A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies

Abstract

Background. Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients.Methods. We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI.Results. The genetic susceptibility to AADquantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e − 16), and 1.2 SD higher in the young patients compared with the old (p = 3e − 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies.Conclusions. The PRS performed well for casecontrol differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity.

Rare copy number variation in autoimmune Addison’s disease

“…We used a recent PRS model for AAD ( 11 ) (PRS14 AAD ) to test whether the PRS-distribution in patients with rare large deletions (>1,000 kb) is different compared to patients without rare large deletions, which can indicate different etiologies. For this purpose, we compared the previously derived AAD-PRS for carrier patients (n = 13), non-carriers patients (n = 1,167), carrier controls (n = 10) and non-carrier controls (n = 3,994) ( Figure 2 ).…”

“…The PRS model was developed from the original case-control GWAS-study of AAD and healthy controls ( 7 , 11 ). A total of 1,182 cases and 4,010 controls, all of them unrelated and European-ancestry samples passing the quality control, were selected for the PRS estimation.…”

“…A considerable familial aggregation of AAD has been recognized for decades ( 8 , 9 ) and twin studies have estimated the heritability to be approximately 0.97, 35-41% of this heritability is explained by common variants ( 7 ), indicating that genetic variation is a major contributor to disease liability ( 10 ). Taking these findings into consideration, a polygenic risk score (PRS) model was constructed and evaluated for AAD to estimate the risk of this condition at the collective influence of different genetic variants ( 11 ). This model showed a good performance for case-control differentiation and ability to estimate the risk of AAD at the individual level.…”