Hypothyroidism and Kidney Function: A Mendelian Randomization Study

Background: Uncertainty in the mechanism and directionality of observational associations between thyroid function and kidney function may be addressed by genetic analysis with an instrumental variable method termed bidirectional Mendelian randomization (MR). Methods: In the Women's Genome Health Study (WGHS), observational associations between thyroid measures and kidney function were evaluated. Genetic instruments for MR were from recent genome-wide association studies (GWAS) of hypothyroidism, thyrotropin (TSH), and free thyroxine (fT4) concentrations within the reference range, thyroid peroxidase antibodies (TPOAb), estimated glomerular filtration rate from creatinine (eGFRcrea), eGFR from cystatin C (eGFRcys), and chronic kidney disease (CKD). In WGHS individual-level data, these instruments were used for bidirectional MR between thyroid (N = 3336) and kidney (N = 23,186) functions. To increase power, MR was also performed using GWAS summary statistics from the Chronic Kidney Disease Genetics Consortium (CKDGen) for eGFRcrea (N = 567,460), eGFRcys (N = 24,063), CKD N(total) = 480,698, N(cases) = 41,395, and urinary albumin/creatinine ratio (UACR/N = 54,450). Results: In the WGHS, hypothyroidism was observationally associated with decreased eGFRcrea beta (standard error, SE): −0.024 (0.009) ln(mL/min/1.73 m2), p = 0.01. By MR, hypothyroidism was associated with decreased eGFRcrea in the WGHS beta (SE): −0.007 (0.002) per doubled odds hypothyroidism, p = 1.7 × 10−3 and in CKDGen beta (SE): −0.004 (0.0005), p = 2.0 × 10−22, and robust to sensitivity analysis. Hypothyroidism was also associated by MR with increased CKD in CKDGen (odds ratio, OR confidence interval, CI: 1.05 1.03–1.08, p = 3.3 × 10−5), but not in the WGHS (OR CI: 1.02 0.95–1.10, p = 0.57). Increased TSH within the reference range had an MR association with increased eGFRcrea in the WGHS beta (SE): −0.018 (0.007) ln(mL/min/1.73 m2)/standard deviation, SD, p = 6.5 × 10−3 and CKDGen beta (SE): −0.008 (0.001) ln(mL/min/1.73 m2)/SD, p = 6.8 × 10−17, and with CKD in CKDGen (OR CI: 1.10 1.04–1.15, p = 3.1 × 10−4). There were no MR associations of hypothyroidism or TSH with eGFRcys or UACR, and MR associations of fT4 in the reference range with kidney function were inconsistent in both the WGHS and CKDGen. However, by MR in CKDGen, TPOAb were robustly associated with decreased eGFRcrea beta (SE): −0.041 (0.009), p = 6.2 × 10−6 and decreased eGFRcys beta (SE): −0.294 (0.065), p = 6.2 × 10−6. TPOAb were less robustly associated with CKD but not associated with UACR. In reverse MR in the WGHS, kidney function was not consistently associated with thyroid function. Conclusions: Bidirectional MR supports a directional association from hypothyroidism, increased TSH, and TPOAb, but not fT4, to decreased eGFRcrea and increased CKD.