TY - JOUR
T1 - Variants in TF and HFE Explain ∼40% of Genetic Variation in Serum-Transferrin Levels
AU - Benyamin, Beben
AU - McRae, Allan F.
AU - Zhu, Gu
AU - Gordon, Scott
AU - Henders, Anjali K.
AU - Palotie, Aarno
AU - Peltonen, Leena
AU - Martin, Nicholas G.
AU - Montgomery, Grant W.
AU - Whitfield, John B.
AU - Visscher, Peter M.
N1 - Funding Information:
This work was supported by the National Health and Medical Research Council of Australia (NHMRC). The genotyping was performed at the Australian Genome Research Facility and the Finnish Genome Center. The GenomEUtwin project is supported by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th Framework Programme (QLG2-CT-2002–01254). We acknowledge support from the Center of Excellence in Complex Disease Genetics of the Academy of Finland. We thank Stuart Macgregor, Rita Middelberg, Harry Beeby, and Dale Nyholt of the Queensland Institute of Medical Research (QIMR) for assistance in data preparation and analysis. We thank Leanne Wallace and Megan Campbell for assistance with sample preparation. We thank Dongliang Ge of Duke Institute for Genome Sciences & Policy for advice on using the WGAViewer software. We thank Nathan Subramaniam and Greg Anderson (QIMR) for helpful discussions. The authors declare that they have no competing financial interests.
PY - 2009/1/9
Y1 - 2009/1/9
N2 - 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 × 10-9; p within-family test = 2.2 × 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 r2 with rs1830084 = 0.86) was significantly associated with serum transferrin (p = 3.0 × 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 ∼40% of genetic variation in serum transferrin (p = 7.8 × 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.
AB - 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 × 10-9; p within-family test = 2.2 × 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 r2 with rs1830084 = 0.86) was significantly associated with serum transferrin (p = 3.0 × 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 ∼40% of genetic variation in serum transferrin (p = 7.8 × 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.
UR - http://www.scopus.com/inward/record.url?scp=58049202750&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2008.11.011
DO - 10.1016/j.ajhg.2008.11.011
M3 - Article
C2 - 19084217
AN - SCOPUS:58049202750
SN - 0002-9297
VL - 84
SP - 60
EP - 65
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -