ORF42-02 - Genetic Co-Localisation Identifies Shared Genetic Architecture for Sleep/Circadian Traits, and Prevalent Cardiometabolic Disease

In the UK, over 4.3 million people live with type 2 diabetes (T2D), and an additional 2.4 million
are at increased risk of developing the disease. T2D, obesity, hypertension, and fatty liver disease
commonly co-occur, collectively termed cardiometabolic multimorbidity. Cardiometabolic
disease (CMD) arises from multiple risk factors, among which sleep disturbances and circadian
rhythm disruption (SCRD) have emerged as significant contributors to disease onset and
severity. Critically, CMD itself promotes SCRD, creating a vicious cycle that exacerbates poor
health and wellbeing.

We employed a genetic co-localisation approach in the UK Biobank to identify loci associated
with both SCRD and CMD traits, aiming to reveal shared genetic architecture between these
interconnected systems. Our analysis identified multiple loci with varying credible intervals and
posterior probabilities of shared causal variants. One locus stood out due to a high posterior
probability of co-localisation, highly resolved credible set centered on a single missense variant,
rs12140153, and strong evidence of replication across independent cohorts.

The putative causal SNP, rs12140153, is a missense variant within PATJ, a gene encoding a
membrane-associated protein involved in tight junctions. PATJ has previously been implicated in
genome-wide association studies (GWAS) of body mass index (BMI) and C-reactive protein (CRP),
a marker of systemic inflammation. PATJ is widely expressed across human tissues, with highest
levels in the brain (especially cerebellum), gastrointestinal tract, muscle, and immune tissues.
Further analyses in an Oxford-based cardiometabolic-focused biobank identified individuals
carrying rare, deleterious coding variants in PATJ. These individuals exhibited notable alterations
in serum lipid profiles, particularly sphingolipids, which are implicated in CMD. Moreover,
sphingolipid metabolism is linked to circadian regulation.

In summary, large-scale human cohort analyses offer strong potential to identify novel genetic
drivers underpinning SCRD and CMD.