Department of Medical Sciences, School of Medicine, Universitat de Girona, Girona, Spain.
Visiting Scholar Program, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Cell Rep Med. 2021 Apr 20;2(4):100250. doi: 10.1016/j.xcrm.2021.100250.
Genome-wide association studies (GWASs) are instrumental in identifying loci harboring common single-nucleotide variants (SNVs) that affect human traits and diseases. GWAS hits emerge in clusters, but the focus is often on the most significant hit in each trait- or disease-associated locus. The remaining hits represent SNVs in linkage disequilibrium (LD) and are considered redundant and thus frequently marginally reported or exploited. Here, we interrogate the value of integrating the full set of GWAS hits in a locus repeatedly associated with cardiac conduction traits and arrhythmia, -. Our analysis reveals 5 common 7-SNV haplotypes (Hap1-5) with 2 combinations associated with life-threatening arrhythmia-Brugada syndrome (the risk Hap and protective Hap genotypes). Hap1 and Hap2 share 3 SNVs; thus, this analysis suggests that assuming redundancy among clustered GWAS hits can lead to confounding disease-risk associations and supports the need to deconstruct GWAS data in the context of haplotype composition.
全基因组关联研究 (GWAS) 在鉴定影响人类特征和疾病的常见单核苷酸变异 (SNV) 所包含的基因座方面发挥了重要作用。GWAS 命中结果会以簇的形式出现，但重点通常是每个与特征或疾病相关的基因座中最显著的命中结果。其余的命中结果代表连锁不平衡 (LD) 中的 SNV，被认为是冗余的，因此经常被边缘化报道或利用。在这里，我们探讨了整合与心脏传导特征和心律失常反复相关的基因座中的全套 GWAS 命中结果的价值，。我们的分析揭示了 5 个常见的 7-SNV 单倍型 (Hap1-5)，其中 2 个组合与危及生命的心律失常 - Brugada 综合征 (风险 Hap 和保护 Hap 基因型) 相关。Hap1 和 Hap2 共享 3 个 SNV；因此，这项分析表明，假设簇状 GWAS 命中结果之间存在冗余可能会导致混淆疾病风险关联，并支持在单倍型组成的背景下解构 GWAS 数据的必要性。
