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This one was extra tough but I think I may have discovered a droplet of insight, so if you're ready, let's dive in! https://twitter.com/SbotGwa/status/1335207398135443458
Although there are at least two GWAS on this trait, I haven't been able to find any bona fide confirmed causal genes.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415688/ https://pubmed.ncbi.nlm.nih.gov/30804565/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415688/ https://pubmed.ncbi.nlm.nih.gov/30804565/
I identified 63 lead SNPs in @SbotGwa's GWAS of insomnia and looked for common pathways or themes but I didn't find any enrichments in any obvious gene sets or pathways. I also don't see the classic circadian rhythm/chronotype genes like PER1, PER3, or CRY1.
I next perused the known rare diseases associated with the implicated genes.
This led me to the legend of Ondine (or Undine), a tale which draws on Greek myths of water nymphs
This led me to the legend of Ondine (or Undine), a tale which draws on Greek myths of water nymphs
In some versions of the tale Ondine falls in love with a mortal male who ends up engaged to a human woman. As a consequence, the man is cursed such that he can only breathe with conscious effort. Eventually he falls asleep and dies.
Much more detail here: https://pubmed.ncbi.nlm.nih.gov/32022123/
Much more detail here: https://pubmed.ncbi.nlm.nih.gov/32022123/
Today “Ondine’s curse” refers to a rare disease, “central hypoventilation syndrome”. Subjects have shallow breathing, especially at night. Symptoms can include drowsiness and insomnia.
https://en.wikipedia.org/wiki/Central_hypoventilation_syndrome
https://en.wikipedia.org/wiki/Central_hypoventilation_syndrome
I am way outside of my expertise here, but the pathophysiology seems to relate to regions of the brain which are supposed to respond to lack of oxygen or build up of CO2 in the blood
Most cases of Ondine’s curse are due to mutations in PHOX2B, a neuronal specific transcription factor. Phox2b is expressed in a set sensory neurons in the brain stem that are activated by hypoxia or CO2 build-up https://www.jneurosci.org/content/26/40/10305
However in 2017 a family afflicted with Ondine's curse was identified but had no PHOX2B mutations. Whole genome sequencing instead identified a rare frameshift mutation in the gene MYO1H
https://pubmed.ncbi.nlm.nih.gov/28779001/
https://pubmed.ncbi.nlm.nih.gov/28779001/
How MYO1H contributes to congenital central hypoventilation syndrome is unknown, but it is expressed in the phox2b CO2-responsive neurons.
Myosins do contribute to vesicle transport in neurons. Perhaps MYO1H has some essential role in these hypoxia neurons https://pubmed.ncbi.nlm.nih.gov/28779001/
Myosins do contribute to vesicle transport in neurons. Perhaps MYO1H has some essential role in these hypoxia neurons https://pubmed.ncbi.nlm.nih.gov/28779001/
The lead SNP from @SbotGwa's Manhattan plot is associated with a number of sleep-related traits including “frequency of tiredness”
It is tempting to speculate that the irritability is related to the tiredness!
https://genetics.opentargets.org/variant/12_109417396_C_T
It is tempting to speculate that the irritability is related to the tiredness!
https://genetics.opentargets.org/variant/12_109417396_C_T
This locus was identified in the two previous GWAS on insomnia. This is not really replication as all the studies used data from the @uk_biobank
Having skimmed the papers I see no mention of MYO1H or Ondine's curse in either one.
https://pubmed.ncbi.nlm.nih.gov/30804565/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415688/
Having skimmed the papers I see no mention of MYO1H or Ondine's curse in either one.
https://pubmed.ncbi.nlm.nih.gov/30804565/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415688/
I had assumed that insomnia genetics would show features related to circadian rhythm that come up in GWAS of "chronotype" but that seems not to be the case. At least with MYO1H it seems to relate to the physiology of sleep itself.
https://en.wikipedia.org/wiki/Autonomic_nervous_system
https://en.wikipedia.org/wiki/Autonomic_nervous_system
o there you have it. Rare disease genetics seems to implicate MYO1H as a gene contributing to insomnia by tweaking the brain's response to hypoxia.
What do you think?
(that's Ondine by the way)
What do you think?
(that's Ondine by the way)
Epilogue:
The sculpture is "Ondine, coming out of water” 1880 by Chauncey Bradley Ives.
The painting is "Undine" by John William Waterhouse
https://www.wikiart.org/en/john-william-waterhouse/undine-1872
The sculpture is "Ondine, coming out of water” 1880 by Chauncey Bradley Ives.
The painting is "Undine" by John William Waterhouse
https://www.wikiart.org/en/john-william-waterhouse/undine-1872
Epilogue 2: Much more detail on the story of Ondine can be found here:
https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-282X2020005003101&lng=en&nrm=iso&tlng=en
or here: https://www.hormonesmatter.com/ondines-curse-breathing-no-longer-automatic/
https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-282X2020005003101&lng=en&nrm=iso&tlng=en
or here: https://www.hormonesmatter.com/ondines-curse-breathing-no-longer-automatic/
Tagging the authors of the MYO1H paper. Do you think common/mild variations in the gene could manifest as insomnia in an otherwise health person?
@StefanMundlos, @malte_spielmann, @Katrinardottir, @IzabelaHC
See thread above for context.
@StefanMundlos, @malte_spielmann, @Katrinardottir, @IzabelaHC
See thread above for context.
