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We hypothesize that the cumulative genomic risk for major depressive disorder may be a candidate cause for the increased conversion risk. Here, we aimed to investigate the predictive effect of the polygenic risk scores of major depressive disorder-specific genetic variants (PRSsMDD) on the conversion from non-depressed amnestic mild cognitive impairment to Alzheimer\u2019s disease, and its underlying neurobiological mechanisms. The PRSsMDD could predict the conversion from amnestic mild cognitive impairment to Alzheimer\u2019s disease, and amnestic mild cognitive impairment patients with high risk scores showed 16.25% higher conversion rate than those with low risk. The PRSsMDD was correlated with the left hippocampal volume, which was found to mediate the predictive effect of the PRSsMDD on the conversion of amnestic mild cognitive impairment. The major depressive disorder-specific genetic variants were mapped into genes using different strategies, and then enrichment analyses and protein\u2013protein interaction network analysis revealed that these genes were involved in developmental process and amyloid-beta binding. They showed temporal-specific expression in the hippocampus in middle and late foetal developmental periods. Cell type-specific expression analysis of these genes demonstrated significant over-representation in the pyramidal neurons and interneurons in the hippocampus. These cross-scale neurobiological analyses and functional annotations indicate that major depressive disorder-specific genetic variants may increase the conversion from amnestic mild cognitive impairment to Alzheimer\u2019s disease by modulating the early hippocampal development and amyloid-beta binding. The PRSsMDD could be used as a complementary measure to select patients with amnestic mild cognitive impairment with high conversion risk to Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awy277","type":"journal-article","created":{"date-parts":[[2018,10,6]],"date-time":"2018-10-06T07:20:25Z","timestamp":1538810425000},"page":"3457-3471","source":"Crossref","is-referenced-by-count":28,"title":["Neurobiological substrates underlying the effect of genomic risk for depression on the conversion of amnestic mild cognitive impairment"],"prefix":"10.1093","volume":"141","author":[{"given":"Jiayuan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaojun","family":"Li","sequence":"additional","affiliation":[{"name":"College of Information Engineering, Tianjin University of Commerce, Tianjin, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mulin","family":"Jun Li","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Pharmacology, Tianjin Medical University, Tianjin, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanjun","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, P.R. China"},{"name":"Department of Psychiatry Functional Neuroimaging Laboratory, Tianjin Mental Health Center, Tianjin Anding Hospital, Tianjin, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaigui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junping","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunter","family":"Schumann","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, UK"},{"name":"Medical Research Council Social, Genetic and Developmental Psychiatry Centre, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunshui","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, P.R. China"},{"name":"CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,11,14]]},"reference":[{"key":"2019081408050982200_awy277-B1","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/j.jalz.2014.12.008","article-title":"Genetic risk of neurodegenerative diseases is associated with mild cognitive impairment and conversion to dementia","volume":"11","author":"Adams","year":"2015","journal-title":"Alzheimers Dement"},{"key":"2019081408050982200_awy277-B2","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.jad.2017.07.008","article-title":"Trajectories of depressive symptoms and their relationship to the progression of dementia","volume":"222","author":"Barca","year":"2017","journal-title":"J Affect Disord"},{"key":"2019081408050982200_awy277-B3","doi-asserted-by":"crossref","first-page":"683","DOI":"10.3233\/JAD-2011-110659","article-title":"Abnormal tau phosphorylation in the thorny excrescences of CA3 hippocampal 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