- Home
- About
- Collaborative Data Access (SAGs)
- Publications
- For Members
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. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Teslovich TM, Kim DSeung, Yin X, Stancáková A, Jackson AU, Wielscher M, Naj A, Perry JRB, Huyghe JR, Stringham HM, Davis JP, Raulerson CK, Welch RP, Fuchsberger C, Locke AE, Sim X, Chines PS, Narisu N, Kangas AJ, Soininen P, Ala-Korpela M, Gudnason V, Musani SK, Jarvelin M-R, Schellenberg GD, Speliotes EK, Kuusisto J, Collins FS, Boehnke M, Laakso M, Mohlke KL |
Corporate Authors | Genetics of Obesity-Related Liver Disease Consortium(GOLD), The Alzheimer's Disease Genetics Consortium(ADGC), The DIAbetes Genetics Replication And Meta-analysis(DIAGRAM) |
Journal | Hum Mol Genet |
Volume | 27 |
Issue | 9 |
Pagination | 1664-1674 |
Date Published | 2018 05 01 |
ISSN | 1460-2083 |
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. |
DOI | 10.1093/hmg/ddy067 |
Alternate Journal | Hum. Mol. Genet. |
PubMed ID | 29481666 |
PubMed Central ID | PMC5905595 |
Grant List | RL1 MH083268 / MH / NIMH NIH HHS / United States R01 DK106621 / DK / NIDDK NIH HHS / United States T32 GM067553 / GM / NIGMS NIH HHS / United States R01 DK072193 / DK / NIDDK NIH HHS / United States R01 DK093757 / DK / NIDDK NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States MC_UU_1201/1 / / Medical Research Council / United Kingdom R01 MH063706 / MH / NIMH NIH HHS / United States G0500539 / / Medical Research Council / United Kingdom R01 DK062370 / DK / NIDDK NIH HHS / United States T32 HL129982 / HL / NHLBI NIH HHS / United States U01 DK105561 / DK / NIDDK NIH HHS / United States U01 DK062370 / DK / NIDDK NIH HHS / United States Z01 HG000024 / HG / NHGRI NIH HHS / United States R01 DK107904 / DK / NIDDK NIH HHS / United States P30 DK020572 / DK / NIDDK NIH HHS / United States R01 HL087679 / HL / NHLBI NIH HHS / United States G1002319 / / Medical Research Council / United Kingdom G0600705 / / Medical Research Council / United Kingdom |