Dilution of candidates: the case of iron-related genes in restless legs syndrome
Dilution of candidates: the case of iron-related genes in restless legs syndrome
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DOI：
10.1038/ejhg.2012.193
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发表时间：
2013-04-01
影响因子：
5.2
通讯作者：
Winkelmann, Juliane
中科院分区：
文献类型：
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作者：
Oexle, Konrad;Schormair, Barbara;Winkelmann, Juliane
不宁腿综合征（RLS）是一种常见的多因素疾病。已经确定了一些遗传风险因素。RLS的易感性也与铁有关。因此，我们询问已知的铁相关基因是否与RLS相关，反之亦然，已知的RLS相关位点是否影响血清中的铁参数。RLS/对照样本（在发现步骤中n=954/1814，在复制1中n= 735/736，在复制2中n= 736/735）与111个铁相关基因列表中每个基因周围4 Mb间隔内的snp进行相关性测试，发现阈值为P=5 × 10（-4）。两个人群队列（KORA F3和F4，共n=3447）检测了6个已知的RLS位点与铁、铁蛋白、转铁蛋白、转铁蛋白饱和度和可溶性转铁蛋白受体的关联。结果是否定的。铁相关基因位点上的候选snp均未得到显著证实。KATNAL2在18q21.1位点的内含子SNP rs2576036在第一步中显著（P=0.00085），但在第二步中不显著（联合名义P值=0.044）。特别是，HFE基因中的rs1800652 （C282Y）与RLS没有相关性。此外，已知RLS位点的snp对KORA队列中的血清铁参数没有显著影响。总之，RLS与血清铁参数的相关性可能比假设的要弱。此外，在一般功率分析中，我们表明，如果遗传效应通过中间性状传递到末端表型，则遗传效应会被稀释。为小效应量提供了样本量公式。欧洲人类遗传学杂志（2013）21,410-414；doi: 10.1038 / ejhg.2012.193;2012年8月29日在线发布
Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n=954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P=5 x 10(-4). Two population cohorts (KORA F3 and F4 with together n=3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P=0.00085) but not in the second replication step (joint nominal P-value=0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes. European Journal of Human Genetics (2013) 21, 410-414; doi:10.1038/ejhg.2012.193; published online 29 August 2012