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.
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 test...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
OUP
2018
|
Subjects: | |
Online Access: | https://www.repository.cam.ac.uk/handle/1810/282983 https://doi.org/10.17863/CAM.30345 |
id |
ftunivcam:oai:www.repository.cam.ac.uk:1810/282983 |
---|---|
record_format |
openpolar |
spelling |
ftunivcam:oai:www.repository.cam.ac.uk:1810/282983 2024-02-04T10:03:15+01:00 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. Teslovich, Tanya M Kim, Daniel Seung Yin, Xianyong Stancáková, Alena Jackson, Anne U Wielscher, Matthias Naj, Adam Perry, John RB Huyghe, Jeroen R Stringham, Heather M Davis, James P Raulerson, Chelsea K Welch, Ryan P Fuchsberger, Christian Locke, Adam E Sim, Xueling Chines, Peter S Narisu, Narisu Kangas, Antti J Soininen, Pasi Genetics of Obesity-Related Liver Disease Consortium (GOLD), The Alzheimer's Disease Genetics Consortium (ADGC), The DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Ala-Korpela, Mika Gudnason, Vilmundur Musani, Solomon K Jarvelin, Marjo-Riitta Schellenberg, Gerard D Speliotes, Elizabeth K Kuusisto, Johanna Collins, Francis S Boehnke, Michael Laakso, Markku Mohlke, Karen L 2018-05-01 application/vnd.openxmlformats-officedocument.wordprocessingml.document https://www.repository.cam.ac.uk/handle/1810/282983 https://doi.org/10.17863/CAM.30345 eng eng OUP https://academic.oup.com/hmg/article/27/9/1664/4899080 Human Molecular Genetics https://www.repository.cam.ac.uk/handle/1810/282983 doi:10.17863/CAM.30345 Amino Acids Finland Gene Frequency Genome-Wide Association Study Genotype Humans Male Middle Aged Article 2018 ftunivcam https://doi.org/10.17863/CAM.30345 2024-01-11T23:25:58Z 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. Article in Journal/Newspaper Northern Finland Apollo - University of Cambridge Repository |
institution |
Open Polar |
collection |
Apollo - University of Cambridge Repository |
op_collection_id |
ftunivcam |
language |
English |
topic |
Amino Acids Finland Gene Frequency Genome-Wide Association Study Genotype Humans Male Middle Aged |
spellingShingle |
Amino Acids Finland Gene Frequency Genome-Wide Association Study Genotype Humans Male Middle Aged Teslovich, Tanya M Kim, Daniel Seung Yin, Xianyong Stancáková, Alena Jackson, Anne U Wielscher, Matthias Naj, Adam Perry, John RB Huyghe, Jeroen R Stringham, Heather M Davis, James P Raulerson, Chelsea K Welch, Ryan P Fuchsberger, Christian Locke, Adam E Sim, Xueling Chines, Peter S Narisu, Narisu Kangas, Antti J Soininen, Pasi Genetics of Obesity-Related Liver Disease Consortium (GOLD), The Alzheimer's Disease Genetics Consortium (ADGC), The DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Ala-Korpela, Mika Gudnason, Vilmundur Musani, Solomon K Jarvelin, Marjo-Riitta Schellenberg, Gerard D Speliotes, Elizabeth K Kuusisto, Johanna Collins, Francis S Boehnke, Michael Laakso, Markku Mohlke, Karen L 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. |
topic_facet |
Amino Acids Finland Gene Frequency Genome-Wide Association Study Genotype Humans Male Middle Aged |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Teslovich, Tanya M Kim, Daniel Seung Yin, Xianyong Stancáková, Alena Jackson, Anne U Wielscher, Matthias Naj, Adam Perry, John RB Huyghe, Jeroen R Stringham, Heather M Davis, James P Raulerson, Chelsea K Welch, Ryan P Fuchsberger, Christian Locke, Adam E Sim, Xueling Chines, Peter S Narisu, Narisu Kangas, Antti J Soininen, Pasi Genetics of Obesity-Related Liver Disease Consortium (GOLD), The Alzheimer's Disease Genetics Consortium (ADGC), The DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Ala-Korpela, Mika Gudnason, Vilmundur Musani, Solomon K Jarvelin, Marjo-Riitta Schellenberg, Gerard D Speliotes, Elizabeth K Kuusisto, Johanna Collins, Francis S Boehnke, Michael Laakso, Markku Mohlke, Karen L |
author_facet |
Teslovich, Tanya M Kim, Daniel Seung Yin, Xianyong Stancáková, Alena Jackson, Anne U Wielscher, Matthias Naj, Adam Perry, John RB Huyghe, Jeroen R Stringham, Heather M Davis, James P Raulerson, Chelsea K Welch, Ryan P Fuchsberger, Christian Locke, Adam E Sim, Xueling Chines, Peter S Narisu, Narisu Kangas, Antti J Soininen, Pasi Genetics of Obesity-Related Liver Disease Consortium (GOLD), The Alzheimer's Disease Genetics Consortium (ADGC), The DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Ala-Korpela, Mika Gudnason, Vilmundur Musani, Solomon K Jarvelin, Marjo-Riitta Schellenberg, Gerard D Speliotes, Elizabeth K Kuusisto, Johanna Collins, Francis S Boehnke, Michael Laakso, Markku Mohlke, Karen L |
author_sort |
Teslovich, Tanya M |
title |
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. |
title_short |
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. |
title_full |
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. |
title_fullStr |
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. |
title_full_unstemmed |
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. |
title_sort |
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. |
publisher |
OUP |
publishDate |
2018 |
url |
https://www.repository.cam.ac.uk/handle/1810/282983 https://doi.org/10.17863/CAM.30345 |
genre |
Northern Finland |
genre_facet |
Northern Finland |
op_relation |
https://www.repository.cam.ac.uk/handle/1810/282983 doi:10.17863/CAM.30345 |
op_doi |
https://doi.org/10.17863/CAM.30345 |
_version_ |
1789970526575263744 |