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.