# Circadian ADCY3 Ser107Pro variant bridges difficulty awakening in the morning and adiposity

## TL;DR

A genetic variant in ADCY3 is linked to morning difficulty awakening and increased body fat, connecting circadian rhythms to metabolic health.

## Contribution

Identifies a novel ADCY3 variant that links circadian preference and adiposity through genetic and molecular mechanisms.

## Key findings

- The ADCY3 Ser107Pro variant increases eveningness, BMI, and fat mass in multiple ancestry groups.
- The variant alters adipose-specific splicing and destabilizes ADCY3 protein structure.
- BMAL1 binds near residue 107 in mouse adipose tissue, suggesting a conserved regulatory mechanism.

## Abstract

Modern lifestyles often disturb circadian rhythms, yet the genetic circuits that convert this stress into metabolic dysfunction remain poorly defined. Here, we identify a missense variant in ADCY3 (rs11676272; Ser107Pro) as a pleiotropic regulator of circadian preference and adiposity. Using genome-wide pleiotropy analysis in ∼480,000 UK Biobank participants, we show that the G risk allele (Pro107) increases eveningness, BMI, and fat mass in European (n = 451,324) and African (n = 8,738) ancestry groups, with behavioral amplification by morning difficulty awakening in Europeans and power-limited modeling in other populations. Structural modeling and transcriptomic analysis suggest this allele alters adipose-specific splicing and expression and destabilizes ADCY3 protein. In mice, Adcy3 is rhythmically expressed in adipose tissue, with BMAL1 binding near the orthologous residue 107 site. Human adipose ADCY3 expression also increases after weight loss. Together, these findings reveal a genotype-dependent, behaviorally modifiable axis connecting difficulty awakening to metabolic risk through circadian and adipose regulatory pathways.

•ADCY3 Ser107Pro is a shared coding variant linking circadian traits and adiposity•Difficulty awakening amplifies the adiposity effect of the ADCY3 risk G allele•Ser107Pro alters ADCY3 in adipose tissue and destabilizes the protein structure•BMAL1 binds Adcy3 at the residue 107 orthologous region in mouse adipose tissue

ADCY3 Ser107Pro is a shared coding variant linking circadian traits and adiposity

Difficulty awakening amplifies the adiposity effect of the ADCY3 risk G allele

Ser107Pro alters ADCY3 in adipose tissue and destabilizes the protein structure

BMAL1 binds Adcy3 at the residue 107 orthologous region in mouse adipose tissue

Human metabolism; Genomics