Year: 2012
Type: article
Study design: Observational Study
Abstract: OBJECTIVE: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression. METHODS: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations. RESULTS: CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)). CONCLUSIONS: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.
Source: Neurology
Authors: Mariet Allen, Fanggeng Zou, High Seng Chai, Curtis S. Younkin, Julia Crook, V. Shane Pankratz, Minerva M. Carrasquillo, Christopher N. Rowley, Asha A. Nair, Sumit Middha, Sooraj Maharjan, Thuy Nguyen, Li Ma, Kimberly G. Malphrus, Ryan Palusak, Sarah Lincoln, Gina Bisceglio, Constantin Georgescu, Debra Schultz, Fariborz Rakhshan, Christopher P. Kolbert, Jin Jen, Jonathan L. Haines, Richard Mayeux, Margaret A. Pericak-Vance, Lindsay A. Farrer, Gerard D. Schellenberg, Ronald C. Petersen, Neill R. Graff-Radford, Dennis W. Dickson, Steven G. Younkin, Nilüfer Ertekin-Taner
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G1258278173, G1309605592, G2227922493, Neurobiology of Alzheimer's Disease and Aging, G2716290505, G2844648250, Plasma AB as a Surrogate Genetic Marker for LOAD, National Alzheimer's Coordinating Center, G3342163884, G36881302, G4000272535, Einstein Aging Study, G413369726, Alzheimer's Disease Genetics Consortium, Epidemiology of Familial Late-Onset Alzheimer's Disease, Genetic Discovery and Application in a Clinical Setting Continuing a Partnership, G6530347775, Genome wide association study of gene expression levels in Alzheimer's disease, G727781925, Boston University Alzheimer's Disease Center, G7742288561, G8289575266, G8629123209, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), Mayo Alzheimer's Disease Research Center
OpenAlex ID: W2138746692