rs10735341 (ELK3): TSH Levels and Brain Expression
Key takeaways
- rs10735341 is one of 260 genetic variants linked to TSH levels in a study of more than 247,000 people.
- Higher TSH polygenic scores, shaped partly by loci like this one, are associated with lower thyroid cancer risk across four independent study populations.
- The alternative allele reduces expression of a nearby gene across five brain regions, with the strongest signal in the anterior cingulate cortex.
- This variant contributes to the genetic architecture of thyroid function, though its individual effect size is not separately reported in the provided studies.
- The brain expression effects and TSH association may reflect separate biological pathways - no functional link between them has been established in the provided literature.
Key takeaways
- rs10735341 is among 260 genetic variants associated with thyroid-stimulating hormone (TSH) levels in a genome-wide study of more than 247,000 people.
- Higher TSH polygenic scores derived from loci like this one are associated with reduced risk of thyroid cancer across multiple independent study populations.
- The alternative allele at this position reduces expression of a nearby gene (ENSG00000287454) across five brain regions, with the strongest effect in the anterior cingulate cortex.
- The biological connection between this brain gene-expression effect and thyroid biology has not been established in the provided literature.
- Evidence comes from large, multi-ancestry studies reaching genome-wide significance, though this variant's individual effect size is not separately reported in the provided study excerpts.
What the research says
rs10735341, located near ELK3 (an ETS-family transcription factor - a protein that controls the activity of other genes, involved in regulating cell growth and differentiation), was identified among TSH-associated loci in two independent GWAS (genome-wide association study) meta-analyses. A meta-analysis spanning 247,107 participants identified 260 independent sentinel variants for TSH, of which 158 were novel, and showed that a polygenic score for TSH - a combined measure of many genetic variants - was associated with thyroid cancer risk and age-of-onset of thyroid diseases PMID 37210349. An earlier meta-analysis of up to 119,715 individuals identified 74 TSH-associated loci and used Mendelian randomization (a method that uses genetic variants as natural experiments to test causality) to suggest that higher TSH levels are inversely associated with thyroid cancer risk PMID 32770077. Independently, GTEx v11 eQTL data from 953 donors show that the alternative allele at this locus is associated with reduced expression of ENSG00000287454 across five brain regions GTEx Portal.
Reported associations
- Thyroid-stimulating hormone (TSH) levels: rs10735341 is among 260 independent variants associated with TSH at genome-wide significance (p < 5 x 10^-8) in a stage-1 meta-analysis of 247,107 participants spanning multiple ancestries, with replication in additional European and South Asian ancestry cohorts PMID 37210349
- Thyroid-stimulating hormone (TSH) levels: Also among 74 genome-wide significant TSH loci in a meta-analysis of up to 119,715 individuals across HUNT, MGI, and the ThyroidOmics consortium, 28 of which were previously unreported PMID 32770077
- Thyroid cancer risk (polygenic context): Higher TSH polygenic scores, which aggregate effects of novel loci in this class, are associated with reduced thyroid cancer risk in the UK Biobank and three independent study populations, with Mendelian randomization supporting a protective effect of higher TSH on thyroid cancer PMID 32770077
- Age-of-onset of hypothyroidism and hyperthyroidism: TSH polygenic scores incorporating novel loci are associated with the age at which hypothyroidism and hyperthyroidism are diagnosed in European ancestry populations PMID 37210349
- Brain gene expression - ENSG00000287454: The alternative allele is associated with reduced expression of ENSG00000287454 in the anterior cingulate cortex, nucleus accumbens (basal ganglia), hippocampus, cerebellum, and cerebellar hemisphere; all five signals indicate reduced expression GTEx Portal
Evidence quality
The two TSH GWAS provide robust population-level evidence. The larger study included 247,107 stage-1 participants with replication in 63,326 European ancestry and 33,171 South Asian ancestry individuals, with sentinel variants required to reach p < 5 x 10^-8 PMID 37210349. The earlier study replicated findings across multiple independent cohorts and validated polygenic score associations for thyroid cancer in four separate study populations PMID 32770077. No conflicting findings between the two GWAS are apparent in the available excerpts. However, neither provided study text explicitly reports the individual effect size or p-value for rs10735341 in isolation; the variant is one of a large set of sentinel associations reported at locus level. The brain eQTL data from GTEx v11 (953 donors, FDR < 0.05) show consistent directionality across five regions, with the strongest signal in the anterior cingulate cortex (p = 2.1 x 10^-15) GTEx Portal. The functional link between these brain expression effects and thyroid biology is not established in the provided sources and should be treated as preliminary mechanistic context only.
Tissue-specific expression effects
- ENSG00000287454: The alternative allele is associated with reduced expression across five brain regions - anterior cingulate cortex (p = 2.1 x 10^-15), nucleus accumbens basal ganglia (p = 9.0 x 10^-16), hippocampus (p = 2.3 x 10^-10), cerebellum (p = 1.0 x 10^-7), and cerebellar hemisphere (p = 8.7 x 10^-7). All five signals point in the same direction: reduced expression of this gene. These are expression-level, mechanistic findings and do not directly predict clinical outcomes GTEx Portal
Lifestyle considerations
No lifestyle considerations on file for this variant.
Frequently asked questions
What is rs10735341 and what gene is it near?
rs10735341 is a single-nucleotide variant - a single-letter change in the DNA sequence - located near the ELK3 gene, which encodes an ETS-family transcription factor involved in regulating cell growth and differentiation. It has been identified in large-scale studies as a variant associated with thyroid-stimulating hormone levels.
Is rs10735341 linked to thyroid disease?
rs10735341 is associated with circulating TSH levels in genome-wide studies of up to 247,107 people. Higher TSH polygenic scores derived from loci in this region are linked to lower thyroid cancer risk and differences in the age of onset of hypothyroidism and hyperthyroidism, though this variant has not been independently connected to thyroid disease in isolation.
What does the ELK3 gene do?
ELK3, also known as NET, is a transcription factor in the ETS family - a group of proteins that switch other genes on or off, involved in processes including cell growth and differentiation. Its specific role in thyroid biology is not described in the provided research literature for this variant.
Why does this TSH variant affect brain gene expression?
GTEx v11 data show that the alternative allele at rs10735341 reduces expression of a nearby gene (ENSG00000287454) across five brain regions, including the hippocampus and anterior cingulate cortex. This is an eQTL (expression quantitative trait locus) effect, meaning the variant influences how much of that gene is produced in those tissues. The biological significance of this finding in relation to thyroid function has not been established in the provided literature.
How strong is the evidence for rs10735341?
The TSH association is supported by large-scale GWAS with over 247,000 participants reaching genome-wide significance (p < 5 x 10^-8), replicated across multiple ancestries. The brain eQTL signal meets a strict false discovery rate threshold (FDR < 0.05) across five brain regions in 953 GTEx donors, with p-values as low as 2.1 x 10^-15. However, the individual effect size for rs10735341 specifically is not reported in isolation in the provided study excerpts.