Polygenic risk factors related to neurodegenration in Alzheimer disease: calculation of a genetic predisposition score (gps)

摘要

Introduction Alzheimer disease (AD) is the most common cause of dementia worldwide and is considered a genetically heterogeneous disorder. Early-onset familial AD is linked to mutations in the genes for beta-amyloid precursor protein (APP), presenilin 1 (PSEN1) and 2 (PSEN2); whereas late-onset AD or sporadic AD is associated with genetic polymorphisms that act as either risk factors and/or genetic modifiers (1, 2). There is a great interest in the study of polymorphic markers at the DNA level for the study of complex, multifactorial human diseases. The final goal of this strategy is to identify and characterize the effects of mutations influencing phenotypic variation and interindividual susceptibility to complex disorders. Using a genetic predisposition score (GPS) approach, based on the method reported by Yiannakouris N et al (3), we analyzed four polymorphisms associated with AD predisposition. The GPS score was developed for a total of four polymorphisms (APOE, ACE insdel, A2M V10001 and PSEN1 rs 16593 2), each polymorphism contributed to 1 unit if the subject was homozygous for the risk allele, 0.5 units when the subject was heterozygous and 0 units if the subject was homozygous for the low-risk allele. According to this, individuals could have score values between 0 (very low genetic risk) and 4 (very high genetic risk).