Sleep disorders among the elderly are pervasive, yet frequently undiagnosed and untreated. 'Poor sleep'has been associated with a variety of age-related conditions, including reduced cognitive function, depression and mortality. Sleep-wake regulation is a complex process involving environmental influences and genetic predisposing factors and little is known about the effect of circadian gene variants on human sleep function and age-related outcomes. This project will test the hypothesis that genetic variations in circadian pathway genes affect human sleep function and other age-related outcomes.
Our specific aims are to test common genetic variants and haplotypes in 21 circadian rhythm and 4 melatonin metabolism genes for association with rest activity rhythms and sleep characteristics as measured by actigraphy, and with cognitive function, depression and mortality in two prospective cohorts of elderly U.S. women and men participating in the SOF and MrOS cohorts. During 2002-2003, wrist actigraphy was recorded in all returning Caucasian and African American SOF participants (n>2600 with DNA collected). During the MrOS sleep visit in 2004-2005, 2,846 Caucasian and African American participants (all with available DNA) completed wrist actigraphy and in-home overnight polysomnography. We are also including all African Americans with available DNA to improve our power to detect genotype associations with mortality, cognitive function and depression. This is one of the largest data sets of objective sleep data and associated mental, depression, and health data available in the world. We are uniquely positioned to examine the role of circadian rhythm and melatonin metabolism gene variants in a large sample. Compared to the cost of recruitment, phenotyping, and DNA collection, which have already been accomplished in >5700 participants, the genotyping cost will be small. The 2003 National Sleep Disorders Research Plan as put forward by The National Center on Sleep Disorders Research calls for an assessment of normal human sleep phenotypes and a full evaluation of """"""""associated genotypes"""""""" to define the genetic underpinning of abnormal sleep or altered circadian rhythm profiles. Understanding the underlying causes and consequences of sleep disturbances and cognitive impairments is a high priority in terms of public health. Discovering gene polymorphisms that affect sleep and other age-related outcomes could lead to interventions that have a very significant impact on improving health, safety, and productivity of the elderly population.

Public Health Relevance

This project will test whether genetic variants in the 21 circadian rhythm and 4 melatonin metabolism genes are associated with rest activity rhythms and sleep characteristics (as measured by actigraphy), mortality, cognitive function and depression in older men and women participating in the Study of Osteoporotic Fractures and Osteoporotic Fractures in Men cohorts. These are two of the largest data sets of objective sleep data and associated mental, depression, and health data available in the world and relative to the costs of recruitment and phenotyping, which have already been accomplished, the genotyping cost is small. Discovering genes that affect sleep and age-related outcomes could lead to interventions that have a very significant impact on improving health, quality of life and longevity on the elderly population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG030474-02
Application #
7673719
Study Section
Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Mackiewicz, Miroslaw
Project Start
2008-08-15
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$553,912
Indirect Cost
Name
California Pacific Medical Center Research Institute
Department
Type
DUNS #
071882724
City
San Francisco
State
CA
Country
United States
Zip Code
94107
Amin, Najaf; Allebrandt, Karla V; van der Spek, Ashley et al. (2016) Genetic variants in RBFOX3 are associated with sleep latency. Eur J Hum Genet 24:1488-95
Kripke, Daniel F; Kline, Lawrence E; Nievergelt, Caroline M et al. (2015) Genetic variants associated with sleep disorders. Sleep Med 16:217-24
Gottlieb, D J; Hek, K; Chen, T-H et al. (2015) Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. Mol Psychiatry 20:1232-9
Maglione, Jeanne E; Nievergelt, Caroline M; Parimi, Neeta et al. (2015) Associations of PER3 and RORA Circadian Gene Polymorphisms and Depressive Symptoms in Older Adults. Am J Geriatr Psychiatry 23:1075-87
Winkelman, John W; Blackwell, Terri; Stone, Katie et al. (2015) Genetic associations of periodic limb movements of sleep in the elderly for the MrOS sleep study. Sleep Med 16:1360-1365
Bendjilali, Nasrine; Hsueh, Wen-Chi; He, Qimei et al. (2014) Who are the Okinawans? Ancestry, genome diversity, and implications for the genetic study of human longevity from a geographically isolated population. J Gerontol A Biol Sci Med Sci 69:1474-84
Napoli, Nicola; Schwartz, Ann V; Palermo, Lisa et al. (2013) Risk factors for subtrochanteric and diaphyseal fractures: the study of osteoporotic fractures. J Clin Endocrinol Metab 98:659-67
Evans, Daniel S; Parimi, Neeta; Nievergelt, Caroline M et al. (2013) Common genetic variants in ARNTL and NPAS2 and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly. Sleep 36:431-46
Torkamani, A; Schork, N J (2012) Background gene expression networks significantly enhance drug response prediction by transcriptional profiling. Pharmacogenomics J 12:446-52
Napoli, Nicola; Jin, Jenny; Peters, Katherine et al. (2012) Are women with thicker cortices in the femoral shaft at higher risk of subtrochanteric/diaphyseal fractures? The study of osteoporotic fractures. J Clin Endocrinol Metab 97:2414-22

Showing the most recent 10 out of 25 publications