Sleepless in Seattle?

Sleepless in Seattle? We spend a third of our lives asleep. But some of us suffer profound sleep deficits and abnormal circadian rhythms that are linked with psychiatric disorders, hypertension, cardiovascular disease, learning and memory problems and general mortality.

Twin studies have shown a strong genetic component (40% heritability) to sleep. Sleep duration is a polygenic trait- influenced by many genes. Several clock genes are known. A study just published in Molecular Psychiatry uncovers a new player: ABCC9, better known as SUR2, is critical for the release of insulin in response to blood glucose levels. Mutations in SUR2 were previously linked to childhood diabetes. SUR is also the acronym for Sulphonyl Urea Receptor, for a drug used to treat diabetes.

In this new study, investigators performed GWAS (Genome Wide Association Study; want to sound science-y? Say gee-wahs) on >4000 people to identify SNPs (Single Nucleotide Polymorphisms, i.e., gene variants), linked to sleep duration. To confirm the link, they knocked out the same gene in the fruit fly nervous system ( Drosophila ) and found a dramatic decrease in night sleep, but not in daytime sleep (apparently, flies sleep both during the day and night! How to tell if a fly is asleep? No movement for 5 min is assumed to mean that the fly is in the arms of Morpheus). In fact, onset of night sleep was delayed by 3 h.

So what is the connection to sleep? ABCC9/SUR2 is part of an ATP-regulated potassium channel that links metabolic state (i.e., carbohydrate availability) to cortical neuron responses. It is thought that KATP channels balance adaptive response to stress and the metabolic resources to ensure survival. Other potassium channel regulatory genes have also been shown to alter fruit fly sleep. They have been called Hyperkinetic and Sleepless (so my lede was not that farfetched after all!).


Image: ABCC9 genetic interaction network (generated with SNPs 3D). Oval nodes represent genes associated with diseases, and rectangular nodes represent other genes. Genes in red have deleterious SNPs.

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13 Responses to Sleepless in Seattle?

  1. Matt Kuenzel says:

    That’s a complex network! You say 3D – does that mean it will pop-out if I wear red-green glasses? Another reason to get a genetic scan – to check ABCC9 status.

  2. Molecular psychiatry? that’s a new one on me!

    Never let a day go by without learning something new 🙂

  3. Rajini Rao says:

    Matt Kuenzel , I think Google+ users must have some common SNP’s, linked to Hyperkinetic and Sleepless loci. We should test this hypothesis..

  4. Matt Kuenzel says:

    Tonight at 3AM how many will still be online …

    Does this mean that sleep onset is a result of changing the threshold at which some neurons spike?

  5. Rajini Rao says:

    Matt Kuenzel , from what I saw in the paper, it sounded horribly complicated, I’m afraid. Some channel subtypes mediate slow wave oscillations during sleep, others seem to block the hunger-arousal response. Deciphering this is going to keep me up at night.

  6. Rajini Rao says:

    Actually, Matt Kuenzel , you are absolutely correct…these KATP channels normally hyperpolarize a subpopulation of neurons (orexic neurons) which means they change the making the inside more negative, it makes it harder for the neuron to fire. I’m guessing the variant makes it easier for the neurons to fire and promotes wakefulness in response to hunger. I should have made this clear, sorry.

  7. Rajini Rao says:

    Owen Phillips , it’s in the methods section of the paper, I’m sure..the link is above, if you don’t have access to Mol. Psych. let me know and I will be happy to send you a pdf.

  8. Rahul Joshi says:

    And I thought my Insomnia was linked to decreased GABA and melatonin levels!

  9. Rajini Rao says:

    Rahul Joshi , probably all that and more 🙂

  10. Matt Kuenzel says:

    Ah ha … caught you awake at 3:26 AM !!!

    This brings up an interesting question: is sleep passive or active? Does each individual neuron “sleep” so that it has time to repair and replenish its own internal state? Or is sleep an active process in which the neurons (for the most part) are busy reorganizing and consolidating information from the prior day’s experience.

  11. Rajini Rao says:

    Matt Kuenzel , the neurologically biased answer is that the “basic unit of sleep is the electrical activity of a single cortical neuron”. Check this out:

    Fortunately or unfortunately, I don’t sleep a lot. I’ve never noticed any negative effects, except on recall memory if my sleep is really messed up…usually with people’s names. But I compensate by beating around the bush until I extract their names from some dim recess 🙂

  12. Matt Kuenzel says:

    Rajini Rao Interestng, thanks!

  13. Hmm.. And there is another man called Al Herpin who never slept. This gene definitely deserves to be investigated more.

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