rs1145084 (GATM): Creatine and Kidney Function Variant
Key takeaways
- Two large-scale GWAS studies link this GATM variant to both blood creatine levels and creatinine-based kidney function (eGFR).
- A kidney function GWAS in over 1.2 million people identified 424 associated loci explaining 9.8% of eGFR variance.
- Creatine was among the most polygenic non-lipid metabolites in a 233-trait GWAS of 136,016 participants, with 49 loci.
- GTEx tissue data show this variant reduces expression of two nearby genes across nerve, skin, thyroid, artery, muscle, and fat.
Key takeaways
- Two large-scale genome-wide studies link the GATM locus to circulating creatine levels and to creatinine-based kidney filtration estimates (eGFR).
- A GWAS of 233 metabolic traits in up to 136,016 participants found creatine among the most polygenic non-lipid metabolites, with 49 associated loci.
- A kidney function GWAS in over 1.2 million individuals identified 424 eGFR loci (201 novel), collectively explaining 9.8% of its variance.
- GTEx v11 data show this variant reduces expression of two nearby genes across nerve, skin, thyroid, artery, muscle, and fat tissue.
What the research says A genome-wide association meta-analysis of 233 circulating metabolic traits - measured by nuclear magnetic resonance spectroscopy across 33 cohorts in up to 136,016 participants - identified more than 400 independent loci and found creatine to be among the most polygenic non-lipid metabolic traits, with associations at 49 loci. A separate kidney function meta-analysis in 1,201,909 individuals identified 424 loci (201 novel) for creatinine-based estimated glomerular filtration rate (eGFR, a standard clinical measure of kidney filtering capacity), explaining 9.8% of its variance; the authors explicitly note that serum creatinine is a metabolite from muscle metabolism and may not reflect only kidney function. GTEx v11 eQTL data (953 donors, FDR < 0.05) show that rs1145084 is associated with reduced expression of two nearby genes across multiple tissues, with association p values reaching 1.9e-142, indicating a strong regulatory signal at this locus GTEx Portal.
Reported associations
- Circulating creatine: Among 233 metabolic traits studied in up to 136,016 participants, creatine had 49 associated genomic loci, placing it among the highest locus counts of any non-lipid metabolite in the analysis.
- Kidney function (eGFRcrea): In a meta-analysis of 1,201,909 individuals, 424 loci were associated with creatinine-based eGFR, of which 201 were novel; fine-mapping in 1,004,040 individuals resolved 44 signals to a single credible variant and 138 signals to 5 or fewer variants. The study notes that serum creatinine reflects both kidney filtration capacity and muscle metabolism.
- Tissue-specific gene expression: GTEx v11 data link this variant to reduced expression of ENSG00000259433 in two tissues and of SLC28A2-AS1 across six tissues GTEx Portal.
Evidence quality The metabolic GWAS applied a stringent genome-wide significance threshold of P < 1.8 x 10^-9 across 33 cohorts (up to 136,016 participants), providing robust power for common-variant discovery; creatine's 49-locus count places it among the more polygenic non-lipid traits in that analysis. The kidney function GWAS is among the largest reported for this phenotype, with 1,201,909 participants for discovery and 1,004,040 for fine-mapping, resolving 44 signals to a single credible variant. Both studies are predominantly European-ancestry, which limits generalizability to other populations. The two studies address related but distinct traits - circulating creatine and creatinine-based kidney function - and their findings at this locus are consistent with rather than conflicting with each other. The study authors themselves caution that serum creatinine reflects muscle-derived creatine metabolism as well as kidney filtration, a distinction that is directly relevant to interpreting associations at GATM-region loci. GTEx eQTL p values at this locus are exceptionally strong (1.9e-142 for ENSG00000259433 in tibial nerve; 1.1e-131 for SLC28A2-AS1 in the same tissue), but eQTL effects represent tissue-level regulatory associations and do not directly establish clinical disease outcomes GTEx Portal.
Tissue-specific expression effects
- ENSG00000259433: Reduced expression in tibial nerve and sun-exposed lower leg skin, with particularly strong statistical support in both tissues GTEx Portal.
- SLC28A2-AS1: Reduced expression across tibial nerve, thyroid, tibial artery, subcutaneous adipose tissue, sun-exposed lower leg skin, and skeletal muscle - the broadest tissue distribution of any gene at this locus GTEx Portal.
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What does the GATM gene do?
GATM encodes glycine amidinotransferase, the enzyme that catalyzes the first step in creatine biosynthesis. Creatine concentrates in muscle and brain, and its breakdown product creatinine is the molecule measured in standard blood tests to estimate how well kidneys filter waste.
Is rs1145084 associated with kidney disease?
Large-scale genome-wide studies associate this variant with creatinine-based eGFR, a standard kidney function marker. Researchers note that serum creatinine reflects muscle creatine production as well as kidney filtration, so GATM-region variants may influence the eGFR calculation through muscle metabolism rather than kidney health alone.
What is eGFR and how could this variant affect it?
eGFR (estimated glomerular filtration rate) measures how well kidneys filter waste and is calculated from serum creatinine. Because GATM influences creatine and creatinine production in muscle, variants at this locus can affect eGFR scores independent of kidney filtration capacity itself.
What tissues are affected by rs1145084?
GTEx data from 953 donors show rs1145084 is linked to reduced expression of two nearby genes across tibial nerve, thyroid, tibial artery, subcutaneous fat, sun-exposed skin, and skeletal muscle.
How strong is the evidence for this variant?
Evidence comes from two large meta-analyses - one in 136,016 participants for metabolic traits and one in over 1.2 million individuals for kidney function. GTEx eQTL p values at this locus reach 1.9e-142, indicating very strong regulatory effects on nearby gene expression.