Polygenic risk of Alzheimer's disease in the Faroe Islands

Malan Johansen; Sofus Joensen; Marjun Restorff; Tórmóður Stórá; Darren Christy; Emil K Gustavsson; Jiang Bian; Yi Guo; Matthew J Farrer; Maria Skaalum Petersen

doi:10.1111/ene.15351

Polygenic risk of Alzheimer's disease in the Faroe Islands

Eur J Neurol. 2022 Aug;29(8):2192-2200. doi: 10.1111/ene.15351. Epub 2022 Apr 19.

Authors

Malan Johansen^{1

2}, Sofus Joensen³, Marjun Restorff³, Tórmóður Stórá³, Darren Christy⁴, Emil K Gustavsson^{5

6}, Jiang Bian⁷, Yi Guo⁷, Matthew J Farrer^{4

8}, Maria Skaalum Petersen^{1

2}

Affiliations

¹ Center of Health Science, University of the Faroe Islands, Tórshavn, Faroe Islands.
² Department of Occupational Medicine and Public Health, Faroese Hospital System, Tórshavn, Faroe Islands.
³ Psychiatric Center, Dementia Clinic, National Hospital of the Faroe Islands, Tórshavn, Faroe Islands.
⁴ Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada.
⁵ Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK.
⁶ Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
⁷ Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, USA.
⁸ Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.

PMID: 35384166
DOI: 10.1111/ene.15351

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.

Keywords: Alzheimer's disease; Faroe Islands; all-cause dementia; genetic risk; polygenic risk score.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / epidemiology
Alzheimer Disease* / genetics
Apolipoproteins E / genetics
Genotype
Humans
Multifactorial Inheritance / genetics
Polymorphism, Single Nucleotide / genetics

Substances

Apolipoproteins E