SLEEP 2011 Abstract Supplement

A. Basic Science II. Cell and Molecular Biology and Genetics
0024
COMMON VARIANT IN THE P2Y11 RECEPTOR GENE IS
ASSOCIATED WITH NARCOLEPSY AND WITH HIGHER
SUSCEPTIBILITY TO ATP INDUCED CELL DEATH IN T
LYMPHOCYTES
Kornum BR 1,2 , Kawashima M 1,3 , Faraco J 1 , Lin L 1 , Kassack MU 4 ,
Axtell RC 5 , Jennum P 2 , Hallmayer J 1 , Mignot E 1
1
Department of Psychiatry and Behavior, Stanford University, Palo
Alto, CA, USA, 2 Danish Center for Sleep Medicine, Glostrup Hospital,
Glostrup, Denmark, 3 Department of Human Genetics, University
of Tokyo, Tokyo, Japan, 4 Institute of Pharmaceutical and Medicinal
Chemistry, Heinrich-Heine-University of Dusseldorf, Dusseldorf,
Germany, 5 Department of Neurology and Neurological Sciences,
Stanford University, Palo Alto, CA, USA
Introduction: The human sleep disorder narcolepsy-cataplexy affects 1
in 2,000 individuals. Narcolepsy symptoms are primarily caused by the
loss of approximately 70,000 hypocretin producing neurons located in
the hypothalamus, and growing evidence supports the hypothesis that
narcolepsy with cataplexy is an autoimmune disease targeting these neurons.
Methods: Following on a recently published GWAS of narcolepsy,
we conducted replication of 10 additional loci in 1,525 Caucasians.
Of these, only one loci replicated strongly (rs4804122, p= 5.42x10-4;
odds ratio 0.77), but this association was not seen in other ethnic groups.
Based on differential LD patterns for this marker across ethnic groups 6
SNPs were then genotyped in 3,406 Caucasians, 2,414 Asians, and 302
African Americans. Based on a hit in P2RY11, we determined P2Y11
expression levels in white blood cells of different genotypes. We further
examined the effect of P2Y11 stimulation on ATP induced cell death in
different white blood cell types.
Results: Rs2305795, a SNP located in the 3’untranslated region of the
P2RY11 gene, is highly associated with narcolepsy across all ethnic
groups (p= 6.1x10-10; odds ratio 1.28). Additional experiments indicate
rs2305795 effects on P2Y11 expression in white blood cells, most notably
CD8+ T cells and NK cells where the disease associated allele show
a significantly lower expression. ATP induces cell death via the P2X7
receptor, and we find that co-stimulation of P2Y11 rescues the cells.
Further, lymphocytes with the narcolepsy associated genotype show a
lower response to P2Y11 stimulation in our cell death assay.
Conclusion: We have identified a novel narcolepsy susceptibility locus
on chromosome 19 with a highly significant association to rs2305795,
a SNP in the 3’UTR of P2RY11. This receptor is highly expressed in
CD8+ T cells and NK cells, and modulates ATP induced cell death. This
association may reflect the importance of immune system regulation in
the etiology of narcolepsy.
Support (If Any): We thank our other collaborators not listed here for
contributing samples, cohort genotypes and participating in the genetic
analysis. Funded by NS23724.
0025
GENOME-WIDE ASSOCIATION STUDY OF INSOMNIA
PHENOTYPES
Gehrman P 1 , Byrne EM 2 , Martin NG 2 , Wray NR 2
1
Psychiatry, University of Pennsylvania, Philadelphia, PA, USA,
2
Queensland Institute of Medical Research, Brisbane, QLD, Australia
Introduction: Insomnia phenotypes assessed by self-report have demonstrated
evidence of heritability, yet little is known about specific genes
that may confer risk for these phenotypes. This is surprising given that
insomnia is the most prevalent sleep disorder and is associated with
negative sequelae. Here we present the results of the first genome-wide
association study (GWAS) of insomnia phenotypes.
Methods: A Health and Lifestyle Questionnaire was completed by
2,323 Australian twins and their siblings who subsequently provided
blood samples for DNA analysis. There were a series of questions as-
sessing insomnia-related phenotypes including sleep latency, sleep duration,
sleep quality, and bedtime. Genotypes were assessed for 274,604
SNPs and imputation based on the HapMap project yielded a total of
2,380,486 SNPs. GWAS analyses were performed in Merlin with each
SNP tested in a singlepoint analysis.
Results: Although no SNPs passed the genome-wide significance
threshold (p