University of Oulu

Tanya M Teslovich, Daniel Seung Kim, Xianyong Yin, Alena Stančáková, Anne U Jackson, Matthias Wielscher, Adam Naj, John R B Perry, Jeroen R Huyghe, Heather M Stringham, James P Davis, Chelsea K Raulerson, Ryan P Welch, Christian Fuchsberger, Adam E Locke, Xueling Sim, Peter S Chines, Narisu Narisu, Antti J Kangas, Pasi Soininen, Genetics of Obesity-Related Liver Disease Consortium (GOLD), The Alzheimer's Disease Genetics Consortium (ADGC), The DIAbetes Genetics Replication And Meta-analysis (DIAGRAM), Mika Ala-Korpela, Vilmundur Gudnason, Solomon K Musani, Marjo-Riitta Jarvelin, Gerard D Schellenberg, Elizabeth K Speliotes, Johanna Kuusisto, Francis S Collins, Michael Boehnke, Markku Laakso, Karen L Mohlke, Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study, Human Molecular Genetics, Volume 27, Issue 9, 01 May 2018, Pages 1664–1674, https://doi.org/10.1093/hmg/ddy067

Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study

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Author: Teslovich, Tanya M1; Kim, Daniel Seung1; Yin, Xianyong1;
Organizations: 1Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA
2Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
3Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA
4Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
5Department of Pathology and Laboratory Medicine, Penn Neurodegeneration Genomics Center
6Departments of Biostatistics, and Epidemiology (DBE) and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, PA 19104, USA
7MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
8Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
9National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
10Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
11NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
12Population Health Science, Bristol Medical School and Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
13Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
14Department of Epidemiology and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, School of Public Health and Preventive Medicine, The Alfred Hospital, Monash University, Melbourne, VIC, Australia
15Icelandic Heart Association and the Faculty of Medicine, University of Iceland, Kopavogur, Iceland
16University of Mississippi Medical Center, Jackson, MS 39213, USA
17Center for Life Course Health Research, Faculty of Medicine and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
18Unit of Primary Care, Oulu University Hospital, Oulu, Finland
19Division of Gastroenterology, Department of Internal Medicine and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 0.5 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019050614504
Language: English
Published: Oxford University Press, 2018
Publish Date: 2019-02-21
Description:

Abstract

Comprehensive metabolite profiling captures many highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serum amino acids (alanine, glutamine, glycine, histidine, isoleucine, leucine, phenylalanine, tyrosine, and valine) and 16.6 million genotyped and imputed variants in 8545 non-diabetic Finnish men from the METabolic Syndrome In Men (METSIM) study with replication in Northern Finland Birth Cohort (NFBC1966). We identified five novel loci associated with amino acid levels (P = < 5×10−8): LOC157273/PPP1R3B with glycine (rs9987289, P = 2.3×10−26); ZFHX3 (chr16:73326579, minor allele frequency (MAF) = 0.42%, P = 3.6×10−9), LIPC (rs10468017, P = 1.5×10−8), and WWOX (rs9937914, P = 3.8×10−8) with alanine; and TRIB1 with tyrosine (rs28601761, P = 8×10−9). Gene-based tests identified two novel genes harboring missense variants of MAF < 1% that show aggregate association with amino acid levels: PYCR1 with glycine (Pgene = 1.5×10−6) and BCAT2 with valine (Pgene = 7.4×10−7); neither gene was implicated by single variant association tests. These findings are among the first applications of gene-based tests to identify new loci for amino acid levels. In addition to the seven novel gene associations, we identified five independent signals at established amino acid loci, including two rare variant signals at GLDC (rs138640017, MAF=0.95%, Pconditional = 5.8×10−40) with glycine levels and HAL (rs141635447, MAF = 0.46%, Pconditional = 9.4×10−11) with histidine levels. Examination of all single variant association results in our data revealed a strong inverse relationship between effect size and MAF (Ptrend<0.001). These novel signals provide further insight into the molecular mechanisms of amino acid metabolism and potentially, their perturbations in disease.

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Series: Human molecular genetics
ISSN: 0964-6906
ISSN-E: 1460-2083
ISSN-L: 0964-6906
Volume: 27
Issue: 9
Pages: 1664 - 1674
DOI: 10.1093/hmg/ddy067
OADOI: https://oadoi.org/10.1093/hmg/ddy067
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
Subjects:
Funding: This study was supported by Academy of Finland grants 77299, 124243, and 141226 (M.L.); the Finnish Heart Foundation (M.L.); the Finnish Diabetes Foundation (M.L.); the Juselius Foundation (M.L.); the Commission of the European Community HEALTH-F2–2007-201681 (M.L.); National Institutes of Health grants R01DK093757 (K.L.M.), R01DK072193 (K.L.M.), U01DK105561 (K.L.M.), R01DK062370 (M.B.), T32 HL129982 (J.P.D.) and T32 GM067553 (C.K.R.); National Human Genome Research Institute Division of Intramural Research project number Z01HG000024 (F.S.C.) and American Heart Association 16POST27250048 (D.S.K.). M.A.K. has been supported by the Sigrid Juselius Foundation and the Strategic Research Funding from the University of Oulu. M.A.K. works in a Unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_1201/1). NFBC1966 received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268–01), NIH/NIMH (5R01MH63706: 02), ENGAGE project and grant agreement HEALTH-F4-2007-201413, EU FP7 EurHEALTHAgeing-277849, the Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and the MRC, Centenary Early Career Award. The program is currently being funded by the H2020-633595 DynaHEALTH action, academy of Finland EGEA-project (285547) and EU H2020 ALEC project (Grant Agreement 633212).
EU Grant Number: (277849) EURHEALTHAGEING - European ResearcH on DevElopmentAL, BirtH and Genetic Determinants of Ageing
(633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
Academy of Finland Grant Number: 285547
Detailed Information: 285547 (Academy of Finland Funding decision)
Copyright information: © The Author(s) 2018. Published by Oxford University Press. All rights reserved.