RT Journal Article
SR Electronic
T1 Gene-Based Analysis in HRC Imputed Genome Wide Association Data Identifies Three Novel Genes For Alzheimer’s Disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 374876
DO 10.1101/374876
A1 Emily Baker
A1 Rebecca Sims
A1 Ganna Leonenko
A1 Aura Frizzati
A1 Janet Harwood
A1 Detelina Grozeva
A1 GERAD/PERADES
A1 IGAP consortia
A1 Kevin Morgan
A1 Peter Passmore
A1 Clive Holmes
A1 John Powell
A1 Carol Brayne
A1 Michael Gill
A1 Simon Mead
A1 Reiner Heun
A1 Paola Bossù
A1 Gianfranco Spalletta
A1 Alison Goate
A1 Carlos Cruchaga
A1 Cornelia van Duijn
A1 Wolfgang Maier
A1 Alfredo Ramirez
A1 Lesley Jones
A1 John Hardy
A1 Dobril Ivanov
A1 Matthew Hill
A1 Peter Holmans
A1 Nicholas Allen
A1 Paul Morgan
A1 Julie Williams
A1 Valentina Escott-Price
A1 GERAD Consortium
A1 ADGC Consortium
A1 CHARGE Consortium
A1 EADI Consortium
YR 2018
UL http://biorxiv.org/content/early/2018/07/23/374876.abstract
AB 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.