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Meta-Analysis
. 2013 Jun;9(6):e1003530.
doi: 10.1371/journal.pgen.1003530. Epub 2013 Jun 6.

Genetic Architecture of Vitamin B12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets

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Free PMC article
Meta-Analysis

Genetic Architecture of Vitamin B12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets

Niels Grarup et al. PLoS Genet. .
Free PMC article

Abstract

Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.

Conflict of interest statement

I have read the journal's policy and declare that the authors from deCODE Genetics (P. Sulem, G. Thorleifsson, V. Steinthorsdottir, H. Bjarnason, D. F. Gudbjartsson, O. T. Magnusson, A. Kong, G. Masson, U. Thorsteinsdottir, and K. Stefánsson) are employees of deCODE Genetics or own stock options in deCODE Genetics. The remaining authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Schematic overview of the study.
Figure 2
Figure 2. Regional plots illustrating conditional analyses of loci with more than one independent association signal for serum B12 (CUBN, TCN1 and TCN2) or serum folate (MTHFR).
Genotyped and imputed SNVs passing quality control measures in the Icelandic data are plotted with their P-values (as −log10 values) as a function of genomic position (NCBI Build 36). Only SNVs with P<10−5 in at least one of the models are shown. The analyses were performed in 25,960 and 20,717 chip-genotyped Icelanders for B12 and folate, respectively. Data points illustrated by open circles represent unconditional analyses (M0); blue dots are results of analyses conditional on the most significant SNV in M0 (M1) and orange dots are results of analyses conditional on most significant SNVs in M0 and M1. Estimated recombination rates (HapMap CEU) are plotted to reflect the local LD structure. Gene annotations were obtained from RefGene.
Figure 3
Figure 3. Genes that associate with serum B12 and folate levels are in pathways affecting their metabolism.
Genes previously identified to harbor variants regulating serum levels of B12 are shown in green. In blue are novel genes identified in the present study. In red, genes containing variants previously suggested to associate with serum folate and in purple are novel genes for serum folate. B12: vitamin B12; HC: Heptocorrin (TCN1); IF: Intrinsic factor; R-A-P: Receptor-Associated-Protein; CUBN: cubilin (intrinsic factor-cobalamin receptor); TCII: Transcobalamin II (TCN2); TCII-R: Transcobalamin II receptor (CD320); MMACHC: methylmalonic aciduria (cobalamin deficiency) cblC type, with homocystinuria; MMAA: methylmalonic aciduria (cobalamin deficiency) cblA type; ABDC4: ATP-binding cassette, sub-family D (ALD), member 4; LMBD1: LMBR1 domain containing 1; FOLR1–3: folate receptors 1–3; Ado-B12: Adenosyl-cobalamin; Me-B12: Methyl-cobalamin; Me-mal-CoA: Methyl-malonyl-CoenzymeA; Suc-CoA: Succinyl-CoenzymeA; MUT: methylmalonyl-CoA mutase; H. pylori: Helicobacter pylori; DHFR: Dihydrofolate reductase; MS: methionin synthase; THF: Tetrahydrofolate; 5,10-MTHF: 5,10-Methyl-tetrahydrofolate; Hcy: Homocysteine MTHFR: 5-methyl-tetrahydrafolate reductase.

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Grant support

This project was funded by the ENGAGE project (HEALTH-F4-2007-201413) and by the Lundbeck Foundation (The Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp), www.lucamp.org). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). Further funding came from the Danish Council for Independent Research (Medical Sciences). The Inter99 study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk Inc., Research Foundation of Copenhagen County, Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation, and the Danish Diabetes Association. The Health2006 was financially supported by grants from the Velux Foundation; The Danish Medical Research Council, Danish Agency for Science, Technology and Innovation; The Aase and Ejner Danielsens Foundation; ALK-Abelló A/S, Hørsholm, Denmark, and Research Centre for Prevention and Health, the Capital Region of Denmark. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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