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

      research-article
      1 , 2 , 1 , 2 , 1 , 2 , 2 , 2 , 2 , 1 , 3 , 2 , 2 , 4 , 4 , 4 , 5 , 6 , 6 , 4 ,   3 , 7 , 8 , 6 , 9 , 10 , 6 , 11 , 12 , 1 , 4 , 5 , 1 , 13 , 2 , 14 , 2 , 14 , * , 1 , 15 , 16 , 17 , *
      PLoS Genetics
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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 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 Summary

          Genome-wide association studies have in recent years revealed a wealth of common variants associated with common diseases and phenotypes. We took advantage of the advances in sequencing technologies to study the association of low frequency and rare variants in conjunction with common variants with serum levels of vitamin B 12 (B 12) and folate in Icelanders and Danes. We found 18 independent signals in 13 loci associated with serum B 12 or folate levels. Interestingly, 13 of the 18 identified variants are coding and 11 of the 13 target genes have known functions related to B 12 and folate pathways. These data indicate that the target genes at all of the loci have been identified. Epidemiological studies have shown a relationship between serum B 12 and folate levels and the risk of cardiovascular diseases, cancers, and Alzheimer's disease. We investigated association between the identified variants and these diseases but did not find consistent association.

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          Genetics of gene expression and its effect on disease.

          Common human diseases result from the interplay of many genes and environmental factors. Therefore, a more integrative biology approach is needed to unravel the complexity and causes of such diseases. To elucidate the complexity of common human diseases such as obesity, we have analysed the expression of 23,720 transcripts in large population-based blood and adipose tissue cohorts comprehensively assessed for various phenotypes, including traits related to clinical obesity. In contrast to the blood expression profiles, we observed a marked correlation between gene expression in adipose tissue and obesity-related traits. Genome-wide linkage and association mapping revealed a highly significant genetic component to gene expression traits, including a strong genetic effect of proximal (cis) signals, with 50% of the cis signals overlapping between the two tissues profiled. Here we demonstrate an extensive transcriptional network constructed from the human adipose data that exhibits significant overlap with similar network modules constructed from mouse adipose data. A core network module in humans and mice was identified that is enriched for genes involved in the inflammatory and immune response and has been found to be causally associated to obesity-related traits.
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            An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people.

            Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases) and geographically localized, so that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. We conclude that because of rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.
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              Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.

              Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD. To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects. Referral population to a hospital clinic between July 1988 and April 1996. Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry. Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (> or = 14 micromol/L) compared with the bottom third (< or = 11 micromol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E epsilon4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry. Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                June 2013
                June 2013
                6 June 2013
                : 9
                : 6
                : e1003530
                Affiliations
                [1 ]The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [2 ]deCODE Genetics, Reykjavik, Iceland
                [3 ]Centre of Bioinformatics, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
                [4 ]BGI-Shenzhen, Shenzhen, China
                [5 ]Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
                [6 ]Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
                [7 ]Department of Integrative Biology, University of California, Berkeley, Berkeley, California, United States of America
                [8 ]Department of Statistics, University of California, Berkeley, Berkeley, California, United States of America
                [9 ]Landspitali, The National University Hospital of Iceland, Department of Clinical Biochemistry, Reykjavik, Iceland
                [10 ]Icelandic Medical Center (Laeknasetrid) Laboratory in Mjodd (RAM), Reykjavik, Iceland
                [11 ]Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [12 ]Faculty of Medicine, University of Aalborg, Aalborg, Denmark
                [13 ]Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
                [14 ]University of Iceland Faculty of Medicine, Reykjavik, Iceland
                [15 ]Faculty of Health Sciences, Aarhus University, Aarhus, Denmark
                [16 ]Hagedorn Research Institute, Gentofte, Denmark
                [17 ]Institute of Biomedical Science, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                Dartmouth College, United States of America
                Author notes
                * E-mail: kstefans@ 123456decode.is (K. Stefánsson); oluf@ 123456sund.ku.dk (O. Pedersen)

                I have read the journal's policy and declare that the authors from deCODE Genetics (P. Sulem, G. Thorleifsson, V. Steinthorsdottir, H. Bjarnason, D. F. Gudbjartsson, O. T. Magnusson, A. Kong, G. Masson, U. Thorsteinsdottir, and K. Stefánsson) are employees of deCODE Genetics or own stock options in deCODE Genetics. The remaining authors have declared that no competing interests exist.

                Conceived and designed the experiments: N. Grarup, P. Sulem, C.H. Sandholt, T. Jørgensen, U. Thorsteinsdottir, K. Stefánsson, O. Pedersen. Performed the experiments: I. Olafsson, G.I. Eyjolfsson, A. Linneberg, L.L. Husemoen, B. Thuesen, T. Hansen, O. Pedersen, T. Jørgensen, P. Sulem, D.F. Gudbjartsson, H. Bjarnason, G. Thorleifsson, A. Kong, V. Steinthorsdottir, G. Masson, O.T. Magnusson, U. Thorsteinsdottir, K. Stefánsson, N. Grarup, C.H. Sandholt, T. Sparsø, A. Albrechtsen, G. Tian, H. Cao, C. Nie, K. Kristiansen, Y. Li, R. Nielsen, J. Wang. Analyzed the data: N. Grarup, P. Sulem, T.S. Ahluwalia, H. Bjarnason, T. Sparsø, A. Albrechtsen, A. Kong, G. Masson. Contributed reagents/materials/analysis tools: A. Albrechtsen, A. Kong, G. Masson. Wrote the paper: N. Grarup, P. Sulem, C.H. Sandholt, T. Jørgensen, U. Thorsteinsdottir, K. Stefánsson, O. Pedersen. Recruited participants study and collected clinical or paraclinical information: I. Olafsson, G.I. Eyjolfsson, A. Linneberg, L.L. Husemoen, B. Thuesen, N. Grarup, T. Hansen, O. Pedersen, T. Jørgensen. Developed, analyzed and interpreted Icelandic whole genome sequencing and chip-genotyping data: P. Sulem, H. Bjarnason, D.F. Gudbjartsson, G. Thorleifsson, A. Kong, V. Steinthorsdottir, G. Masson, O.T. Magnusson, U. Thorsteinsdottir, K. Stefánsson. Developed, analyzed, and interpreted Danish exome sequencing and chip-genotyping data: N. Grarup, C.H. Sandholt, T. Sparsø, A. Albrechtsen, G. Tian, H. Cao, C. Nie, K. Kristiansen, Y. Li, R. Nielsen, A. Linneberg, T. Jørgensen, J. Wang, T. Hansen, O. Pedersen.

                Article
                PGENETICS-D-12-03166
                10.1371/journal.pgen.1003530
                3674994
                23754956
                6b3e34d9-7791-4527-afa4-3f492b528cd6
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 20 December 2012
                : 11 April 2013
                Page count
                Pages: 12
                Funding
                This project was funded by the ENGAGE project (HEALTH-F4-2007-201413) and by the Lundbeck Foundation (The Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp), www.lucamp.org). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation ( www.metabol.ku.dk). Further funding came from the Danish Council for Independent Research (Medical Sciences). The Inter99 study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk Inc., Research Foundation of Copenhagen County, Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation, and the Danish Diabetes Association. The Health2006 was financially supported by grants from the Velux Foundation; The Danish Medical Research Council, Danish Agency for Science, Technology and Innovation; The Aase and Ejner Danielsens Foundation; ALK-Abelló A/S, Hørsholm, Denmark, and Research Centre for Prevention and Health, the Capital Region of Denmark. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genetics
                Human Genetics
                Genome-Wide Association Studies
                Genome-Wide Association Studies
                Genomics
                Genome Sequencing
                Medicine
                Epidemiology
                Disease Mapping
                Genetic Epidemiology

                Genetics
                Genetics

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