Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes
Abstract
:1. Introduction
2. Materials and Methods
2.1. Workflow
2.2. Study Populations
2.2.1. Individual-Level Data from the EPIC-Potsdam Study
2.2.2. Summary-Level Data for Single Amino Acids
2.2.3. Summary-Level Data for Type 2 Diabetes
2.2.4. Summary-Level Data for Fasting Insulin
2.3. DNA-Extraction, Genotyping and Quality Control within EPIC-Potsdam
2.4. Metabolite Measurements in EPIC-Potsdam
2.5. Statistical Analysis
2.5.1. Genome-Wide Association Study in EPIC-Potsdam
2.5.2. Gene Set Enrichment Analysis Using EPIC-Potsdam GWAS Data
2.5.3. Two-Sample Mendelian Randomization Analyses Using EPIC-Potsdam GWAS Data on Amino Acids and Ratios
2.5.4. Two-Sample Mendelian Randomization Analyses Using Public GWAS Data on Single Amino Acids
2.5.5. Reverse Two-Sample Mendelian Randomization Analyses of Insulin Resistance and Amino Acids
3. Results
3.1. Selection of Genetic Instruments by GWAS on Amino Acid Traits in EPIC-Potsdam
3.2. Enrichment of Amino Acid-Associated SNPs in Type 2 Diabetes-Related Pathways
3.3. Causal Estimates for Amino Acid Traits on Risk of Type 2 Diabetes
3.4. Causal Estimates for Insulin Resistance on Amino Acid Traits
4. Discussion
4.1. Amino Acids and Type 2 Diabetes
4.2. Biological Mechanisms Linking Tyrosine to Type 2 Diabetes
4.3. Strengths and Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Ethics Approval and Consent to Participate
Availability of Data and Materials
Code Availability
References
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EPIC-Potsdam | |
---|---|
N | 2265 |
Sex (% men) | 37.8 |
Age in years; median (interquartile range) | 49.5 (15.6) |
Waist circumference in cm; mean (SD) | 85.3 (12.6) |
Glycine in μmol/L; median (interquartile range) | 241.0 (86.0) |
Isoleucine + Leucine in μmol/L; median (interquartile range) | 200.0 (70.0) |
Phenylalanine in μmol/L; median (interquartile range) | 55.0 (13.4) |
Tryptophan in μmol/L; median (interquartile range) | 80.0 (15.1) |
Tyrosine in μmol/L; median (interquartile range) | 78.7 (27.1) |
Valine in μmol/L; median (interquartile range) | 286.0 (83.0) |
Amino Acid Trait | SNP | SNP Coordinates | Gene | EA/OA | EAF | N | Beta (SE) | p-Value | Consequence (GRCH37) | CADD-Score [40] |
---|---|---|---|---|---|---|---|---|---|---|
Glycine/Serine | rs1047891 | 2:211540507 | CPS1 | A/C | 0.31 | 2265 | 0.50 (0.03) | 7.58 × 10−54 | Thr1406Asn | 22.1 |
rs2010825 | 7:44188220 | GCK | C/T | 0.51 | 2265 | 0.15 (0.03) | 5.78 × 10−7 | Downstream gene variant | 5.97 | |
rs561931 | 1:120254506 | PHGDH | G/A | 0.61 | 2265 | −0.18 (0.03) | 2.28 × 10−9 | Upstream gene variant | 7.61 | |
rs9851577 | 3:125908310 | ALDH1L1; ALDH1L1-AS2 | T/C | 0.46 | 2265 | 0.15 (0.03) | 7.36 × 10−7 | Intron variant | 2.44 | |
Glycine | rs1047891 | 2:211540507 | CPS1 | A/C | 0.31 | 2264 | 0.59 (0.03) | 2.79 × 10−76 | Thr1406Asn | 22.1 |
rs61992673 | 14:101542105 | AL132709.1; MEG9 | A/C | 0.20 | 2264 | −0.22 (0.04) | 1.62 × 10−8 | Intron variant | 5.34 | |
Phenylalanine/ | rs1451722 | 11:3856553 | RHOG | T/C | 0.58 | 2265 | −0.15 (0.03) | 3.51 × 10−7 | Intron variant | 12.7 |
Arginine | rs1718309 | 12:103242396 | PAH | G/A | 0.60 | 2265 | −0.17 (0.03) | 3.44 × 10−8 | Intron variant | 3.32 |
Phenylalanine | rs55940357 | 19:2610628 | GNG7; CTC-265F19.2 | C/T | 0.88 | 2265 | 0.24 (0.05) | 1.03 × 10−6 | Intron variant | 1.72 |
Serine/ | rs1047891 | 2:211540507 | CPS1 | A/C | 0.31 | 2265 | 0.18 (0.03) | 5.95 × 10−8 | Thr1406Asn | 22.1 |
Phenylalanine | rs11024310 | 11:17520786 | USH1C | G/C | 0.08 | 2265 | −0.31 (0.06) | 9.83 × 10−7 | Intron variant | 1.25 |
rs2992975 | 1:194106746 | - | A/G | 0.41 | 2265 | 0.17 (0.03) | 5.65 × 10−7 | Intergenic variant | 0.63 | |
rs478093 | 1:120255126 | PHGDH | G/A | 0.69 | 2265 | 0.18 (0.03) | 1.27 × 10−8 | Intron variant | 8.15 | |
Tryptophan/ | rs4903067 | 14:73286300 | DPF3 | C/T | 0.34 | 2260 | −0.15 (0.03) | 6.28 × 10−7 | Intron variant | 0.88 |
Glutamine | rs7973936 | 12:64333645 | SRGAP1 | A/G | 0.31 | 2260 | 0.18 (0.03) | 3.07 × 10−8 | Intron variant | 1.58 |
Tyrosine/ | rs12756904 | 1:104337030 | - | C/T | 0.20 | 2261 | −0.18 (0.04) | 1.08 × 10−6 | Intergenic variant | 2.96 |
Methionine | rs17606481 | 6:111542388 | SLC16A10 | G/A | 0.15 | 2261 | 0.28 (0.04) | 1.70 × 10−11 | Intron variant | 2.49 |
rs72792419 | 16:58741949 | GOT2 | C/T | 0.08 | 2261 | −0.30 (0.06) | 6.59 × 10−7 | Downstream gene variant | 4.23 | |
Valine/xLeucine | rs2456586 | 19:51434353 | CTB-147C22.3 | C/T | 0.39 | 2258 | 0.15 (0.03) | 6.11 × 10−7 | Upstream gene variant | 0.64 |
xLeucine/ | rs12642299 | 4:90942633 | - | G/C | 0.67 | 2263 | 0.17 (0.03) | 6.16 × 10−8 | Intergenic variant | 0.99 |
Methionine | rs1958029 | 14:21491151 | NDRG2; AL161668.5; TPPP2 | G/A | 0.11 | 2263 | −0.25 (0.05) | 1.84 × 10−7 | Upstream gene variant | 3.12 |
Amino Acid Trait | Instruments | N (SNPs) a | Beta (SE) from IVW | p-Value | Heterogeneity between SNPs; Q-Statistic, p-Value | Directional Horizontal Pleiotropy b; Egger-Intercept (SE), p-Value | Outlier Detected |
---|---|---|---|---|---|---|---|
Glycine | suggestive | 13/16 | −0.003 (0.011) | 0.804 | no; 12.43,0.41 | no; −0.001 (0.003), 0.85 | no |
genome-wide | 9/11 | −0.005 (0.011) | 0.686 | no; 8.62, 0.38 | no; 0.004 (0.004), 0.37 | no | |
Glycine/Serine | suggestive | 17/18 | 0.018 (0.019) | 0.348 | yes; 48.24, <0.001 | yes; 0.009 (0.004), 0.02 | Yes (rs2010825) |
suggestive (excluding outlier) | 16/17 | −0.001 (0.011) | 0.895 | no; 15.04, 0.45 | no; 0.005 (0.003), 0.15 | - | |
genome-wide | 12/12 | −0.003 (0.012) | 0.800 | no; 10.47, 0.49 | no; 0.006 (0.004), 0.14 | no | |
Phenylalanine | suggestive | 1/1 | 0.053 (0.045) | 0.237 | n.a. | n.a. | n.a. |
Phenylalanine/Arginine | suggestive | 2/2 | 0.043 (0.028) | 0.120 | no; 0.36, 0.54 | n.a. | no |
Serine/Phenylalanine | suggestive | 3/4 | 0.000 (0.023) | 0.990 | no; 0.59, 0.74 | no; 0.08 (0.26), 0.77 | n.a. |
Tryptophan/Glutamine | suggestive | 2/2 | 0.002 (0.028) | 0.931 | no; 0.16, 0.69 | n.a. | n.a. |
Tyrosine/Methionine | suggestive | 4/4 | −0.012 (0.069) | 0.857 | yes; 29.59, <0.001 | no; 0.04 (0.02), 0.08 | n.a. |
genome-wide | 1/1 | −0.141 (0.033) | <0.001 | n.a. | n.a. | n.a. | |
xLeucine/Methionine | suggestive | 2/3 | 0.05 (0.031) | 0.108 | yes; 7.54, 0.01 | n.a. | n.a. |
Valine/xLeucine | suggestive | 1/1 | −0.012 (0.044) | 0.777 | n.a. | n.a. | n.a. |
Data Source | N Variants Used to Calculate Nuisance Parameters | N Variants to Estimate CAUSE Posteriors | Model 1 * | Model 2 * | ∆ ELPD ** | SE ∆ ELPD | z-Score | p-Value |
---|---|---|---|---|---|---|---|---|
Tyrosine from Shin et al. 2014 [11] | 83,936 | 124 | Null | Sharing | −1.1 | 0.74 | −1.5 | 0.069 |
Null | Causal | −4.0 | 3.10 | −1.3 | 0.100 | |||
Sharing | Causal | −2.9 | 2.40 | −1.2 | 0.120 | |||
Tyrosine from Kettunen et al. 2016 [37] | 75,155 | 37 | Null | Sharing | 0.0033 | 0.00061 | 5.4 | 1 |
Null | Causal | 0.0400 | 0.00710 | 5.7 | 1 | |||
Sharing | Causal | 0.0370 | 0.00650 | 5.7 | 1 | |||
Tyrosine from Locke et al. 2019 [38] | 260,603 | 150 | Null | Sharing | −0.4 | 0.49 | −0.82 | 0.210 |
Null | Causal | −4.1 | 2.20 | −1.80 | 0.035 | |||
Sharing | Causal | −3.7 | 1.80 | −2.00 | 0.020 |
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Jäger, S.; Cuadrat, R.; Wittenbecher, C.; Floegel, A.; Hoffmann, P.; Prehn, C.; Adamski, J.; Pischon, T.; Schulze, M.B. Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes. Nutrients 2020, 12, 3890. https://doi.org/10.3390/nu12123890
Jäger S, Cuadrat R, Wittenbecher C, Floegel A, Hoffmann P, Prehn C, Adamski J, Pischon T, Schulze MB. Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes. Nutrients. 2020; 12(12):3890. https://doi.org/10.3390/nu12123890
Chicago/Turabian StyleJäger, Susanne, Rafael Cuadrat, Clemens Wittenbecher, Anna Floegel, Per Hoffmann, Cornelia Prehn, Jerzy Adamski, Tobias Pischon, and Matthias B. Schulze. 2020. "Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes" Nutrients 12, no. 12: 3890. https://doi.org/10.3390/nu12123890
APA StyleJäger, S., Cuadrat, R., Wittenbecher, C., Floegel, A., Hoffmann, P., Prehn, C., Adamski, J., Pischon, T., & Schulze, M. B. (2020). Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes. Nutrients, 12(12), 3890. https://doi.org/10.3390/nu12123890