Association of Alzheimer disease GWAS loci with MRI-markers of brain aging

• Published in: Neurobiology of aging 2015-01, Vol.36 (4), p.1765.e7-1765.e16
• Main Authors: Chauhan, Ganesh, Adams, Hieab H.H., Bis, Joshua C, Weinstein, Galit, Yu, Lei, Töglhofer, Anna Maria, Smith, Albert Vernon, van der Lee, Sven, Gottesman, Rebecca F, Thomson, Russell, Wang, Jing, Yang, Qiong, Niessen, Wiro J., Lopez, Oscar L, Becker, James T, Phan, Thanh G, Beare, Richard J, Arfanakis, Konstantinos, Fleischman, Debra, Vernooij, Meike W., Mazoyer, Bernard, Schmidt, Helena, Srikanth, Velandai, Knopman, Dave S, Jack, Clifford R, Amouyel, Philippe, Hofman, Albert, DeCarli, Charlie, Tzourio, Christophe, van Duijn, Cornelia M, Bennett, David A, Schmidt, Reinhold, Longstreth, William T, Mosley, Thomas H, Fornage, Myriam, Launer, Lenore J, Seshadri, Sudha, Ikram, M Arfan, Debette, Stephanie
• Format: Article
• Language: English
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2014.12.028

Whether novel risk variants of Alzheimer’s disease (AD) identified through genome-wide association studies (GWAS) also influence MRI-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume (ICV), total brain volume (TBV), hippocampal volume (HV), white matter hyperintensity (WMH) burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N=8,175–11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p=0.0054) and CD33 (rs3865444) with smaller ICV (p=0.0058) In gene-based tests, there was associations of HLA-DRB1 with TBV (p=0.0006) and BIN1 with HV (p=0.00089). A weighted AD genetic risk score was associated with smaller HV (beta±SE=−0.047±0.013, p=0.00041), even after excluding the APOE locus (p=0.029). However, only association of AD genetic risk score with HV, including APOE , was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in non-demented older community persons.