deCODE genetics, Reykjavik, Iceland.
Nat Genet. 2011 Oct 9;43(11):1127-30. doi: 10.1038/ng.972.
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 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 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 × 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.
我们测试了 1600 万个通过对 457 名冰岛人进行全基因组测序而识别出的单核苷酸多态性（SNPs），以确定它们与痛风和血清尿酸水平的关联。基因型被导入到 41675 名芯片基因分型的冰岛人和他们的亲属中，有效样本量为 968 名痛风患者和 15506 名可获得血清尿酸测量值的个体。我们在 ALDH16A1 中发现了一个低频错义变异（c.1580C>G）与痛风（OR = 3.12，P = 1.5×10（-16），风险等位基因频率 = 0.019）和血清尿酸水平（效应 = 0.36 个标准差，P = 4.5×10（-21））相关。我们通过对 6017 名冰岛人进行 Sanger 测序来确认与痛风的关联。与女性相比，男性的痛风关联更强。我们还在 1 号染色体上发现了另一个与痛风相关的变异（OR = 1.92，P = 0.046，风险等位基因频率 = 0.986）和血清尿酸水平（效应 = 0.48 个标准差，P = 4.5×10（-16））。该变体接近先前与血清尿酸水平相关的常见变体。这项工作说明了全基因组测序数据如何能够检测低频变体与复杂性状之间的关联。
