;

Heideman, Warren .

TOXICOLOGICAL SCIENCES, 2006, 94 (01) :175-182

[3] Uncoupling of Expression of an Intronic MicroRNA and Its Myosin Host Gene by Exon Skipping [J].

Bell, Matthew L. ;

Buvoli, Massimo ;

Leinwand, Leslie A. .

MOLECULAR AND CELLULAR BIOLOGY, 2010, 30 (08) :1937-1945

[4] Congenital heart disease: current knowledge about causes and inheritance [J].

Blue, Gillian M. ;

Kirk, Edwin P. ;

Sholler, Gary F. ;

Harvey, Richard P. ;

Winlaw, David S. .

MEDICAL JOURNAL OF AUSTRALIA, 2012, 197 (03) :155-159

[5] Seeking causes: Classifying and evaluating congenital heart defects in etiologic studies [J].

Botto, Lorenzo D. ;

Lin, Angela E. ;

Riehle-Colarusso, Tiffany ;

Malik, Sadia ;

Correa, Adolfo .

BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY, 2007, 79 (10) :714-727

[6] Annotation of functional variation in personal genomes using RegulomeDB [J].

Boyle, Alan P. ;

Hong, Eurie L. ;

Hariharan, Manoj ;

Cheng, Yong ;

Schaub, Marc A. ;

Kasowski, Maya ;

Karczewski, Konrad J. ;

Park, Julie ;

Hitz, Benjamin C. ;

Weng, Shuai ;

Cherry, J. Michael ;

Snyder, Michael .

GENOME RESEARCH, 2012, 22 (09) :1790-1797

[7] Second-generation PLINK: rising to the challenge of larger and richer datasets [J].

Chang, Christopher C. ;

Chow, Carson C. ;

Tellier, Laurent C. A. M. ;

Vattikuti, Shashaank ;

Purcell, Shaun M. ;

Lee, James J. .

GIGASCIENCE, 2015, 4

[8] Genetic Abnormalities in FOXP1 Are Associated with Congenital Heart Defects [J].

Chang, Sheng-Wei ;

Mislankar, Mona ;

Misra, Chaitali ;

Huang, Nianyuan ;

DaJusta, Daniel G. ;

Harrison, Steven M. ;

McBride, Kim L. ;

Baker, Linda A. ;

Garg, Vidu .

HUMAN MUTATION, 2013, 34 (09) :1226-1230

[9] Role for Cysteine Protease Cathepsins in Heart Disease Focus on Biology and Mechanisms With Clinical Implication [J].

Cheng, Xian Wu ;

Shi, Guo-Ping ;

Kuzuya, Masafumi ;

Sasaki, Takeshi ;

Okumura, Kenji ;

Murohara, Toyoaki .

CIRCULATION, 2012, 125 (12) :1551-1562

[10] Pathogenetic mechanisms of congenital cardiovascular malformations revisited [J].

Clark, EB .

SEMINARS IN PERINATOLOGY, 1996, 20 (06) :465-472

← 1 2 3 4 5 6 7 8 →