# Genetic and molecular basis of circadian rhythm disorders

> **NIH NIH K01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $179,712

## Abstract

Circadian rhythms regulate human behavior and physiology within the 24 hour day to optimize processes, from
gene expression to cognition. Dysregulation of those rhythms are associated with sleep disorders, cognitive
and physical performance, cancer, and chronic metabolic and neurologic disease. Despite the importance of
circadian rhythms to human health and their fundamental role demonstrated in model organisms, little is known
about the biological connection between human circadian rhythms and our health and physiology. We propose
to identify novel genetic factors involved in circadian rhythms by sequencing extreme circadian rhythm disorder
patients from clinical cohorts (n~200). Advanced Sleep Phase Syndrome (ASPS) and Delayed Sleep Phase
Syndrome (DSPS) are inherited neurological sleep disorders of the circadian clock, which present as extremely
shifted sleep timing. Familial studies identified mutations in genes encoding molecular components of the
circadian clock (PER2, PER3) or regulating the speed/pace of the clock (CSNK1D), causing extreme advance
or delay in sleep onset. We hypothesize that ASPS and DSPS subjects harbor rare loss-of-function mutations
in components of the circadian clock, including input/output pathways and the core molecular clock. This
hypothesis will be tested in 2 specific aims: Aim 1 will identify genetic variants robustly associated with
Advanced and Delayed Sleep Phase Syndrome in clinical cohorts. I will learn phenotyping of circadian
disorders and exome sequencing and analysis. Aim 2 will determine the mechanisms underlying the disease
process by determining the function of ASPS and DSPS genetic mutations on cellular circadian rhythms and
screening for novel therapeutic compounds. Through Aim 2 I will develop skills in circadian cell culture assays
and associated analysis techniques, as well as learn compound screening. The results of this study will
identify new causal genetic factors for ASPS and DSPS. Through these results we will elucidate novel genes
and pathways underlying circadian regulation. These findings will open potential new avenues of therapeutics
for rare circadian rhythms disorders, increase our understanding of the basic mechanisms of circadian biology,
and open new avenues for treatment of more common circadian rhythm associated chronic diseases. To
achieve my long-term career goal to be one of the leading human geneticists in the field of chronobiology, I
will expand my current expertise in genome-wide studies of common variation in complex traits into circadian
clinical sample phenotyping and exome sequencing identification of causal rare variants to achieve my career
goal. The research proposed in this K01 will serve as an essential stepping stone to acquire this training.

## Key facts

- **NIH application ID:** 9900859
- **Project number:** 5K01HL136884-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Jacqueline Marie Lane
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $179,712
- **Award type:** 5
- **Project period:** 2018-03-05 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900859

## Citation

> US National Institutes of Health, RePORTER application 9900859, Genetic and molecular basis of circadian rhythm disorders (5K01HL136884-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9900859. Licensed CC0.

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