Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets

Grarup, Niels, Sulem, Patrick, Sandholt, Camilla H., Thorleifsson, Gudmar, Ahluwalia, Tarunveer S., Steinthorsdottir, Valgerdur, Bjarnason, Helgi, Gudbjartsson, Daniel F., Magnusson, Olafur T., Sparso, Thomas, Albrechtsen, Anders, Kong, Augustine, Masson, Gisli, Tian, Geng, Cao, Hongzhi, Nie, Chao, Kristiansen, Karsten, Husemoen, Lise Lotte, Thuesen, Betina, Li, Yingrui, Nielsen, Rasmus, Linneberg, Allan, Olafsson, Isleifur, Eyjolfsson, Gudmundur I., Jorgensen, Torben, Wang, Jun, Hansen, Torben, Thorsteinsdottir, Unnur, Stefansson, Kari and Pedersen, Oluf (2013) Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS Genetics, 9 6: . doi:10.1371/journal.pgen.1003530

Author Grarup, Niels
Sulem, Patrick
Sandholt, Camilla H.
Thorleifsson, Gudmar
Ahluwalia, Tarunveer S.
Steinthorsdottir, Valgerdur
Bjarnason, Helgi
Gudbjartsson, Daniel F.
Magnusson, Olafur T.
Sparso, Thomas
Albrechtsen, Anders
Kong, Augustine
Masson, Gisli
Tian, Geng
Cao, Hongzhi
Nie, Chao
Kristiansen, Karsten
Husemoen, Lise Lotte
Thuesen, Betina
Li, Yingrui
Nielsen, Rasmus
Linneberg, Allan
Olafsson, Isleifur
Eyjolfsson, Gudmundur I.
Jorgensen, Torben
Wang, Jun
Hansen, Torben
Thorsteinsdottir, Unnur
Stefansson, Kari
Pedersen, Oluf
Title Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7390
Publication date 2013-06-06
Year available 2013
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1003530
Open Access Status DOI
Volume 9
Issue 6
Total pages 12
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Formatted 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 B12 (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B12 and folate measurements, respectively. We found six novel loci associating with serum B12 (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 B12 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 B12 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Chemistry and Molecular Biosciences
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Citation counts: TR Web of Science Citation Count  Cited 29 times in Thomson Reuters Web of Science Article | Citations
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