Journal
PLOS GENETICS
Volume 9, Issue 6, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1003530
Keywords
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Funding
- ENGAGE [HEALTH-F4-2007-201413]
- Lundbeck Foundation (The Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care)
- Novo Nordisk Foundation
- Danish Council for Independent Research (Medical Sciences)
- Danish Research Council
- Danish Centre for Health Technology Assessment
- Novo Nordisk Inc.
- Research Foundation of Copenhagen County
- Ministry of Internal Affairs and Health
- Danish Heart Foundation
- Danish Pharmaceutical Association
- Augustinus Foundation
- Ib Henriksen Foundation
- Becket Foundation
- Danish Diabetes Association
- Velux Foundation
- Danish Medical Research Council, Danish Agency for Science, Technology and Innovation
- Aase and Ejner Danielsens Foundation
- ALK-Abello A/S, Horsholm, Denmark
- Research Centre for Prevention and Health, the Capital Region of Denmark
- Villum Fonden [00007171] Funding Source: researchfish
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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 (B-12) 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.
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