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

Niels Grarup; Patrick Sulem; Camilla H Sandholt; Gudmar Thorleifsson; Tarun Veer Singh Ahluwalia; Valgerdur Steinthorsdottir; Helgi Bjarnason; Daniel F Gudbjartsson; Olafur T Magnusson; Thomas Sparsø; Anders Albrechtsen; Augustine Kong; Gisli Masson; Geng Tian; Hongzhi Cao; Chao Nie; Karsten Kristiansen; Lise Lotte Husemoen; Betina Thuesen; Yingrui Li; Rasmus Nielsen; Allan Linneberg; Isleifur Olafsson; Gudmundur I Eyjolfsson; Torben Jørgensen; Jun Wang; Torben Hansen; Unnur Thorsteinsdottir; Kari Stefánsson; Oluf Borbye Pedersen

doi:10.1371/journal.pgen.1003530

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

Niels Grarup, Patrick Sulem, Camilla H Sandholt, Gudmar Thorleifsson, Tarun Veer Singh Ahluwalia, Valgerdur Steinthorsdottir, Helgi Bjarnason, Daniel F Gudbjartsson, Olafur T Magnusson, Thomas Sparsø, Anders Albrechtsen, Augustine Kong, Gisli Masson, Geng Tian, Hongzhi Cao, Chao Nie, Karsten Kristiansen, Lise Lotte Husemoen, Betina Thuesen, Yingrui LiRasmus Nielsen, Allan Linneberg, Isleifur Olafsson, Gudmundur I Eyjolfsson, Torben Jørgensen, Jun Wang, Torben Hansen, Unnur Thorsteinsdottir, Kari Stefánsson, Oluf Borbye Pedersen

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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.

Original language	English
Article number	e1003530
Journal	P L o S Genetics
Volume	9
Issue number	6
Number of pages	12
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1003530
Publication status	Published - Jun 2013

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Grarup, N., Sulem, P., Sandholt, C. H., Thorleifsson, G., Ahluwalia, T. V. S., Steinthorsdottir, V., Bjarnason, H., Gudbjartsson, D. F., Magnusson, O. T., Sparsø, T., Albrechtsen, A., Kong, A., Masson, G., Tian, G., Cao, H., Nie, C., Kristiansen, K., Husemoen, L. L., Thuesen, B., ... Pedersen, O. B. (2013). Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. P L o S Genetics, 9(6), Article e1003530. https://doi.org/10.1371/journal.pgen.1003530

Grarup, N, Sulem, P, Sandholt, CH, Thorleifsson, G, Ahluwalia, TVS, 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 & Pedersen, OB 2013, 'Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets', P L o S Genetics, vol. 9, no. 6, e1003530. https://doi.org/10.1371/journal.pgen.1003530

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title = "Genetic architecture of vitamin B12 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 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.",

author = "Niels Grarup and Patrick Sulem and Sandholt, {Camilla H} and Gudmar Thorleifsson and Ahluwalia, {Tarun Veer Singh} and Valgerdur Steinthorsdottir and Helgi Bjarnason and Gudbjartsson, {Daniel F} and Magnusson, {Olafur T} and Thomas Spars{\o} and Anders Albrechtsen and Augustine Kong and Gisli Masson and Geng Tian and Hongzhi Cao and Chao Nie and Karsten Kristiansen and Husemoen, {Lise Lotte} and Betina Thuesen and Yingrui Li and Rasmus Nielsen and Allan Linneberg and Isleifur Olafsson and Eyjolfsson, {Gudmundur I} and Torben J{\o}rgensen and Jun Wang and Torben Hansen and Unnur Thorsteinsdottir and Kari Stef{\'a}nsson and Pedersen, {Oluf Borbye}",

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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 - 2013/6

Y1 - 2013/6

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

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SN - 1553-7390

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JO - P L o S Genetics

JF - P L o S Genetics

IS - 6

M1 - e1003530

ER -

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

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