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Design and rationale of a genetic cohort study on congenital cardiac disease: experiences from a multi-institutional platform in Quebec

Published online by Cambridge University Press:  04 July 2011

Marie-Pierre Dubé ,
Jean-Luc Bigras ,
Maryse Thibeault ,
Nathalie Bureau ,
Philippe Chetaille ,
Andrea Richter ,
Jocelyne Mercier ,
Marc Bellavance ,
Charles Rohlicek  and
Rima Rozen
...Show all authors
Marie-Pierre Dubé
Affiliation:
Montreal Heart Institute, University of Montreal, 5000, Rue Belanger, Canada
Jean-Luc Bigras
Affiliation:
Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine, University of Montreal, 3175 Chemin Côte Sainte Catherine, Montréal, Canada
Maryse Thibeault
Affiliation:
Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine, University of Montreal, 3175 Chemin Côte Sainte Catherine, Montréal, Canada
Nathalie Bureau
Affiliation:
Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine, University of Montreal, 3175 Chemin Côte Sainte Catherine, Montréal, Canada
Philippe Chetaille
Affiliation:
Cardiology Service, Centre Mère-Enfants, Centre Hospitalier Universitaire de Québec, 2705, boulevard Laurier, Québec, Canada
Andrea Richter
Affiliation:
Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine, University of Montreal, 3175 Chemin Côte Sainte Catherine, Montréal, Canada
Jocelyne Mercier
Affiliation:
Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine, University of Montreal, 3175 Chemin Côte Sainte Catherine, Montréal, Canada
Marc Bellavance
Affiliation:
Department of Pediatrics, University of Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, QC, Canada
Charles Rohlicek
Affiliation:
Department of Pediatrics, McGill University, Montréal, 3400, boulevard De Maisonneuve Ouest, Montreal, QC, Canada
Rima Rozen
Affiliation:
Department of Pediatrics, McGill University, Montréal, 3400, boulevard De Maisonneuve Ouest, Montreal, QC, Canada
Mona Nemer
Affiliation:
University of Ottawa, 550, rue Cumberland, Ottawa, ON, Canada
Paul Khairy
Affiliation:
Montreal Heart Institute, University of Montreal, 5000, Rue Belanger, Canada
Roxanne Gendron
Affiliation:
Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine, University of Montreal, 3175 Chemin Côte Sainte Catherine, Montréal, Canada
Gregor Andelfinger*
Affiliation:
Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine, University of Montreal, 3175 Chemin Côte Sainte Catherine, Montréal, Canada
*
Correspondence to: Dr G. Andelfinger, MD, Research Center, Room 2724, CHU Sainte Justine, 3175, Côte Sainte Catherine, Montréal, Québec H3T 1C5, Canada. Tel: 514 345 4931x3244; Fax: 514 345 4896; E-mail: [email protected]
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Abstract

Background

Congenital cardiac disease is the most common malformation, and a substantial source of mortality and morbidity in children and young adults. A role for genetic factors is recognised for these malformations, but overall few predisposing loci have been identified. Here we report the rationale, design, and first results of a multi-institutional congenital cardiac disease cohort, assembled mainly from the French-Canadian population of the province of Quebec and centred on families with multiple affected members afflicted by cardiac malformations.

Methods

Families were recruited into the study, phenotyped and sampled for DNA in cardiology clinics over the first 3 years of enrolment. We performed segregation analysis and linkage simulations in the subgroup of families with left ventricular outflow tract obstruction (LVOTO).

Results

A total of 1603 participants from 300 families were recruited, with 169 out of 300 (56.3%) families having more than one affected member. For the LVOTO group, we estimate heritability to be 0.46–0.52 in our cohort. Simulation analysis demonstrated sufficient power to carry out linkage analyses, with an expected mean log-of-odds (LOD) score of 3.8 in 67 pedigrees with LVOTO.

Conclusion

We show feasibility and usefulness of a population-based biobank for genetic investigations into the causes of congenital cardiac disease. Heritability of LVOTO is high and could be accounted for by multiple loci. This platform is ideally suited for multiple analysis approaches, including linkage analysis and novel gene sequencing approaches, and will allow to establish segregation of risk alleles at family and population levels.

Keywords

Cardiac malformationspopulation studybiobankingheritability analysispower simulations
Type
Original Articles
Information
Cardiology in the Young , Volume 21 , Issue 6 , 28 October 2011 , pp. 654 - 664
Copyright
Copyright © Cambridge University Press 2011

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References

1.Pierpont, ME, Basson, CT, JrBenson, DW, et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007; 115: 3015–3038.CrossRefGoogle Scholar
2.Statistics Canada. Deaths, by cause – Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities (Q00–Q99), 2005.Google Scholar
3.Health Canada. Congenital anomalies in Canada – a perinatal health report. Minister of Public Works and Government Services, Ottawa, 2002.Google Scholar
4.Marelli, AJ, Mackie, AS, Ionescu-Ittu, R, Rahme, E, Pilote, L. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation 2007; 115: 163–172.CrossRefGoogle ScholarPubMed
5.Allan, LD, Crawford, DC, Chita, SK, Anderson, RH, Tynan, MJ. Familial recurrence of congenital heart disease in a prospective series of mothers referred for fetal echocardiography. Am J Cardiol 1986; 58: 334–337.CrossRefGoogle Scholar
6.Oyen, N, Poulsen, G, Boyd, HA, Wohlfahrt, J, Jensen, PK, Melbye, M. Recurrence of congenital heart defects in families. Circulation 2009; 120: 295–301.CrossRefGoogle ScholarPubMed
7.Ferencz, C, Loffredo, CA, Correa-Villasenor, A, Wilson, PD. Genetic and environmental risk factors of major cardiovascular malformations: the Baltimore–Washington Infant Study: 1981–1989. Future Publishing Co, Armonk, NY, 1997.Google Scholar
8.Whittemore, R, Wells, JA, Castellsague, X. A second-generation study of 427 probands with congenital heart defects and their 837 children. J Am Coll Cardiol 1994; 23: 1459–1467.CrossRefGoogle ScholarPubMed
9.Brenner, JI, Berg, KA, Schneider, DS, Clark, EB, Boughman, JA. Cardiac malformations in relatives of infants with hypoplastic left-heart syndrome. Am J Dis Child 1989; 143: 1492–1494.Google ScholarPubMed
10.Digilio, MC, Marino, B, Giannotti, A, Toscano, A, Dallapiccola, B. Recurrence risk figures for isolated tetralogy of Fallot after screening for 22q11 microdeletion. J Med Genet 1997; 34: 188–190.CrossRefGoogle ScholarPubMed
11.Gill, HK, Splitt, M, Sharland, GK, Simpson, JM. Patterns of recurrence of congenital heart disease: an analysis of 6640 consecutive pregnancies evaluated by detailed fetal echocardiography. J Am Coll Cardiol 2003; 42: 923–929.CrossRefGoogle Scholar
12.McBride, KL, Pignatelli, R, Lewin, M, et al. Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: segregation, multiplex relative risk, and heritability. Am J Med Genet A 2005; 134: 180–186.CrossRefGoogle Scholar
13.Oyen, N, Poulsen, G, Wohlfahrt, J, Boyd, HA, Jensen, PK, Melbye, M. Recurrence of discordant congenital heart defects in families. Circ Cardiovasc Genet 2010; 3: 122–128.CrossRefGoogle ScholarPubMed
14.Hoffman, JI, Kaplan, S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 1890–1900.CrossRefGoogle ScholarPubMed
15.Pradat, P. A case–control study of major congenital heart defects in Sweden – 1981–1986. Eur J Epidemiol 1992; 8: 789–796.CrossRefGoogle ScholarPubMed
16.Boon, AR, Roberts, DF. A family study of coarctation of the aorta. J Med Genet 1976; 13: 420–433.CrossRefGoogle ScholarPubMed
17.Brownell, LG, Shokeir, MH. Inheritance of hypoplastic left heart syndrome (HLHS): further observations. Clin Genet 1976; 9: 245–249.CrossRefGoogle ScholarPubMed
18.Cripe, L, Andelfinger, G, Martin, LJ, Shooner, K, Benson, DW. Bicuspid aortic valve is heritable. J Am Coll Cardiol 2004; 44: 138–143.CrossRefGoogle ScholarPubMed
19.JrHinton, RB, Martin, LJ, Tabangin, ME, Mazwi, ML, Cripe, LH, Benson, DW. Hypoplastic left heart syndrome is heritable. J Am Coll Cardiol 2007; 50: 1590–1595.CrossRefGoogle ScholarPubMed
20.Hinton, RB, Martin, LJ, Rame-Gowda, S, Tabangin, ME, Cripe, LH, Benson, DW. Hypoplastic left heart syndrome links to chromosomes 10q and 6q and is genetically related to bicuspid aortic valve. J Am Coll Cardiol 2009; 53: 1065–1071.CrossRefGoogle ScholarPubMed
21.Martin, LJ, Ramachandran, V, Cripe, LH, et al. Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations. Hum Genet 2007; 121: 275–284.CrossRefGoogle ScholarPubMed
22.Hinton, RB, Andelfinger, G, Sekar, P, et al. Prenatal head growth and white matter injury in hypoplastic left heart syndrome. Pediatr Res 2008; 64: 364–369.CrossRefGoogle ScholarPubMed
23.McBride, KL, Zender, GA, Fitzgerald-Butt, SM, et al. Linkage analysis of left ventricular outflow tract malformations (aortic valve stenosis, coarctation of the aorta, and hypoplastic left heart syndrome). Eur J Hum Genet 2009; 17: 811–819.CrossRefGoogle ScholarPubMed
24.Roessler, E, Ouspenskaia, MV, Karkera, JD, et al. Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly. Am J Hum Genet 2008; 83: 18–29.CrossRefGoogle ScholarPubMed
25.Chapman, NH, Thompson, EA. Linkage disequilibrium mapping: the role of population history, size, and structure. Adv Genet 2001; 42: 413–437.CrossRefGoogle ScholarPubMed
26.Moreau, C, Vezina, H, Labuda, D. Founder effects and genetic variability in Quebec. Med Sci (Paris) 2007; 23: 1008–1013.CrossRefGoogle ScholarPubMed
27.Scriver, CR. Human genetics: lessons from Quebec populations. Annu Rev Genomics Hum Genet 2001; 2: 69–101.CrossRefGoogle ScholarPubMed
28.Yotova, V, Labuda, D, Zietkiewicz, E, et al. Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec. Hum Genet 2005; 117: 177–187.CrossRefGoogle ScholarPubMed
29.Laberge, AM, Jomphe, M, Houde, L, et al. A “Fille du Roy” introduced the T14484C Leber hereditary optic neuropathy mutation in French Canadians. Am J Hum Genet 2005; 77: 313–317.CrossRefGoogle Scholar
30.Laberge, AM, Michaud, J, Richter, A, et al. Population history and its impact on medical genetics in Quebec. Clin Genet 2005; 68: 287–301.CrossRefGoogle ScholarPubMed
31.Plante, M, Claveau, S, Lepage, P, et al. Mucolipidosis II: a single causal mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB) in a French Canadian founder population. Clin Genet 2008; 73: 236–244.CrossRefGoogle Scholar
32.Bouchard, G Projet BALSAC. www.uqac.ca/balsac 2006.Google Scholar
33.Christensen, KE, Rohlicek, CV, Andelfinger, GU, et al. The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects. Hum Mutat 2009; 30: 212–220.CrossRefGoogle ScholarPubMed
34.Allen, HD, Phillips, JR, Chan, DP. History and physical examination. In: Allen HD, Clark EB, Gutgesell HP, Driscoll DJ (eds.). Moss’ and Adams’ Heart Disease in Infants, Children and Adolescents. Lippincott Williams&Wilkins, Philadelphia, 2001, pp. 143–153.Google Scholar
35.Bhopal, RS. Ethnicity, Race, and Health in Multicultural Societies: Foundations for Better Epidemiology, Public Health and Health Care, 1st edn. Oxford University Press, Oxford, New York, 2007.CrossRefGoogle Scholar
36.Bhat, M, Nguyen, GC, Pare, P, et al. Phenotypic and genotypic characteristics of inflammatory bowel disease in French Canadians: comparison with a large North American repository. Am J Gastroenterol 2009; 104: 2233–2240.CrossRefGoogle ScholarPubMed
37.Hasstedt, SJ. jPAP: document-driven software for genetic analysis. Genet Epidemiol 2005; 29: 255.Google Scholar
38.Ott, J. Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci 1989; 86: 4175–4178.CrossRefGoogle ScholarPubMed
39.Weeks, DE, Ott, J, Lathrop, GM. SLINK: a general simulation program for linkage analysis. Am J Hum Genet 1990; 47: A204.Google Scholar
40.Biben, C, Weber, R, Kesteven, S, et al. Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circ Res 2000; 87: 888–895.CrossRefGoogle ScholarPubMed
41.Laird, NM, Lange, C. Family-based methods for linkage and association analysis. Adv Genet 2008; 60: 219–252.CrossRefGoogle ScholarPubMed
42.Risch, N, Merikangas, K. The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.CrossRefGoogle ScholarPubMed
43.Ng, SB, Buckingham, KJ, Lee, C, et al. Exome sequencing identifies the cause of a Mendelian disorder. Nat Genet 2010; 42: 30–35.CrossRefGoogle ScholarPubMed
44.Durbin, RM, Abecasis, GR, Altshuler, DL, et al. A map of human genome variation from population-scale sequencing. Nature 2010; 467: 1061–1073.Google Scholar
45.Fortin, S, Pathmasiri, S, Grintuch, R, Deschenes, M. “Access arrangements” for Biobanks: a fine line between facilitating and hindering collaboration. Public Health Genomics 2010; Epub ahead of print.Google ScholarPubMed