Evidence map›Paper›PMID 42481375›Full record

ArticleEBioMedicine2026

Genetic architecture of a Circadian Imbalance Index: genome-wide association, phenome-wide association, and Mendelian randomisation analyses.

Magdalena Żebrowska, Matthias Wielscher, Jing Zhang, Ingvild Saksvik-Lehouillier, Lee DiMilia, Angus Burns, Jesse Valliere, Leonardo Vincenzi, Susan Redline, Olivia Okereke and 4 more

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Article in EBioMedicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

14 authors.

Magdalena ŻebrowskaDepartment of Epidemiology, Center for Public Health, Medical University of Vienna, Vienna, Austria; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: magdalena.zebrowska@meduniwien.ac.at.
Matthias WielscherDepartment of Epidemiology, Center for Public Health, Medical University of Vienna, Vienna, Austria; Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Jing ZhangDepartment of Epidemiology, Center for Public Health, Medical University of Vienna, Vienna, Austria.
Ingvild Saksvik-LehouillierDepartment of Psychology, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway.
Lee DiMiliaSchool of Business and Law, Central Queensland University, Rockhampton, Queensland, Australia.
Angus BurnsDivision of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Turner Institute for Brain and Mental Health, School of Psychological Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jesse ValliereCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Leonardo VincenziDepartment of Dermatology, Medical University of Vienna, Vienna, Austria.
Susan RedlineDivision of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA.
Olivia OkerekeChanning Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02215, USA.
Richa SaxenaDivision of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
Rebecca RichmondNIHR Oxford Health Biomedical Research Centre, University of Oxford, Oxford, UK; MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Martin K RutterCentre for Biological Timing, Division of Endocrinology, Diabetes and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; Diabetes, Endocrinology and Metabolism Centre, NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, UK.
Eva S SchernhammerDepartment of Epidemiology, Center for Public Health, Medical University of Vienna, Vienna, Austria; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: eva.schernhammer@channing.harvard.edu.

Funding

Life Course Cancer Epidemiology Cohort in WomenU01CA176726 · NCI · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · PI ELIASSEN, A. HEATHER, WILLETT, WALTER C. · 2018 to 2025
$22.4M
Integrating lifecourse approaches, biologic and digital phenotypes in support of heart and lung disease epidemiologic researchU01HL145386 · NHLBI · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · PI CHAVARRO, JORGE EDUARDO, MANSON, JOANN ELISABETH · 2019 to 2025
$17.8M
Premonopausal Hormone Levels and Risk of Breast CancerR01CA067262 · NCI · HARVARD UNIVERSITY (SCH OF PUBLIC HLTH) · PI HANKINSON, SUSAN E · 2002 to 2011
$11.9M
NCI NIH HHS R01 CA067262NCI NIH HHS U01 CA176726NHLBI NIH HHS U01 HL145386
6 · The paper itself

Abstract

backgroundCircadian disruption affects multiple aspects of human health, but the genetic architecture of individual susceptibility remains unclear. We examined the genetics of the Circadian Imbalance Index (CII), an additive 0-5 score combining evening chronotype, short/long sleep, high neuroticism, atypical caffeinated coffee intake, and low vitamin D.

methodsWe ran a genome-wide association study (GWAS) of CII in 312,935 European-ancestry UK Biobank participants, compared signals with component-specific and leave-one-component-out (LOCO) GWASs, and tested sex and shift work interactions. CII polygenic score (PRS) PheWAS analyses were evaluated in Mass General Brigham Biobank (N = 50,908) and All of US (N = 98,182), with component-weighted PRS sensitivity analyses. Replication was assessed in Nurses' Health Study II women (N = 11,344). We estimated genetic correlations and performed bidirectional two-sample Mendelian randomisation (MR) with MR-Egger, weighted median and LOCO sensitivity analyses.

findingsWe identified 27 loci mapping to 72 genes, including genes with reported links to circadian regulation or circadian-related pathways, such as CALCA, DHCR7, KDM5A, HAL, and CRX. Five genes (EPHB1, SERPING1, C12orf74, PLEKHG7, and EEA1) were observed in the CII analysis but not in component-specific analyses. LOCO analyses indicated that the CII genetic signal was not reducible to any single component. The CII PRS was associated with metabolic and psychiatric phenotypes. CII was genetically correlated with insomnia, mood swings, body mass index, type 2 diabetes, coronary artery disease, and myocardial infarction. MR analyses provided suggestive directional evidence, strongest for reverse associations of mood swings and coronary artery disease with CII.

interpretationThe CII captures a polygenic composite susceptibility signal associated with cardiometabolic and mood outcomes, with suggestive evidence of directional relationships.

fundingEuropean Research Council Advanced Grant CLOCKrisk (101053225).

Indexed as

Circadian RhythmGenome-Wide Association StudyMendelian Randomization AnalysisPhenomicsChronotypeFemaleGenetic Predisposition to DiseaseGenetic Risk ScoreHumansMaleMultifactorial InheritancePhenotypePolymorphism, Single NucleotideCircadian disruptionCircadian imbalance indexGWASShift work

Identifiers

PMID42481375
PMCPMC13476902

What Socratic holds

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.