Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies
Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies
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DOI：
10.1111/j.1528-1167.2011.03379.x
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发表时间：
2012-02-01
期刊：
影响因子：
5.6
通讯作者：
Sander, Thomas
中科院分区：
文献类型：
--
作者：
Leu, Costin;de Kovel, Carolien G. F.;Sander, Thomas
目的：遗传性全身性癫痫（GGEs）的终生患病率为0.3%，遗传率估计为80%。相当大比例的家庭与受影响的GGEs兄弟姐妹大概显示寡基因遗传。目前的全基因组连锁荟萃分析旨在绘制：（1）广泛的GGE共有的易感基因座，以及（2）癫痫发作类型相关的遗传因素，分别优先诱发典型的缺席或肌阵挛性癫痫发作。方法：对379个欧洲血统的GGE多重家族（包括982名患有GGE的亲属）进行了三个全基因组连锁数据集的荟萃分析。为了剖析癫痫发作类型相关的易感基因，对两个家庭亚组进行了分层，包括235个主要遗传缺失癫痫（GAE）的家庭和118个青少年肌阵挛性癫痫（JME）聚集的家庭。为了定位共享的和癫痫类型相关的易感基因座，对整个GGE多重家庭的宽性状模型和窄性状模型进行了非参数基因座（NPL）和参数连锁分析（典型的缺席或肌阵挛发作）在JME和GAE家族的亚组。关键发现：对379个GGE多重家系进行连锁分析，发现6个位点在1p36.22、3p14.2、5 q34、13q12.12、13q31.3、19q13.42在5 q34的连锁发现是一致的支持NPL和参数连锁结果在所有三个家庭组。在118个JME家系中，在2 q34处获得了全基因组显著的非参数对数比值分数3.43。在235个假定为隐性遗传的GAE家系中发现了与13q31.3的显着参数连锁（异质性比值对数= 5.02.Significance）：我们的连锁结果支持家族性GGE综合征的寡基因易感性。5 q34的遗传风险因子赋予广泛的家族性GGE综合征的风险，而2 q34和13q31.3的易感基因座分别优先易感肌阵挛性癫痫发作或失神性癫痫发作。表型-基因型策略在表型同质的家族亚群中应用狭义性状定义，改善了解开常见家族性GGE综合征遗传基础的前景。
Purpose: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure typerelated genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively.Methods: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families.Key Findings: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02).Significance: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype-genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.