Genome-wide association and Mendelian randomization study of blood copper levels and 213 deep phenotypes in humans

Abstract

Metal elements are present in the human body, and their levels in the blood have important impacts on health. In this study, 2488 Chinese individuals were included in a genome-wide association study of 21 serum metal levels, with approximately 179,000 East Asian individuals in a bidirectional two-sample Mendelian randomization (MR) analysis, and 628,000 Europeans in a two-sample MR analysis. We identified two single nucleotide polymorphisms (SNPs) rs35691438 and rs671 that were significantly associated with serum copper levels (SCLs). The bidirectional two-sample MR analysis in the East Asian population showed that gamma-glutamyl transpeptidase levels have a causal effect on SCLs. SCLs have causal effects on six outcomes, namely risks of esophageal varix, glaucoma, sleep apnea syndrome, and systemic lupus erythematosus, white blood cell count, and usage of drugs affecting bone structure and mineralization. The two-sample MR analyses in the European population showed causal effects of erythrocyte copper levels on risks of carpal tunnel syndrome and compression fracture. Our results provide original insights into the causal relationship between blood metal levels and multiple human phenotypes.

Fig. 1. The Manhattan, Quantile-Quantile, and LocusZoom plots of GWAS meta-analysis of serum copper levels.

a Manhattan plot. The X-axis presents the genomic position, while the Y-axis presents the −log₁₀(P) of SNPs. The solid red line is the genome-wide significance threshold (P = 5.0 × 10⁻⁸), and the black dashed line is the genome-wide suggestive threshold (P = 1.0 × 10⁻⁵). b The Quantile-Quantile plot shows the deviation of the observed from the expected P-values under the null hypothesis of no association. c LocusZoom plot for gene CP. Purple diamond indicates SNP at the locus with the strongest association evidence (rs35691438) and the r² (degree of linkage disequilibrium) is 1. Each point represents one SNP. d LocusZoom plot for gene ALDH2. Purple diamond indicates SNP at the locus with the strongest association evidence (rs671) and the r² (degree of linkage disequilibrium) is 1.

Fig. 2. Scatter plots for four robust results in the first round two-sample Mendelian randomization analyses.

The error bars indicate standard error. a Usage of drugs affecting bone structure and mineralization. b Esophageal varix. c Glaucoma. d Sleep apnea syndrome. MR Mendelian randomization.

Fig. 3. Plots of leave-one-out analyses for four robust results in the first round two-sample Mendelian randomization analyses.

The error bars indicate the 95% confidence interval. a Usage of drugs affecting bone structure and mineralization. b Esophageal varix. c Glaucoma. d Sleep apnea syndrome. MR Mendelian randomization.

Fig. 4. Scatter and leave-one-out analyses plots for two robust results in the first round two-sample Mendelian randomization analyses and one robust result in the second round two-sample Mendelian randomization analyses.

The error bars in panels a–c indicate standard error. The error bars in panels d–f indicate the 95% confidence interval. a, d Systemic lupus erythematosus. b, e White blood cell count. c, f Gamma-glutamyl transpeptidase levels are exposure factors, and serum copper levels are the outcome. MR Mendelian randomization.

Fig. 5. Scatter and leave-one-out analyses plots for two robust results in the third round two-sample Mendelian randomization analyses.

The error bars in panels a and b indicate standard error. The error bars in panels c and d indicate the 95% confidence interval. a, c Carpal tunnel syndrome. b, d Compression fracture. MR Mendelian randomization.

Fig. 6. Flow chart of the two-sample Mendelian randomization analysis in East Asian and European populations.

IVs instrumental variables, MR Mendelian randomization, IVW inverse-variance weighted, WM weighted median, MR-PRESSO Mendelian randomization pleiotropy residual sum and outlier.