Allele frequency spectrum of known ankylosing spondylitis associated variants in a Swedish population.

Objective: The genetic predisposition to ankylosing spondylitis (AS) has been most widely studied in cohorts with European ancestry. However, within Europe, disease prevalence is higher in Sweden. Given this, we aimed to characterize known AS susceptibility variants in a homogeneous Swedish data set, assessing reproducibility and direction of effect.Method: The power to detect association within an existing Swedish targeted sequencing study (381 controls; 310 AS cases) was examined, and a set of published associations (n = 151) was intersected with available genotypes. Association to disease was calculated using logistic regression accounting for population structure, and HLA-B27 status was determined with direct polymerase chain reaction genotyping.Results: The cases were found to be 92.3% HLA-B27 positive, with the data set showing ≥ 80% predictive power to replicate associations, with odds ratios ≥ 1.6 over a range of allele frequencies (0.1-0.7). Thirty-four markers, representing 23 gene loci, were available for investigation. The replicated variants tagged MICA and IL23R loci (p < 1.47 × 10-3), with variable direction of effect noted for gene loci IL1R1 and MST1.Conclusion: The Swedish data set successfully replicated both major histocompatibility complex (MHC) and non-MHC loci, and revealed a different replication pattern compared to discovery data sets. This was possibly due to population demographics, including HLA-B27 frequency and measured comorbidities.

Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease.

BACKGROUND: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. METHODS: To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. RESULTS: We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10-15 , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. CONCLUSION: Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.