Dubé Marie-Pierre, Bigras Jean-Luc, Thibeault Maryse, Bureau Nathalie, Chetaille Philippe, Richter Andrea, Mercier Jocelyne, Bellavance Marc, Rohlicek Charles, Rozen Rima, Nemer Mona, Khairy Paul, Gendron Roxanne, Andelfinger Gregor
Montreal Heart Institute, University of Montreal, Rue Belanger, Canada.
Cardiol Young. 2011 Dec;21(6):654-64. doi: 10.1017/S1047951111000813. Epub 2011 Jul 4.
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.
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).
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.
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.
先天性心脏病是最常见的畸形，是儿童和青年死亡和发病的重要原因。这些畸形的遗传因素作用已得到认可，但总体而言，已确定的易感基因座很少。在此，我们报告了一个多机构先天性心脏病队列研究的基本原理、设计和初步结果，该队列主要由魁北克省的法裔加拿大人组成，以有多个成员患心脏畸形的家庭为中心。
在入组的前3年中，研究人员在心脏病诊所招募家庭，对其进行表型分析并采集DNA样本。我们对左心室流出道梗阻（LVOTO）家庭亚组进行了分离分析和连锁模拟。
共招募了来自300个家庭的1603名参与者，其中300个家庭中有169个（56.3%）有不止一名患病成员。对于LVOTO组，我们估计在我们的队列中遗传度为0.46 - 0.52。模拟分析表明有足够的能力进行连锁分析，在67个LVOTO家系中，预期平均优势对数（LOD）评分为3.8。
我们证明了基于人群的生物样本库用于先天性心脏病病因遗传研究的可行性和实用性。LVOTO的遗传度很高，可能由多个基因座所致。这个平台非常适合多种分析方法，包括连锁分析和新型基因测序方法，并将有助于在家庭和人群层面确定风险等位基因的分离情况。
