1. Centre d'Études Avancées en Médecine du Sommeil (CÉAMS)
Hôpital du Sacré-Cœur de Montréal
Université de Montréal
Implications of genetics and genomics
information for understanding sleep
Sleep: the Fourth Pillar of Health
B-Debate, International Center for Scientific Debate
Barcelona
October 18th, 2018
Simon Warby, PhD
Chaire Pfizer, Bristol-Myers Squibb, SmithKline Beecham, Eli Lilly
en psychopharmacologie de l’Université de Montréal

2. Hôpital du Sacré-Cœur de Montréal
http://www.ceams-carsm.ca

3. Why study sleep?
Impaired sleep affects multiple
domains of health:
• Learning and Memory
• Emotional stability
• Cognition
• Psychiatric, Neurodegenerative,
Developmental disorders
• Cardiovascular and Metabolic
disease
www.healthline.com

4. Sleep is a dynamic process
• The brain undergoes dynamic and predictable changes throughout the night.
• Sleep is essential for mental and physical health.

5. 3 Basic Genetic Questions:
1. Do our genes influence how we sleep?
2. Which genes influence sleep?
3. Does sleep influence our genes?

6. Phenotype = any observable / measurable trait or behavior

7. DNA
RNA
Protein
Metabolites
Phenotypes
David Wishart (http://wishartlab.com/)
Less Difficult
Difficult
Ease of High
Throughput
Measurement

8. DNA
RNA
Protein
Metabolites
Phenotypes
David Wishart (http://wishartlab.com/)
Less Difficult
Easy
Ease of High
Throughput
Measurement
Genomics
Transcriptomics
Proteomics
Metabolomics
Phenomics (etc.)
The Human Genome Project has facilitated Big Data approaches to Genetics

9. (to what extent?)
1. Do our genes influence how we sleep?

10. EEG profiles are variable between people
Frequency (Hz)
2011

11. All-night NREM
• 2 nights baseline
• 2 nights 1.5 – 3 years later
Within an individual, EEG profiles during sleep are very stable over
time, even across periods of adolescent development.
Age 10 (+ 1 Tanner) Age 15-16 (Tanner 5)

12. 12
ICC=0.459 ICC= 0.934
Heritability (h2) = 0.959
Monozygotic
(Identical) Twins
Dizygotic Twins
Twin studies
suggest the EEG
profile during sleep
is highly heritable

13. 2. Which genes influence sleep?

14. Pasternak 2005
Genome-wide
Candidate Gene
Typical Approaches for ‘Forward Genetics’ (Gene Finding)
Next Generation
Sequencing
Microarrays

15. 2. Which genes influence sleep?
Numerous sleep disorders are known to have genetic risk factors:
• Narcolepsy
• Restless Legs Syndrome (RLS)
• Chronic Insomnia
• Fatal Familial Insomnia
• Circadian Rhythm Disorders
• Delayed Sleep Phase Syndrome
• Advanced Sleep Phase Syndrome
• Kleine-Levin Syndrome
• Primary Nocturnal Enuresis
• REM sleep Behaviour Disorder
• Sleep Apnea
• Sleepwalking
Several sleep traits are known to be influenced by genetics:
• Habitual Sleep Duration
• Circadian Preference
• Sleep Quality
• EEG Features (Sleep Spindles)

16. 2. Which genes influence sleep?
Numerous sleep disorders are known to have genetic risk factors:
• Narcolepsy
• Restless Legs Syndrome (RLS)
• Chronic Insomnia
• Fatal Familial Insomnia
• Circadian Rhythm Disorders
• Delayed Sleep Phase Syndrome
• Advanced Sleep Phase Syndrome
• Kleine-Levin Syndrome
• Primary Nocturnal Enuresis
• REM sleep Behaviour Disorder
• Sleep Apnea
• Sleepwalking
Several sleep traits are known to be influenced by genetics:
• Habitual Sleep Duration
• Circadian Preference
• Sleep Quality
• EEG Features (Sleep Spindles)
How does identifying genes help us to
understand these traits or treat these
disorders?

17. Narcolepsy
• Excessive daytime sleepiness
• *Cataplexy (brief episodes of muscle weakness triggered by emotions)
• Symptoms of dissociated REM sleep
(sleep paralysis, hypnagogic hallucinations)
• Disrupted nocturnal sleep
• Familial risk (+10-40x), Monozygotic concordance 30-40%

18. Narcolepsy is due to the loss of hypocretin/orexin in the brain.
How and why is it lost?
Major human genes associated with narcolepsy:
DQBI*0602 Major histocompatibility complex, class II, DQ beta 1
TCRA T-cell receptor alpha
CHKB Carnitine palmitoyltransferase 1B, choline kinase β
NCKAP5 NCK-associated protein 5
P2RY11 Purinergic receptor subtype 2Y11
CTSH Cathepsin H
TNF4 Tumor necrosis factor superfamily member 4
TCRB T-cell receptor β locus
ZNF365 Zinc finger gene 365
Narcolepsy – GWAS results
Faraco et al., 2013
Hallmayer et al., 2009
Han et al., 2013
Kornum et al., 2011
Toyoda et al., 2015
Many of these genes have a known function in the immune system.
Consistent with the autoimmune hypothesis of narcolepsy.

19. Faraco and Mignot, 2011
Genetic evidence suggests that interactions at the immunological
synapse are playing a key role in the pathogenesis of narcolepsy.

20. Faraco and Mignot, 2011
Genetic evidence suggests that interactions at the immunological
synapse are playing a key role in the pathogenesis of narcolepsy.

21. Narcolepsy - HLA genotype
Longstreth, 2007
~98% of narcoleptics have the HLA DQB1*0602 genotype
Not everyone who has HLA DQB1*0602 gets narcolepsy (prevalence ~20%)

22. Restless Legs Syndrome (RLS)
Diagnostic Criteria:
(1) A persistent urge to move or stretch the legs,
(2) Symptoms that occur with rest or inactivity,
(3) Relief by stretching or walking,
(4) Occurrence in the evening or night.
• Heritability estimates (54 - 60%) for self-reported RLS symptoms
• Early form appears to be more severe and more heritable
https://healthblog.uofmhealth.org

23. Restless Legs Syndrome - GWAS Results
Major Genes associated with RLS:
MEIS1 Meis homeobox 1
BTBD9 BTB/POZ domain-containing protein 9
MAP2K5 MAP2K5 mitogen-activated protein kinase kinase 5
SKOR1 SKI family transcriptional corepressor 1
PTPRD protein tyrosine phosphatase, receptor type D
Role of development (motor/sensory pathways) & iron
metabolism in the disorder.
Winkelmann 2007, 2011

24. Chronic Insomnia Disorder
A combination of candidate-gene and GWAS studies are
starting to unravel the genetic basis of Insomnia Disorder

25. Sleep spindles are EEG features found in NREM sleep that are associated with learning &
memory, and are altered by a variety of neurological disorders.
Genetics of Sleep Spindles: Generating Large Datasets
Recall / Sensitivity
Nature Methods 2014

26. 2. Which genes influence sleep?
How does identifying genes help us to
understand these traits or treat these
disorders?
• Identifies genetic pathways / key molecules involved
• Potential drug targets
• Entry point for reverse genetics....

27. Gene of interest is known.
Addition or deletion experiments.
Reverse Genetics:
Genetically Modified Organisms
2. Which genes influence sleep?
Reverse genetics has made numerous
contributions to our understanding of the biology
of normal sleep, and the pathogenesis of sleep
disorders.

28. 3. Does sleep influence our genes?

29. 3. Does sleep influence our genes?
DNA
RNA
Protein
Metabolites
Phenotypes
Genomics
Transcriptomics
Proteomics
Metabolomics
Phenomics (etc.)
Changes in sleep
Changes in gene expression
when?
how much?
where?

30. Summary 3
• Many genes change expression levels depending on wake/sleep state.
• Many genes are upregulated during sleep.
• Sleep and wake favor different cellular processes.
Macromolecule biosynthesis
Synaptic plasticity (learning)
• Some neurons are sleep active (and have minimal activity during wake).
What are we learning from gene expression studies?
otogenetics.com

31. Where do we go from here?
Canadian Sleep Research Biobank
https://www.physionet.org/https://www.ncbi.nlm.nih.gov/gaphttps://biolincc.nhlbi.nih.gov/home/
https://www.nhlbi.nih.gov/science/trans-omics-precision-medicine-topmed-program
https://www.cscnweb.ca/platforms
https://sleepdata.org/
Collaborative projects and resources are driving Big Data approaches to better
understand the biology of sleep and the etiology of sleep disorders.

32. Acknowledgements
Julie Carrier
Marie Dumont
Jacques Montplaisir
Chaire Pfizer, Bristol-Myers Squibb, SmithKline Beecham, Eli Lilly
en psychopharmacologie de l’Université de Montréal
Maryam El Gewely
Karine Lacourse
Jacques Delfrate
Marie-Josée Quinn
Catherine Bourguinat
Dominique Petit
Aurélie Boivin de Billy
Julien Beaudry
Simon Fournier
Guy Rouleau