Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease

[helvella]

Over the years, we have seen a lot of discussion here about genes – things like whether individuals have particular DIO2 variants, haemochromatosis genes, etc. Where members can get tests run, how much they cost, and what to do with them!

A critical issue is that genetic analysis is so new, so current. We simply do not have the basic information available – neither us nor anyone else.

This paper is clearly a significant step with respect to thyroid disorders. While we have inevitably been focussed on that DIO2 variant simply because we know of it, we have been ignoring almost every other gene. And, in particular, we have ignored combinations. It could be that it takes several gene variants together to have any identifiable effect.

Therefore, this sentence should be seen as being positively ground-breaking:

We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated.

One implication is that we need to do much more extensive gene testing and go beyond testing for a handful of known issues. Whole Genome Sequencing (WGS) is the obvious direction. You might ask about a DIO2 variant, but you can place that in the context of other genes.

After all, we see considerable variations even among those with the known DIO2 variants as to how seriously it affects the individuals.

Also, as soon as we think about DIO2 genes, we surely also think whether DIO1 or DIO3 related genes affect them?

I feel it is a shame that this is still so TSH-oriented. Maybe, for those who have had FT4 and FT3, antibody tests, etc., they will look further.

[At present there are a few WGS suppliers who offer their testing in the UK – and elsewhere. I’m afraid I simply do not have the understanding required to point at any one of them and recommend it – nor to say anything negative about others. The only things that are apparent is the need to be able to get your data in a suitable format for future use, and the cost! Interpretation can now cost as much as the WGS itself – or more.]

Open access

Published: 23 October 2023

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease

Alexander T. Williams, Jing Chen, Kayesha Coley, Chiara Batini, Abril Izquierdo, Richard Packer, Erik Abner, Stavroula Kanoni, David J. Shepherd, Robert C. Free, Edward J. Hollox, Nigel J. Brunskill, Ioanna Ntalla, Nicola Reeve, Christopher E. Brightling, Laura Venn, Emma Adams, Catherine Bee, Susan E. Wallace, Manish Pareek, Anna L. Hansell, Tõnu Esko, Estonian Biobank Research Team, Daniel Stow, Genes & Health Research Team, …Catherine John

Nature Communications volume 14, Article number: 6713 (2023)

Abstract

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Thankfully, this is published as Open Access:

nature.com/articles/s41467-...

I'm quite sure that I have missed lots I should have said, and written confusingly, etc. But it is so complicated and I am personally pretty excited about this.

[DippyDame]

"We just don't know!" was the response from a geneticist after I tested positive for a very rare genetic deletion which I have passed to one of my sons and so on to one of his sons. Fortunately it hasn't resulted in the known effects. Long story not for here....but the boys are fine and both highly intelligent!

I had asked if there could be a connection to my having a form of Thyroid Hormone Resistance. I also tested positive for the Dio2 snp/ homozygous.

And, in particular, we have ignored combinations. It could be that it takes several gene variants together to have any identifiable effect.

Maybe the key to unlocking boxes of mysteries!

Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Maybe one day, meantime, hope springs eternal....thank you helvella.

[diogenes Remembering]

I'm very willing to agree that genetical variation can have significant effects especially when thyroid is completely knocked out . However, the adaptability of the system lacking thyroid activity is extremely versatile at minimising effects such as these. For example it is known that if rats are produced with little or no extra -thyroidal deiodinase activity, they get along perfectly well by the thyroid producing extra T3 direct in compensation for loss of activity elsewhere. So it all depends on the exact type of genetical difference as to whether it has sufficient effects on T3 production either direct or by deodinisation in the rest of the body. One has to consider both situations in context.

[crimple]

helvella, thank you for posting. I have saved the info for when I hopefully recover from my under treatment with levothyroxine. Really good to see that they are using info from Biobank and that there were over 200, 000 people involved.

I read about some research the other day that looked at 20 participants, can't see how that can help!