Genetic Architecture of Vitamin B-12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets

N. Grarup, P. Sulem, C. H. Sandholt, G. Thorleifsson, T. S. Ahluwalia, V. Steinthorsdottir, H. Bjarnason, D. F. Gudbjartsson, O. T. Magnusson, T. Sparso, A. Albrechtsen, A. Kong, G. Masson, G. Tian, H. Z. Cao, C. Nie, K. Kristiansen, L. L. Husemoen, B. Thuesen, Y. R. Li & 10 andre R. Nielsen, A. Linneberg, I. Olafsson, G. I. Eyjolfsson, T. Jorgensen, J. Wang, Torben Hansen, U. Thorsteinsdottir, K. Stefansson, O. Pedersen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.
OriginalsprogEngelsk
Artikelnummere1003530
TidsskriftP L o S Genetics
Vol/bind9
Udgave nummer6
Antal sider12
ISSN1553-7390
DOI
StatusUdgivet - 2013

Fingeraftryk

vitamin B12
vitamin
folic acid
serum
genome
Exome
Serum
loci
HapMap Project
cardiovascular disease
Genome-Wide Association Study
cancer
Alzheimer disease
quantitative traits
epidemiological studies
cardiovascular diseases
Epidemiologic Studies
Alzheimer Disease
Datasets
gene

Citer dette

Grarup, N., Sulem, P., Sandholt, C. H., Thorleifsson, G., Ahluwalia, T. S., Steinthorsdottir, V., ... Pedersen, O. (2013). Genetic Architecture of Vitamin B-12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets. P L o S Genetics, 9(6), [e1003530]. https://doi.org/10.1371/journal.pgen.1003530
Grarup, N. ; Sulem, P. ; Sandholt, C. H. ; Thorleifsson, G. ; Ahluwalia, T. S. ; Steinthorsdottir, V. ; Bjarnason, H. ; Gudbjartsson, D. F. ; Magnusson, O. T. ; Sparso, T. ; Albrechtsen, A. ; Kong, A. ; Masson, G. ; Tian, G. ; Cao, H. Z. ; Nie, C. ; Kristiansen, K. ; Husemoen, L. L. ; Thuesen, B. ; Li, Y. R. ; Nielsen, R. ; Linneberg, A. ; Olafsson, I. ; Eyjolfsson, G. I. ; Jorgensen, T. ; Wang, J. ; Hansen, Torben ; Thorsteinsdottir, U. ; Stefansson, K. ; Pedersen, O. / Genetic Architecture of Vitamin B-12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets. I: P L o S Genetics. 2013 ; Bind 9, Nr. 6.
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title = "Genetic Architecture of Vitamin B-12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets",
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 (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.",
author = "N. Grarup and P. Sulem and Sandholt, {C. H.} and G. Thorleifsson and Ahluwalia, {T. S.} and V. Steinthorsdottir and H. Bjarnason and Gudbjartsson, {D. F.} and Magnusson, {O. T.} and T. Sparso and A. Albrechtsen and A. Kong and G. Masson and G. Tian and Cao, {H. Z.} and C. Nie and K. Kristiansen and Husemoen, {L. L.} and B. Thuesen and Li, {Y. R.} and R. Nielsen and A. Linneberg and I. Olafsson and Eyjolfsson, {G. I.} and T. Jorgensen and J. Wang and Torben Hansen and U. Thorsteinsdottir and K. Stefansson and O. Pedersen",
year = "2013",
doi = "10.1371/journal.pgen.1003530",
language = "English",
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journal = "P L o S Genetics",
issn = "1553-7390",
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Grarup, N, Sulem, P, Sandholt, CH, Thorleifsson, G, Ahluwalia, TS, Steinthorsdottir, V, Bjarnason, H, Gudbjartsson, DF, Magnusson, OT, Sparso, T, Albrechtsen, A, Kong, A, Masson, G, Tian, G, Cao, HZ, Nie, C, Kristiansen, K, Husemoen, LL, Thuesen, B, Li, YR, Nielsen, R, Linneberg, A, Olafsson, I, Eyjolfsson, GI, Jorgensen, T, Wang, J, Hansen, T, Thorsteinsdottir, U, Stefansson, K & Pedersen, O 2013, 'Genetic Architecture of Vitamin B-12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets', P L o S Genetics, bind 9, nr. 6, e1003530. https://doi.org/10.1371/journal.pgen.1003530

Genetic Architecture of Vitamin B-12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets. / Grarup, N.; Sulem, P.; Sandholt, C. H.; Thorleifsson, G.; Ahluwalia, T. S.; Steinthorsdottir, V.; Bjarnason, H.; Gudbjartsson, D. F.; Magnusson, O. T.; Sparso, T.; Albrechtsen, A.; Kong, A.; Masson, G.; Tian, G.; Cao, H. Z.; Nie, C.; Kristiansen, K.; Husemoen, L. L.; Thuesen, B.; Li, Y. R.; Nielsen, R.; Linneberg, A.; Olafsson, I.; Eyjolfsson, G. I.; Jorgensen, T.; Wang, J.; Hansen, Torben; Thorsteinsdottir, U.; Stefansson, K.; Pedersen, O.

I: P L o S Genetics, Bind 9, Nr. 6, e1003530, 2013.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Genetic Architecture of Vitamin B-12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets

AU - Grarup, N.

AU - Sulem, P.

AU - Sandholt, C. H.

AU - Thorleifsson, G.

AU - Ahluwalia, T. S.

AU - Steinthorsdottir, V.

AU - Bjarnason, H.

AU - Gudbjartsson, D. F.

AU - Magnusson, O. T.

AU - Sparso, T.

AU - Albrechtsen, A.

AU - Kong, A.

AU - Masson, G.

AU - Tian, G.

AU - Cao, H. Z.

AU - Nie, C.

AU - Kristiansen, K.

AU - Husemoen, L. L.

AU - Thuesen, B.

AU - Li, Y. R.

AU - Nielsen, R.

AU - Linneberg, A.

AU - Olafsson, I.

AU - Eyjolfsson, G. I.

AU - Jorgensen, T.

AU - Wang, J.

AU - Hansen, Torben

AU - Thorsteinsdottir, U.

AU - Stefansson, K.

AU - Pedersen, O.

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 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.

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 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.

U2 - 10.1371/journal.pgen.1003530

DO - 10.1371/journal.pgen.1003530

M3 - Journal article

VL - 9

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 6

M1 - e1003530

ER -

Grarup N, Sulem P, Sandholt CH, Thorleifsson G, Ahluwalia TS, Steinthorsdottir V et al. Genetic Architecture of Vitamin B-12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets. P L o S Genetics. 2013;9(6). e1003530. https://doi.org/10.1371/journal.pgen.1003530