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PMID:23754956

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Citation

Grarup, N, Sulem, P, Sandholt, CH, Thorleifsson, G, Ahluwalia, TS, Steinthorsdottir, V, Bjarnason, H, Gudbjartsson, DF, Magnusson, OT, Sparsø, T, Albrechtsen, A, Kong, A, Masson, G, Tian, G, Cao, H, Nie, C, Kristiansen, K, Husemoen, LL, Thuesen, B, Li, Y, Nielsen, R, Linneberg, A, Olafsson, I, Eyjolfsson, GI, Jørgensen, T, Wang, J, Hansen, T, Thorsteinsdottir, U, Stefánsson, K and Pedersen, O (2013) Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS Genet. 9:e1003530

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.

Links

PubMed PMC3674994 Online version:10.1371/journal.pgen.1003530

Keywords

Alzheimer Disease/genetics; Alzheimer Disease/metabolism; Denmark; Exome; Folic Acid/blood; Folic Acid/metabolism; Folic Acid Deficiency/genetics; Folic Acid Deficiency/metabolism; Genome, Human; Genome-Wide Association Study; Humans; Iceland; Methylenetetrahydrofolate Reductase (NADPH2)/genetics; Quantitative Trait Loci; Vitamin B 12/blood; Vitamin B 12/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:Q5FWT4

GO:0033328: peroxisome membrane targeting sequence binding

ECO:0000316:

PMID:15133130[1]


F

Figure 3

complete
CACAO 8750

See also

References

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  1. Rottensteiner, H et al. (2004) Peroxisomal membrane proteins contain common Pex19p-binding sites that are an integral part of their targeting signals. Mol. Biol. Cell 15 3406-17 PubMed GONUTS page