Polygenic risk of Alzheimer's disease in the Faroe Islands

Abstract

Background and purpose: The Faroe Islands are a geographically isolated population in the North Atlantic with a similar prevalence of Alzheimer's disease (AD) and all-cause dementia as other European populations. However, the genetic risk underlying AD and other dementia susceptibility has yet to be elucidated. Methods: Forty-nine single-nucleotide polymorphisms (SNPs) were genotyped in 174 patients with AD and other dementias and 159 healthy controls. Single variant and polygenic risk score (PRS) associations, with/without APOE variability, were assessed by logistic regression. Performance was examined using receiver operating characteristic area under the curve (ROC AUC) analysis. Results: APOErs429358 was associated with AD in the Faroese cohort after correction for multiple testing (odds ratio [OR] 6.32, 95% confidence interval [CI] 3.98–10.05, p = 6.31e−15), with suggestive evidence for three other variants: NECTIN2 rs41289512 (OR 2.05, 95% CI 1.20–3.51, p = 0.01), HLA-DRB1 rs6931277 (OR 0.67, 95% CI 0.48–0.94, p = 0.02) and APOE rs7412 [ε2] (OR 0.28, 95% CI 0.11–0.73, p = 0.01). PRSs were associated with AD with or without the inclusion of APOE (PRS+APOE OR = 4.5, 95% CI 2.90–5.85, p = 4.56e−15, and PRS−APOE OR = 1.53, 95% CI 1.21–1.98, p = 6.82e−4). AD ROC AUC analyses demonstrated a PRS+APOE AUC = 80.3% and PRS−APOE AUC = 63.4%. However, PRS+APOE was also significantly associated with all-cause dementia (OR = 3.39, 95% CI 2.51–4.71, p = 2.50e−14) with an AUC = 76.9%, that is, all-cause dementia showed similar results albeit less significant. Discussion: In the Faroe Islands, SNP analyses highlighted APOE and immunogenomic variability in AD and dementia risk. PRS+APOE, based on 25 SNPs/loci, had excellent sensitivity and specificity for AD with an AUC of 80.3%. High PRSs were also associated with an earlier onset of late-onset AD.