TY - JOUR
T1 - Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets
AU - Grarup, Niels
AU - Sulem, Patrick
AU - Sandholt, Camilla H
AU - Thorleifsson, Gudmar
AU - Ahluwalia, Tarun Veer Singh
AU - Steinthorsdottir, Valgerdur
AU - Bjarnason, Helgi
AU - Gudbjartsson, Daniel F
AU - Magnusson, Olafur T
AU - Sparsø, Thomas
AU - Albrechtsen, Anders
AU - Kong, Augustine
AU - Masson, Gisli
AU - Tian, Geng
AU - Cao, Hongzhi
AU - Nie, Chao
AU - Kristiansen, Karsten
AU - Husemoen, Lise Lotte
AU - Thuesen, Betina
AU - Li, Yingrui
AU - Nielsen, Rasmus
AU - Linneberg, Allan
AU - Olafsson, Isleifur
AU - Eyjolfsson, Gudmundur I
AU - Jørgensen, Torben
AU - Wang, Jun
AU - Hansen, Torben
AU - Thorsteinsdottir, Unnur
AU - Stefánsson, Kari
AU - Pedersen, Oluf Borbye
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pgen.1003530
DO - 10.1371/journal.pgen.1003530
M3 - Journal article
C2 - 23754956
VL - 9
JO - P L o S Genetics
JF - P L o S Genetics
SN - 1553-7390
IS - 6
M1 - e1003530
ER -