Genetic differences between diagnosed and undiagnosed Celiac disease: a population-based study

Area of Science:

• Genetics
• Gastroenterology
• Epidemiology

Background:

• Celiac disease (CeD) diagnosis is often delayed, with many individuals presenting later in life or with atypical symptoms.
• This diagnostic heterogeneity may stem from underlying genetic variations influencing disease presentation.
• Understanding genetic factors in both diagnosed and undiagnosed CeD populations is crucial for improving detection and management.

Purpose of the Study:

• To compare genetic variants, specifically using a polygenic risk score (PRS), between previously diagnosed CeD cases and newly identified cases within a screened adult population.
• To investigate the genetic architecture differences or similarities between known and newly diagnosed celiac disease individuals.
• To assess the predictive accuracy of a validated PRS in distinguishing CeD cases from the general population.

Main Methods:

• Utilized data from the Trøndelag Health Study (HUNT4), including 826 CeD cases (361 known, 465 new) and 51,516 non-CeD individuals.
• Applied a validated polygenic risk score (PRS) to evaluate genetic predisposition in CeD cases versus controls.
• Analyzed additional genetic variants beyond the PRS to identify potential associations with CeD.

Main Results:

• The PRS demonstrated high accuracy in distinguishing CeD cases (known and new) from non-cases (AUROC 85% and 83%, respectively).
• The PRS explained a comparable proportion of genetic variation in both known (17.1%) and new (14.5%) CeD cases.
• Individuals in the highest genetic risk group (top 10%) had significantly elevated odds of having CeD (OR 22.7 for known, 18.6 for new cases).

Conclusions:

• A validated PRS effectively identifies genetic differences between CeD cases and the general population.
• The genetic architecture appears similar between previously diagnosed and newly diagnosed CeD individuals.
• Non-genetic factors likely play a significant role in the heterogeneity of celiac disease presentation in adults.