An average of over 7,500 large """"""""copy and paste"""""""" DNA insertions occurs in each human brain as somatic mutations, i.e., DNA mutations that occur post-fertilization. Because of the large size of the insertions, they are termed structural genomic mutations. The mechanism of such mutations is mainly retrotransposition of transposable elements in the human genome. This phenomenon may prove relevant to Alzheimer's disease (AD), where somatic mutation hypotheses have been repeatedly proposed. These mutations are thought to lead to AD by interacting with inherited susceptibility variants, in a multiple-hit manner. We propose here to detect somatic mutations, including both point mutations and structural genomic mutations, in temporal cortex in a small sample of 7 AD patients and 7 controls, with two methods of mutation detection, and independent validation of each method. The two complementary methods for somatic mutation detection are microarray- based Transposon Insertion site Profiling (TIP-chip) capture coupled with sequencing (RC-Seq) and paired- end whole-genome sequencing (WGS). We will demonstrate the somatic nature of each mutation by comparison of brain and liver sequences in each individual. Comparative evaluation will inform our choice of methods for future studies. If justified by results of this stdy, we will next propose a large-scale case-control study, to determine if there is a somatic mutational burden, and/or specific genes impacted by somatic mutations, in AD. The PIs in this proposal include Dr. Geoff Faulkner, a pioneer in somatic mutations whose lab produced the 2011 Nature paper reporting the discovery of high-frequency somatic mutations in adult human brain, and Drs. Chunyu Liu and Elliot Gershon, who have published extensively on structural genomics, epigenetics, and bioinformatics in neuropsychiatric disorders.

Public Health Relevance

The ultimate goal of this study is to identify novel risk genes and novel genomic mechanisms for Alzheimer's disease (AD), through study of somatic mutations, which are changes in genes that occur after fertilization in a non-germline cell. The immediate aim of this pilot study is to establish the methodological foundation for a large study of mutational events in brain of normal elderly AD patients and in matched normals. Functional analysis of somatic mutations in AD but not normal brain in this study may generate testable hypotheses on disease biology in AD, and could lead to new pharmacological treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG045789-01A1
Application #
8702850
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Miller, Marilyn
Project Start
2014-06-15
Project End
2016-05-31
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$274,658
Indirect Cost
$55,501
Name
University of Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Li, Ming; Luo, Xiong-jian; Landén, Mikael et al. (2016) Impact of a cis-associated gene expression SNP on chromosome 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive performance. Br J Psychiatry 208:128-37
Li, Jinchen; Cai, Tao; Jiang, Yi et al. (2016) Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database. Mol Psychiatry 21:290-7
Bhutani, Kunal; Nazor, Kristopher L; Williams, Roy et al. (2016) Whole-genome mutational burden analysis of three pluripotency induction methods. Nat Commun 7:10536
Liu, C; Saffen, D; Schulze, T G et al. (2016) Psychiatric genetics in China: achievements and challenges. Mol Psychiatry 21:4-9
Yin, Xianyong; Wineinger, Nathan E; Wang, Kai et al. (2016) Common susceptibility variants are shared between schizophrenia and psoriasis in the Han Chinese population. J Psychiatry Neurosci 41:413-421
Yin, Xianyong; Cheng, Hui; Lin, Yan et al. (2015) A weighted polygenic risk score using 14 known susceptibility variants to estimate risk and age onset of psoriasis in Han Chinese. PLoS One 10:e0125369
Grennan, Kay S; Chen, Chao; Gershon, Elliot S et al. (2014) Molecular network analysis enhances understanding of the biology of mental disorders. Bioessays 36:606-16
Chen, Chao; Zhang, Chunling; Cheng, Lijun et al. (2014) Correlation between DNA methylation and gene expression in the brains of patients with bipolar disorder and schizophrenia. Bipolar Disord 16:790-9