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Effects of HLA-DRB1/DQB1 Genetic Variants on Neuroimaging in Healthy, Mild Cognitive Impairment, and Alzheimer’s Disease Cohorts

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Abstract

Alzheimer’s disease (AD) is the most common form of dementia and exhibits a considerable level of heritability. Previous association studies gave evidence for the associations of HLA-DRB1/DQB1 alleles with AD. However, how and when the gene variants in HLA-DRB1/DQB1 function in AD pathogenesis has yet to be determined. Here, we firstly investigated the association of gene variants in HLA-DRB1/DQB1 alleles and AD related brain structure on magnetic resonance imaging (MRI) in a large sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We selected hippocampus, subregion, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). Twelve SNPs in HLA-DRB1/DQB1 were identified in the dataset following quality control measures. In the total group hybrid population analysis, our study (rs35445101, rs1130399, and rs28746809) were associated with the smaller baseline volume of the left posterior cingulate and rs2854275 was associated with the larger baseline volume of the left posterior cingulate. Furthermore, we detected the above four associations in mild cognitive impairment (MCI) sub-group analysis, and two risk loci (rs35445101 and rs1130399) were also the smaller baseline volume of the left posterior cingulate in (NC) sub-group analysis. Our study suggested that HLA-DRB1/DQB1 gene variants appeared to modulate the alteration of the left posterior cingulate volume, hence modulating the susceptibility of AD.

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Acknowledgments

Data collection and sharing was funded by ADNI (National Institutes of Health U01 AG024904). ADNI is funded by the National Institute on Aging; the National Institute of Biomedical Imaging and Bioengineering; the Alzheimer’s Association; the Alzheimer’s Drug Discovery Foundation; BioClinica, Inc; Biogen Idec Inc; Bristol-Myers Squibb Co, F. Hoffmann-LaRoche Ltd and Genetech, Inc; GE Healthcare; Innogenetics, NV; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development LLC; Medpace, Inc; Merck & Co, Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Novartis Pharmaceuticals, Co, Pfizer, Inc; Piramal Imaging; Servier; Synarc Inc; and Takeda Pharmaceutical Co. The Canadian Institutes of Health Research is providing 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 was the Northern California Institute for Research and Education, and the study was 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 California, Los Angeles.

This work was also supported by grants from the National Natural Science Foundation of China (81471309, 81171209, 81371406, 81501103, 81571245), the Shandong Provincial Outstanding Medical Academic Professional Program, Qingdao Key Health Discipline Development Fund, Qingdao Outstanding Health Professional Development Fund, and Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders.

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    Authors and Affiliations

    1. Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, Shandong Province, 266071, China

      Zi-Xuan Wang, Yu Wan, Fu-Rong Sun, Meng-Shan Tan, Chen-Chen Tan, Lan Tan & Jin-Tai Yu

    2. Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China

      Hui-Fu Wang, Yu Wan & Lan Tan

    3. College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, 266000, China

      Lin Tan & Yu Wan

    4. Columbia College, Columbia University, New York, NY, USA

      Jinyuan Liu & Yu Wan

    5. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

      Yu Wan & Teng Jiang

    6. Memory and Aging Center, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, Box 1207, San Francisco, CA, 94158, USA

      Yu Wan & Jin-Tai Yu

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    Correspondence to Lan Tan or Jin-Tai Yu.

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    Alzheimer’s Disease Neuroimaging Initiative

    Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

    Zi-Xuan Wang and Hui-Fu Wang contributed equally to this work.

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    Wang, ZX., Wang, HF., Tan, L. et al. Effects of HLA-DRB1/DQB1 Genetic Variants on Neuroimaging in Healthy, Mild Cognitive Impairment, and Alzheimer’s Disease Cohorts. Mol Neurobiol 54, 3181–3188 (2017). https://doi.org/10.1007/s12035-016-9890-6

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