For hippocampal asymmetry two SNPs rs and rs

For hippocampal asymmetry, two SNPs (rs1476679 and rs4147929) showed significant interaction with diagnosis. They have an inverse effect on asymmetry, which is consistent with their different roles as preventative or risk loci in AD. rs1476679 is intronic in the ZCWPW1 gene, is a histone modification reader, and is involved in genetic regulation 50, 51. The preventative effect of rs1476679, reducing the risk of AD, was reported in Caucasians (25), a Spanish sample (52), and Han Chinese (53). rs4147929 is within the ABCA7 gene. It is a transmembrane protein that influences neuronal cholesterol efflux and Aβ secretion (54). The gene is strongly expressed in hippocampus subfield CA1 (55) and associated with amyloid plaque burden (56). The minor allele of ABCA7 increases the risk of AD, as shown in an autopsy-confirmed research cohort (57). ABCA7 showed a significant association with hippocampal atrophy (20) and gray matter density (13). The expression of the gene in the subfield CA1 and the association with hippocampal atrophy are supportive of our results, because we have shown in previous work that the increase in asymmetry in hippocampus is not uniform but localized; this is one of the reasons for the improved results with shape descriptors compared with volumetric analyses. There was only one SNP (rs10948363 [CD2AP]) that showed a significant association with shape asymmetry independent of disease status. This confirms previous reports that PF-03084014 receptor structural asymmetry per se is not strongly heritable (11), but also shows that QTL studies can reveal subtle genetic influences that are not detectable in twin studies. CD2AP rs10948363 potentially contributes to amyloid precursor protein metabolism and subsequent amyloid-β generation through its regulation of clathrin-mediated endocytosis (58). It is probably linked to modulating amyloid-β clearance and tau neurotoxicity (56) and was associated with fluorodeoxyglucose positron emission tomography metabolism (13). Our results suggest its influence on amygdala asymmetry, which showed one of the strongest associations to dementia in our previous work (8). Supplementary data from the UK Brain Expression Consortium on gene expression QTLs from postmortem healthy human brains (http://www.braineac.org/) revealed that homozygotes of the minor allele type for rs683250 show greater expression of DLG2 in the putamen of healthy individuals as compared with individuals carrying at least one major allele (Supplemental Figure S3). The results of the cis-eQTL mapping analysis are consistent with our results of the main effect of this SNP on putamen asymmetry. Collectively, our results provide novel evidence for genes that may drive asymmetric accumulation of AD pathology and suggest that sequence variants may act through their influence on neuroanatomical asymmetry. It is important to note that brain structural asymmetry in AD, or disease more generally, is different from the lateralization of language and motor function, where higher asymmetry tends to relate to higher functioning. Instead, higher asymmetry in AD is associated with the progression of preclinical and prodromal stages of disease and reflects an asymmetric effect of pathologic processes on brain morphology. The core genetic mechanisms of lateralized human brain development are unknown (59). Future work may be directed at studying the relation between functional asymmetry in development and asymmetric disease manifestation.
Acknowledgments and Disclosures This work was supported by the Bavarian State Ministry of Education, Science and the Arts in the framework of the Centre Digitisation.Bavaria (to CW). Support for data analysis was provided by National Library of Medicine Grant No. R01 LM012535 (to KN) and National Institute on Aging Grant Nos. R03 AG054936 (to KN), P30 AG010133 and R01 AG019771 (to AJS), and NIH/NCI 5R42CA183150-03 and NIH/NINDS 1R01NS083534-01A1 (to MR). Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which is supported by National Institutes of Health Grant No. U01 AG024904 and Department of Defense Award No. W81XWH-12-2-0012 (principal investigator, Michael W. Weiner). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica, Inc., Biogen Idec Inc., Bristol-Myers Squibb Company, Eisai Inc., Elan Pharmaceuticals, Inc., Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc., Fujirebio, GE Healthcare, IXICO Ltd., Janssen Alzheimer Immunotherapy Research & Development, LLC, Johnson & Johnson Pharmaceutical Research & Development, LLC, Medpace, Inc., Merck & Co., Inc., Meso Scale Diagnostics, LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc., Piramal Imaging, Servier, Synarc Inc., and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.