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 B(12) (B12) 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.
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.forename: Camilla H
authors.initials: CH
authors.lastname: Sandholt
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Tarunveer S
authors.initials: TS
authors.lastname: Ahluwalia
authors.forename: Valgerdur
authors.initials: V
authors.lastname: Steinthorsdottir
authors.forename: Helgi
authors.initials: H
authors.lastname: Bjarnason
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.forename: Olafur T
authors.initials: OT
authors.lastname: Magnusson
authors.forename: Thomas
authors.initials: T
authors.lastname: Sparsø
authors.forename: Anders
authors.initials: A
authors.lastname: Albrechtsen
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.forename: Geng
authors.initials: G
authors.lastname: Tian
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Cao
authors.forename: Chao
authors.initials: C
authors.lastname: Nie
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.forename: Lise Lotte
authors.initials: LL
authors.lastname: Husemoen
authors.forename: Betina
authors.initials: B
authors.lastname: Thuesen
authors.forename: Yingrui
authors.initials: Y
authors.lastname: Li
authors.forename: Rasmus
authors.initials: R
authors.lastname: Nielsen
authors.forename: Allan
authors.initials: A
authors.lastname: Linneberg
authors.forename: Isleifur
authors.initials: I
authors.lastname: Olafsson
authors.forename: Gudmundur I
authors.initials: GI
authors.lastname: Eyjolfsson
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Kari
authors.initials: K
authors.lastname: Stefánsson
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D003718:Denmark; D059472:Exome; D005492:Folic Acid / Q000097:blood* / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000235:genetics* / Q000378:metabolism; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D007055:Iceland; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D040641:Quantitative Trait Loci; D014805:Vitamin B 12 / Q000097:blood* / Q000378:metabolism
chemical_list: D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12