Evidence map›Paper›PMID 33484127›Full record

SynthesisThe Journal of clinical endocrinology and metabolism2021

Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L.

Nicole Lafontaine, Purdey J Campbell, Juan E Castillo-Fernandez, Shelby Mullin, Ee Mun Lim, Phillip Kendrew, Michelle Lewer, Suzanne J Brown, Rae-Chi Huang, Phillip E Melton and 12 more

Open access · greenAbstract readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in The Journal of clinical endocrinology and metabolism, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed, 2 pooled it
1.2field-weighted citation impact, top 22% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed, 2 syntheses or guidelines pooled it, 17 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Review
  4. Genetics of Thyroid Function: Relevance for Biology and Disease Management.The Journal of clinical endocrinology and metabolism · 2025
    Review
  5. Article
  6. Review
  7. Review
  8. Article
  9. Article
  10. Thyroid Function across the Lifespan: Do Age-Related Changes Matter?Endocrinology and metabolism (Seoul, Korea) · 2022
    Article
  11. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

22 authors at 9 institutions in 2 countries.

Nicole LafontaineDepartment of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Purdey J CampbellDepartment of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Juan E Castillo-FernandezDepartment of Twin Research & Genetic Epidemiology, King's College London, London, UK.
Shelby MullinDepartment of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Ee Mun LimDepartment of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Phillip KendrewPathwest Laboratory Medicine, Nedlands, WA, Australia.
Michelle LewerPathwest Laboratory Medicine, Nedlands, WA, Australia.
Suzanne J BrownDepartment of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Rae-Chi HuangTelethon Kids Institute, University of Western Australia, Perth, Australia.
Phillip E MeltonSchool of Biomedical Sciences, University of Western Australia, Perth, Australia.
Trevor A MoriMedical School, Royal Perth Hospital Unit, University of Western Australia, Perth, WA, Australia.
Lawrence J BeilinMedical School, Royal Perth Hospital Unit, University of Western Australia, Perth, WA, Australia.
Frank DudbridgeDepartment of Health Sciences, University of Leicester, Leicester, UK.
Tim D SpectorDepartment of Twin Research & Genetic Epidemiology, King's College London, London, UK.
Margaret J WrightQueensland Brain Institute, University of Queensland, Brisbane, Australia.
Nicholas G MartinQIMR Berghofer Medical Research Institute, Brisbane, Australia.
Allan F McRaeInstitute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
Vijay PanickerDepartment of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Gu ZhuQIMR Berghofer Medical Research Institute, Brisbane, Australia.
John P WalshDepartment of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Jordana T BellDepartment of Twin Research & Genetic Epidemiology, King's College London, London, UK.
Scott G WilsonDepartment of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Sir Charles Gairdner Hospital · AUThe University of Western Australia · AUKing's College London · GBPathwest Laboratory Medicine · AUQIMR Berghofer Medical Research Institute · AUThe University of Queensland · AUThe Kids Research Institute Australia · AUUniversity of Leicester · GBUniversity of Tasmania · AU

Funding

Statistical Methods for X-Chromosome Genetic DataP01GM099568 · NIGMS · UNIVERSITY OF WASHINGTON · PI WEIR, BRUCE S. · 2012 to 2016
$7.3M
NIGMS NIH HHS P01 GM099568
6 · The paper itself

Abstract

contextCirculating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited.

objectiveTo identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts.

methodWe performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, n = 563) and the Raine Study (median age 17.0 years, n = 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed.

resultsWe identified 2 DMPs with epigenome-wide significant (P < 2.4E-7) associations with TSH and 6 with fT3, including cg00049440 in KLF9 (P = 2.88E-10) and cg04173586 in DOT1L (P = 2.09E-16), both genes known to be induced by fT3. All DMPs had a positive association between DNAm and TSH and a negative association between DNAm and fT3. There were no DMPs significantly associated with fT4. We identified 23 differentially methylated regions associated with fT3, fT4, or TSH.

conclusionsThis study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function.

Indexed as

AdolescentAustraliaChildCohort StudiesEpigenomeFemaleGenome-Wide Association StudyHistone-Lysine N-MethyltransferaseHumansKruppel-Like Transcription FactorsMaleObservational Studies as TopicThyroid DiseasesThyroid Function TestsThyroid GlandTriiodothyronineDOT1L protein, humanHistone-Lysine N-MethyltransferaseKLF9 protein, humanKruppel-Like Transcription FactorsTriiodothyronineDNA methylationDOT1LepigeneticsEWASKLF9thyroid hormone

Identifiers

PMID33484127
PMCPMC8063248
OpenAlexW3124332596

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.