Paradoxical Relationship Between Body Mass Index and Thyroid Hormone Levels: A Study Using Mendelian Randomization
Open accessAbstract
CONTEXT: Free T3 (FT3) has been positively associated with body mass index (BMI) in cross-sectional studies in healthy individuals. This is difficult to reconcile with clinical findings in pathological thyroid dysfunction. OBJECTIVE: We aimed to investigate whether childhood adiposity influences FT3 levels. DESIGN: Mendelian randomization using genetic variants robustly associated with BMI. SETTING: Avon Longitudinal Study of Parents and Children, a population-based birth cohort. PARTICIPANTS: A total of 3014 children who had thyroid function measured at age 7, who also underwent dual x-ray absorptiometry scans at ages 9.9 and 15.5 years and have genetic data available. MAIN OUTCOME MEASURES: FT3. RESULTS: Observationally at age 7 years, BMI was positively associated with FT3: β-standardized (β-[std]) = 0.12 (95% confidence interval [CI]: 0.08, 0.16), P = 4.02 × 10(-10); whereas FT4 was negatively associated with BMI: β-(std) = -0.08 (95% CI: -0.12, -0.04), P = 3.00 × 10(-5). These differences persisted after adjustment for age, sex, and early life environment. Genetic analysis indicated 1 allele change in BMI allelic score was associated with a 0.04 (95% CI: 0.03, 0.04) SD increase in BMI (P = 6.41 × 10(-17)). At age 7, a genetically determined increase in BMI of 1.89 kg/m(2) was associated with a 0.22 pmol/L (95% CI: 0.07, 0.36) increase in FT3 (P = .004) but no substantial change in FT4 0.01 mmol/L, (95% CI: -0.37, 0.40), P = .96. CONCLUSION: Our analysis shows that children with a genetically higher BMI had higher FT3 but not FT4 levels, indicating that higher BMI/fat mass has a causal role in increasing FT3 levels. This may explain the paradoxical associations observed in observational analyses. Given rising childhood obesity levels, this relationship merits closer scrutiny.
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Cross-sectional studies generally show higher TSH upper limits in younger children (<5 years) compared with older children (≥5 years), with a gradual decline in TSH concentration towards adult age (15-18 years), and lower FT3 with higher increases in FT4 concentrations from age 4 years.
“Cross-sectional studies generally show higher TSH upper limits in younger children (<5 years) compared with older children (≥5 years), with a gradual decline in TSH concentration towards adult age (15-18 years), 119-124 and lower FT3 with higher increases in FT4 concentrations from age 4 years.[125][126][127][128]”
From Hypothyroidism (2024) · cites this paper as [125]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredFT3 shows a strong relationship with fat mass during pubertal development.
“Free triiodothyronine (FT3) levels fall with age and appear to play a role in pubertal development, during which it shows a strong relationship with fat mass.”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [49]
A Mendelian Randomization study in the ALSPAC cohort identified that higher levels of fat mass appeared to result in higher levels of FT3, particularly in younger children.
“Intriguingly, a Mendelian Randomization study in our cohort identified that higher levels of fat mass appeared to result in higher levels of FT3 particularly in younger children [49].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [49]
The effect of fat mass on FT3 is less apparent in older children and may be diminished in adults.
“This effect was less apparent in older children and may be diminished in adults.”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [49]
Using 97 recently reported independent SNPs to index BMI minimized the risk of shared pleiotropy and linkage-disequilibrium-induced confounding pleiotropic effects.
“However, using as many as 97 recently reported independent SNPs to index BMI, we were able to minimize the risk of shared pleiotropy and linkage-disequilibrium-induced confounding pleiotropic effects [32, 33].”
From Causal relationship between obesity and serum testosterone status in men: A bi-directional mendelian randomization analysis (2017) · cites this paper as [33]
The use of two separate independent genetic instruments with similar point estimates of the causal effect of BMI on serum testosterone further reduced the risk of pleiotropy.
“Moreover, the use of two separate independent genetic instruments with similar point estimates of the causal effect of BMI on serum T further reduced the risk of pleiotropy [32, 33].”
From Causal relationship between obesity and serum testosterone status in men: A bi-directional mendelian randomization analysis (2017) · cites this paper as [33]
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- Authors
- Taylor, P. N., Richmond, R., Davies, N., Sayers, A., Stevenson, K., Woltersdorf, W., Taylor, A., Groom, A., Northstone, K., Ring, S., Okosieme, O., Rees, A., Nitsch, D., Williams, G. R., Smith, G. D., Gregory, J. W., Timpson, N. J., Tobias, J. H., & Dayan, C. M.
- Affiliations
- Bristol Royal Infirmary (GB)
- National Health Service (GB)
- Royal United Hospital (GB)
- Southmead Hospital (GB)
- Corresponding author
- Taylor, Peter N.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-02
- Volume
- 101
- Issue
- 2
- Pages
- 730-738
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC4880123
- OpenAlex
- W2179471409
- Cited by
- 48
- References
- 46
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 10 · 2020: 8 · 2019: 3 · 2018: 2 · 2017: 9 · 2016: 4 · 2015: 1
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Wellcome Trust (102215/2/13/2), 102215)
- Cardiff University
- University of Bristol (102215/2/13/2)
- British Thyroid Foundation
- Medical Research Council (102215, 102215/2/13/2, MC_PC_15018)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- body mass index, free thyroxine, free triiodothyronine, thyroid hormone levels, childhood obesity, childhood adiposity, thyroid function, fat mass, Avon Longitudinal Study of Parents and Children
- MeSH terms
- Age Factors, Child, Environment, Female, Genotype, Humans, Longitudinal Studies, Male, Prospective Studies, Random Allocation, Sex Factors, Thyroid Hormones, Thyroxine, Triiodothyronine, Genetic Variation, Cohort Studies, Body Mass Index, Polymorphism, Single Nucleotide, Adiposity, Mendelian Randomization Analysis, Pediatric Obesity
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