O3‐11‐03: Genetic association of variants with late‐onset Alzheimer's disease risk and brain gene expression
Year: 2012
Type: article
Study design: Observational Study
Abstract: Recent genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) identified nine novel risk loci. There is a need to uncover the actual risk gene and the mechanism of the functional variants at these loci. Further, given that these loci collectively explain part of the risk for LOAD, alternative approaches are required to discover any additional risk genes. Gene expression levels are quantitative traits that are under strong genetic influence. Regulatory variants that modulate levels of gene expression are thought to underlie many human traits including susceptibility to disease. We hypothesize that there are variants that confer risk for LOAD by influencing brain gene expression. We measured expression levels of 24,526 transcripts in 773 brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202) and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within ±100 kb of the tested transcript. We evaluated the novel LOAD GWAS loci for cisSNPs that associate with brain expression levels of nearby genes. We also compared the significant cisSNPs from our eGWAS for association with AD risk in the Alzheimer's Disease Genetics Consortium (ADGC) GWAS. We identified cisSNP associations with brain CLU, MS4A4A and ABCA7 levels (p=7.81x10-4-9.09x10-9) at these respective novel LOAD risk loci. In addition, we found enrichment of significant brain cisSNPs at other loci that also had suggestive AD risk association (p<10-3) in the ADGC GWAS. This enrichment was 2.9-3.3 fold greater than expected by chance and statistically significant (p<10-6). Regulatory variants at the CLU, MS4A4A and ABCA7 loci may confer LOAD risk by influencing brain gene expression. The significant enrichment of brain cisSNPs amongst suggestive LOAD risk loci in the ADGC GWAS could imply presence of additional LOAD risk genes with functional, regulatory variants. Combined assessment of gene expression and disease risk may generate complementary information and aid the discovery of LOAD risk variants with functional implications.
Source: Alzheimer s & Dementia
Authors: Mariet Allen, Fanggeng Zou, High Seng Chai, Curtis Younkin, Julia Crook, Vernon Pankratz, Minerva Carrasquillo, Christopher Rowley, Asha Nair, Sumit Middha, Sooraj Maharjan, Thuy Nguyen, Li Ma, Kimberly Malphrus, Ryan Palusak, Sarah Lincoln, Gina Bisceglio, Constantin Georgescu, Christopher Kolbert, Jin Jen, Jonathan Haines, Richard Mayeux, Margaret Pericak‐Vance, Lindsay Farrer, Gerard Schellenberg, Ronald Petersen, Neill Graff‐Radford, Dennis Dickson, Steven Younkin, Nilufer Ertekin‐Taner
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1996509856