Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
PLoS One. 2018 Jun 18;13(6):e0198166. doi: 10.1371/journal.pone.0198166. eCollection 2018.
Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
大量饮酒是高血压的既定危险因素；酒精摄入影响血压（BP）调节的机制尚不清楚。我们假设，一项考虑了 BP 基因-酒精摄入相互作用的全基因组关联研究可能会发现额外的 BP 位点，并有助于理解与酒精相关的 BP 调节。我们进行了一项大型的两阶段研究，包括主要遗传效应和单核苷酸变异（SNV）-酒精摄入相互作用的联合检验。在第一阶段，对来自多个血统的 ≈131K 个体进行了全基因组发现荟萃分析，产生了 3514 个具有提示性关联证据的 SNV（245 个基因座）（P < 1.0 x 10-5）。在第二阶段，这些 SNV 在外部分布于多个血统的 ≈440K 个体中进行了独立的外部复制检验。我们在欧洲血统中确定并复制了五个新的 BP 位点（21 个基因中的 380 个 SNV）和 49 个先前报道的 BP 位点（109 个基因中的 2159 个 SNV）（Bonferroni 校正阈值为 P < 5.0 x 10-8），以及在多血统荟萃分析中（P < 5.0 x 10-8）。对于非洲血统样本，我们在第一阶段检测到 18 个可能是新的 BP 位点（P < 5.0 x 10-8），需要进一步复制。此外，相关荟萃分析确定了 8 个新的 BP 位点（11 个基因）。这些位点中的几个基因（例如，PINX1、GATA4、BLK、FTO 和 GABBR2）先前已被报道与酒精摄入有关。这些发现为酒精摄入在高血压遗传结构中的作用提供了新的见解。
