Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimer’s Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates. Three novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423 . The ZNF423 gene resides in an Alzheimer’s disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions.

Original publication




Journal article

Publication Date



GERAD/PERADES, IGAP consortia, GERAD Consortium, ADGC Consortium, CHARGE Consortium, EADI Consortium