Jo Hodonsky Chani, Schurmann Claudia, Schick Ursula M, Kocarnik Jonathan, Tao Ran, van Rooij Frank Ja, Wassel Christina, Buyske Steve, Fornage Myriam, Hindorff Lucia A, Floyd James S, Ganesh Santhi K, Lin Dan-Yu, North Kari E, Reiner Alex P, Loos Ruth Jf, Kooperberg Charles, Avery Christy L
Department of Epidemiology, University of North Carolina Gillings School of Public Health, Chapel Hill, NC.
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Am J Hematol. 2018 Jun 15. doi: 10.1002/ajh.25161.
Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p<1.7x10 ); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p=1.9x10 ). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations. This article is protected by copyright. All rights reserved.
红细胞（RBC）特征有助于深入了解多种生理状态，并且具有中度到高度的遗传性，这使其成为开展基因研究以揭示潜在生物学机制的理想对象。先前的红细胞特征全基因组关联研究主要在欧洲或亚洲血统人群中进行，因而错失了增进对不同人群红细胞遗传结构的理解以及通过精细定位缩小假定功能单核苷酸多态性（SNP）周围区间的机会。在此，我们报告了在多达19,036名非裔美国人和19,562名西班牙裔/拉丁裔人群结构利用基因组学和流行病学（PAGE）联盟参与者中对六个相关（皮尔逊相关系数范围：|0.04 - 0.92|）红细胞特征进行的首次精细定位。在对研究和临床协变量进行调整后，使用逆方差荟萃分析对13个先前确定的关联信号侧翼约11,000个SNP以及另外150,000个全阵列SNP进行种族/族裔和特定研究估计值的跨种族荟萃分析。先前报道的索引SNP与红细胞特征关联中约有一半在跨种族研究人群中具有普遍性（p<1.7x10）；ABO区域内先前未报道的独立关联信号强化了多个功能变异影响同一基因座的可能性。跨种族精细定位未在与已知功能变异无关的HFE基因座上揭示其他信号。最后，我们在西班牙裔/拉丁裔研究人群中的HECTD4/RPL6基因座发现了一个与红细胞计数相关的潜在新关联（p = 1.9x10）。识别先前未知的关联、很大一部分已知关联信号的普遍性以及已知关联信号的细化均例证了在不同人群中开展基因研究的益处。本文受版权保护。保留所有权利。
