Multi-ethnic GWAS and meta-analysis of sleep quality identify MPP6 as a novel gene that functions in sleep center neurons

Author:

Khoury Samar1ORCID,Wang Qiao-Ping2ORCID,Parisien Marc1ORCID,Gris Pavel1,Bortsov Andrey V3,Linnstaedt Sarah D4,McLean Samuel A4,Tungate Andrew S4,Sofer Tamar5ORCID,Lee Jiwon5ORCID,Louie Tin6,Redline Susan5,Kaunisto Mari Anneli7ORCID,Kalso Eija A7,Munter Hans Markus8ORCID,Nackley Andrea G3,Slade Gary D9,Smith Shad B3,Zaykin Dmitri V10,Fillingim Roger B11,Ohrbach Richard12,Greenspan Joel D13,Maixner William3,Neely G Gregory14ORCID,Diatchenko Luda1

Affiliation:

1. The Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC, Canada

2. School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Guangzhou, China

3. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University, Durham, NC

4. Institute for Trauma Recovery and Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC

5. Department of Medicine, Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

6. Department of Biostatistics, University of Washington, Seattle, WA

7. Department of Diagnostics and Therapeutics, University of Helsinki, Helsinki, Finland

8. Department of Human Genetics, McGill University, Montréal, QC, Canada

9. School of dentistry, University of North Carolina Chapel Hill, Chapel Hill, NC

10. Biostatistics and Computational Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC

11. College of Dentistry, University of Florida, Gainesville, FL

12. Department of Oral Diagnostic Services, University at Buffalo, Buffalo, NY

13. Department of Neural and Pain Sciences, Brotman Facial Pain Clinic, School of Dentistry and Center to Advance Chronic Pain Research, University of Maryland, Baltimore, MD

14. The Dr. John and Anne Chong Laboratory for Functional Genomics, Charles Perkins Centre and School of Life & Environmental Sciences, The University of Sydney, Sydney, NSW, Australia

Abstract

Abstract Poor sleep quality can have harmful health consequences. Although many aspects of sleep are heritable, the understandings of genetic factors involved in its physiology remain limited. Here, we performed a genome-wide association study (GWAS) using the Pittsburgh Sleep Quality Index (PSQI) in a multi-ethnic discovery cohort (n = 2868) and found two novel genome-wide loci on chromosomes 2 and 7 associated with global sleep quality. A meta-analysis in 12 independent cohorts (100 000 individuals) replicated the association on chromosome 7 between NPY and MPP6. While NPY is an important sleep gene, we tested for an independent functional role of MPP6. Expression data showed an association of this locus with both NPY and MPP6 mRNA levels in brain tissues. Moreover, knockdown of an orthologue of MPP6 in Drosophila melanogaster sleep center neurons resulted in decreased sleep duration. With convergent evidence, we describe a new locus impacting human variability in sleep quality through known NPY and novel MPP6 sleep genes.

Funder

NIDCR

NIH

NINDS

University of North Carolina at Chapel Hill

Canada Excellence Research Chairs, Government of Canada

NHMRC

National Natural Science Foundation of China

Natural Science Foundation of Guangdong, China

National Heart, Lung, and Blood Institute

University of North Carolina

University of Miami

Albert Ein

stein College of Medicine

University of Illinois at Chicago

San Diego State University

National Institute on Minority Health and Health Disparities

National Institute on Deafness and Other Communication Disorders

National Institute of Dental and Craniofacial Research

National Institute of Diabetes and Digestive and Kidney Diseases

University of Washington

NCATS

Seventh Framework Programme

Jackson State University

Mississippi State Department of Health

University of Mississippi Medical Center

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Neurology (clinical)

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