Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie , Japan.
CREST, Japan Science and Technology Agency, Kawaguchi, Saitama , Japan.
Physiol Genomics. 2018 Sep 1;50(9):758-769. doi: 10.1152/physiolgenomics.00088.2017. Epub 2018 Jun 29.
Recent genome-wide association studies have identified various genetic variants associated with hematological traits. Although it is possible that quantitative data of hematological traits are varied among the years examined, conventional genome-wide association studies have been conducted in a cross-sectional manner that measures traits at a single point in time. To address this issue, we have traced blood profiles in 4,884 Japanese individuals who underwent annual health check-ups for several years. In the present study, longitudinal exome-wide association studies were conducted to identify genetic variants related to 13 hematological phenotypes. The generalized estimating equation model showed that a total of 67 single nucleotide polymorphisms (SNPs) were significantly [false discovery rate (FDR) of <0.01] associated with hematological phenotypes. Of the 67 SNPs, nine SNPs were identified as novel hematological markers: rs4686683 of SENP2 for red blood cell count (FDR = 0.008, P = 5.5 × 10); rs3917688 of SELP for mean corpuscular volume (FDR = 0.005, P = 2.4 × 10); rs3133745 of C8orf37-AS1 for white blood cell count (FDR = 0.003, P = 1.3 × 10); rs13121954 at 4q31.2 for basophil count (FDR = 0.007, P = 3.1 × 10); rs7584099 at 2q22.3 (FDR = 2.6 × 10, P = 8.8 × 10), rs1579219 of HCG17 (FDR = 0.003, P = 2.0 × 10), and rs10757049 of DENND4C (FDR = 0.008, P = 5.6 × 10) for eosinophil count; rs12338 of CTSB for neutrophil count (FDR = 0.007, P = 2.9 × 10); and rs395967 of OSMR-AS1 for monocyte count (FDR = 0.008, P = 3.2 × 10).
最近的全基因组关联研究已经确定了各种与血液学特征相关的遗传变异。尽管血液学特征的定量数据可能在不同年份存在差异，但传统的全基因组关联研究是在横断面进行的，即在单个时间点测量特征。为了解决这个问题，我们对 4884 名接受了多年年度健康检查的日本个体的血液情况进行了跟踪。在本研究中，进行了纵向外显子组全基因组关联研究，以鉴定与 13 种血液表型相关的遗传变异。广义估计方程模型显示，共有 67 个单核苷酸多态性（SNP）与血液表型显著相关（错误发现率（FDR）<0.01）。在这 67 个 SNP 中，有 9 个 SNP 被鉴定为新的血液学标志物：SENP2 的 rs4686683 与红细胞计数相关（FDR=0.008，P=5.5×10）；SEL P 的 rs3917688 与平均红细胞体积相关（FDR=0.005，P=2.4×10）；C8orf37-AS1 的 rs3133745 与白细胞计数相关（FDR=0.003，P=1.3×10）；4q31.2 上的 rs13121954 与嗜碱性粒细胞计数相关（FDR=0.007，P=3.1×10）；2q22.3 上的 rs7584099（FDR=2.6×10，P=8.8×10）、HCG17 的 rs1579219（FDR=0.003，P=2.0×10）和 DENND4C 的 rs10757049（FDR=0.008，P=5.6×10）与嗜酸性粒细胞计数相关；CTSB 的 rs12338 与中性粒细胞计数相关（FDR=0.007，P=2.9×10）；OSMR-AS1 的 rs395967 与单核细胞计数相关（FDR=0.008，P=3.2×10）。
