Benyamin Beben, McRae Allan F, Zhu Gu, Gordon Scott, Henders Anjali K, Palotie Aarno, Peltonen Leena, Martin Nicholas G, Montgomery Grant W, Whitfield John B, Visscher Peter M
Queensland Institute of Medical Research, Brisbane 4029, Australia.
Am J Hum Genet. 2009 Jan;84(1):60-5. doi: 10.1016/j.ajhg.2008.11.011. Epub 2008 Dec 11.
Only a small proportion of genetic variation in complex traits has been explained by SNPs from genome-wide association studies (GWASs). We report the results from two GWASs for serum markers of iron status (serum iron, serum transferrin, transferrin saturation with iron, and serum ferritin), which are important in iron overload (e.g., hemochromatosis) and deficiency (e.g., anemia) conditions. We performed two GWASs on samples of Australians of European descent. In the first GWAS, 411 adolescent twins and their siblings were genotyped with 100K SNPs. rs1830084, 10.8 kb 3' of TF, was significantly associated with serum transferrin (p total association test = 1.0 x 10(-9); p within-family test = 2.2 x 10(-5)). In the second GWAS on an independent sample of 459 female monozygotic (MZ) twin pairs genotyped with 300K SNPs, we found rs3811647 (within intron 11 of TF, HapMap CEU r(2) with rs1830084 = 0.86) was significantly associated with serum transferrin (p = 3.0 x 10(-15)). In the second GWAS, we found two additional and independent SNPs on TF (rs1799852 and rs2280673) and confirmed the known C282Y mutation in HFE to be independently associated with serum transferrin. The three variants in TF (rs3811647, rs1799852 and rs2280673) plus the HFE C282Y mutation explained approximately 40% of genetic variation in serum transferrin (p = 7.8 x 10(-25)). These findings are potentially important for our understanding of iron metabolism and of regulation of hepatic protein secretion, and also strongly support the hypothesis that the genetic architecture of some endophenotypes may be simpler than that of disease.
全基因组关联研究（GWAS）中的单核苷酸多态性（SNP）仅解释了复杂性状中一小部分的遗传变异。我们报告了两项针对铁状态血清标志物（血清铁、血清转铁蛋白、铁转铁蛋白饱和度和血清铁蛋白）的GWAS结果，这些标志物在铁过载（如血色素沉着症）和铁缺乏（如贫血）状况中很重要。我们对欧洲血统的澳大利亚人样本进行了两项GWAS。在第一项GWAS中，对411名青少年双胞胎及其兄弟姐妹进行了10万个SNP的基因分型。rs1830084，位于转铁蛋白（TF）下游10.8 kb处，与血清转铁蛋白显著相关（总体关联检验p值 = 1.0×10⁻⁹；家系内检验p值 = 2.2×10⁻⁵）。在第二项GWAS中，对459对女性同卵双胞胎（MZ）的独立样本进行了30万个SNP的基因分型，我们发现rs3811647（位于TF的内含子11内，与rs1830084的HapMap CEU r² = 0.86）与血清转铁蛋白显著相关（p值 = 3.0×10⁻¹⁵）。在第二项GWAS中，我们在TF上发现了另外两个独立的SNP（rs1799852和rs2280673），并证实已知的HFE基因C282Y突变与血清转铁蛋白独立相关。TF中的三个变体（rs3811647、rs1799852和rs2280673）加上HFE C282Y突变解释了血清转铁蛋白中约40%的遗传变异（p值 = 7.8×10⁻²⁵）。这些发现对于我们理解铁代谢和肝脏蛋白质分泌的调节可能具有重要意义，也有力地支持了某些内表型的遗传结构可能比疾病的遗传结构更简单这一假设。
