Identification of low-frequency variants associated with gout and serum uric acid levels
Identification of low-frequency variants associated with gout and serum uric acid levels
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DOI：
10.1038/ng.972
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发表时间：
2011-11-01
期刊：
影响因子：
30.8
通讯作者：
Stefansson, Kari
中科院分区：
文献类型：
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作者：
Sulem, Patrick;Gudbjartsson, Daniel F.;Stefansson, Kari
我们对通过457名冰岛人全基因组测序确定的1600万个单核苷酸多态性（SNP）进行了与痛风和血清尿酸水平相关性的检测。将基因型推算到41675名经芯片基因分型的冰岛人及其亲属中，得到痛风患者的有效样本量为968人，有血清尿酸测量值的个体为15506人。我们在醛脱氢酶16A1（ALDH16A1）中发现了一个与痛风相关的低频错义变异（c.1580C>G）（优势比 = 3.12，P = 1.5×10⁻¹⁶，风险等位基因频率 = 0.019）以及与血清尿酸水平相关（效应 = 0.36标准差，P = 4.5×10⁻²¹）。我们通过对6017名冰岛人进行桑格测序证实了与痛风的相关性。与女性相比，男性与痛风的相关性更强。我们还在1号染色体上发现了另一个与痛风相关的变异（优势比 = 1.92，P = 0.046，风险等位基因频率 = 0.986）以及与血清尿酸水平相关（效应 = 0.48标准差，P = 4.5×10⁻¹⁶）。这个变异靠近一个先前与血清尿酸水平相关的常见变异。这项工作说明了全基因组测序数据如何能够检测低频变异与复杂性状之间的关联。
We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant ( c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 x 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 x 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 x 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.