We propose a novel variant set test for rare-variant association studies, which leverages multiple single-nucleotide variant (SNV) annotations. Our approach optimizes a convex combination of different sequence kernel association test (SKAT) statistics, where each statistic is constructed from a different annotation and combination weights are optimized through a multiple kernel learning algorithm. The combination test statistic is evaluated empirically through data splitting. In simulations, we find our method preserves type I error at α = 2.5 × 1 0 - 6 and has greater power than SKAT(-O) when SNV weights are not misspecified and sample sizes are large ( N ≥ 5 , 000 ). We utilize our method in the Framingham Heart Study (FHS) to identify SNV sets associated with fasting glucose. While we are unable to detect any genome-wide significant associations between fasting glucose and 4-kb windows of rare variants ( p < 1 0 - 7 ) in 6,419 FHS participants, our method identifies suggestive associations between fasting glucose and rare variants near ROCK2 ( p = 2.1 × 1 0 - 5 ) and within CPLX1 ( p = 5.3 × 1 0 - 5 ). These two genes were previously reported to be involved in obesity-mediated insulin resistance and glucose-induced insulin secretion by pancreatic beta-cells, respectively. These findings will need to be replicated in other cohorts and validated by functional genomic studies.

中文翻译：

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用于罕见变异研究的凸组合序列核关联检验。

我们为稀有变异关联研究提出了一种新的变异集测试，它利用了多个单核苷酸变异 (SNV) 注释。我们的方法优化了不同序列核关联测试 (SKAT) 统计量的凸组合，其中每个统计量由不同的注释构成，组合权重通过多核学习算法进行优化。组合检验统计量通过数据拆分凭经验评估。在模拟中，我们发现我们的方法在 α = 2.5 × 1 0 - 6 时保留了 I 类错误，并且当 SNV 权重没有错误指定且样本量很大（N ≥ 5, 000）时，它比 SKAT(-O) 具有更大的功效。我们在弗雷明汉心脏研究 (FHS) 中利用我们的方法来识别与空腹血糖相关的 SNV 集。虽然我们无法在 6,419 名 FHS 参与者中检测到空腹血糖与 4-kb 稀有变异 (p < 1 0 - 7) 窗口之间的任何全基因组显着关联，但我们的方法确定了空腹血糖与 ROCK2 附近稀有变异之间的暗示关联 (p < 1 0 - 7)。 p = 2.1 × 1 0 - 5 ）和在 CPLX1 内（ p = 5.3 × 1 0 - 5 ）。这两个基因先前被报道分别与肥胖介导的胰岛素抵抗和葡萄糖诱导的胰腺β细胞分泌胰岛素有关。这些发现需要在其他队列中复制并通过功能基因组研究进行验证。1 × 1 0 - 5 ）和 CPLX1 内（ p = 5.3 × 1 0 - 5 ）。这两个基因先前被报道分别与肥胖介导的胰岛素抵抗和葡萄糖诱导的胰腺β细胞分泌胰岛素有关。这些发现需要在其他队列中复制并通过功能基因组研究进行验证。1 × 1 0 - 5 ）和 CPLX1 内（ p = 5.3 × 1 0 - 5 ）。这两个基因先前被报道分别与肥胖介导的胰岛素抵抗和葡萄糖诱导的胰腺β细胞分泌胰岛素有关。这些发现需要在其他队列中复制并通过功能基因组研究进行验证。