Rare copy number variation in autoimmune Addison's disease

Area of Science:

• Genetics
• Endocrinology
• Immunology

Background:

• Autoimmune Addison's disease (AAD) results from adrenal cortex autoimmune destruction.
• Genome-wide association studies (GWAS) identified common variants influencing AAD risk.
• The role of copy number variations (CNVs) in AAD susceptibility is largely unknown.

Purpose of the Study:

• To investigate the contribution of CNVs to Autoimmune Addison's disease aetiology.
• To analyze genome-wide genotyping data for CNVs in Norwegian and Swedish populations.

Main Methods:

• Utilized genome-wide genotyping data from 1,182 AAD cases and 3,810 controls.
• Compared the frequency of CNVs, particularly large deletions, between cases and controls.
• Assessed the pathogenicity and clinical impact of identified large deletions.

Main Results:

• No significant difference in rare CNV frequency between AAD cases and controls.
• Larger deletions (>1,000 kb) were more prevalent in AAD patients (OR = 4.23, p = 0.0002).
• No large deletions were definitively pathogenic; clinical presentation and polygenic risk scores were similar in carriers and non-carriers.

Conclusions:

• Rare CNVs are unlikely to be a major driver of Autoimmune Addison's disease.
• Ultra-rare deletions in LRBA and BCL2L11 genes may contribute to polygenic risk in specific cases.
• Further research is needed to clarify the role of rare deletions in AAD susceptibility.