NG00121 – Alzheimer’s disease single-neuron whole-genome sequencing – Miller 2022

As part of the Collaborative for Alzheimer's Disease genetics REsearch (CADRE: NIA grant U01-AG058654), we plan to analyze whole exome and whole genome sequence data generated from subjects with Alzheimer's disease (AD) and elderly normal controls. These data will be generated by the National Human Genome Institute Large-Scale Sequence Program. The goal of the planned analyses is to identify genes that have alleles that protect against or increase susceptibility to AD. We will evaluate variants detected in the sequence data for association with AD to identify protective and susceptibility alleles using the whole exome case-control data. We will also evaluate sequence data from multiplex AD families to identify variants associated with AD risk and protection, and evaluate variant co-segregation with AD. The family data will be whole genome data. The family-based data will be used to inform the cases control analysis and visa versa. We also will focus on structural variants (insertion-deletions, copy number variants, and chromosomal rearrangements). Evaluation of structural variants will involve both whole genome and whole exome data. Structural variants will be analyzed with single nucelotide variants detected and analyzed in the case-control and family-based data.

We are attempting to identify all the inherited elements that contribute to Alzheimer's disease risk. To do this we will analyze DNA sequence data from subjects with Alzheimer's disease and elderly subjects who are cognitively normal. The sequence data from these 2 groups will be compared to identify differences that contribute to the risk of developing Alzheimer's disease of that protect against Alzheimer's disease. These DNA differences can be at a single site in the genetic code, or can span multiple sites, changing the copy number of DNA sequences. Both types of genetic variants will be examined.

The purpose of our study is to identify novel genetic factors associated with Alzheimer’s Disease, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). This includes identifying genetic factors associated with the risk of these conditions, as well as genetic risk factors associated with age-at-onset (AAO) for these conditions. We will also evaluate genetic associations with sub-phenotypes individuals have within these broad disease categories, such as their Braak staging results which provide insights into the level of severity of Alzheimer’s. Thus we are requesting access to the set of genomic Whole Exome and Whole Genome Sequences (WES and WGS) have just been released through the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (DSS NIAGADS). The findings from our genetic association testing have the potential for identification of new therapeutic targets for Alzheimer's Disease, CBD, and PSP. The findings from our studies also have the potential for identification of genetic and phenotypic biomarkers that will be beneficial for subsetting patients in new ways. We will use standard genetic epidemiological methods to handle the WGS and WES data. We will also analyze cell type-specific expression differences in AD to identify biomarkers and disease pathways using standard gene expression analysis methods currently in use. We will also use other multi-omic and other genetic data that has now become available to further understand genetic association results we have found in AD.All data will remain anonymized and securely stored, and only those listed on our application and their staff will have access to these data. We will not share any of the individual level data outside of Genentech nor beyond the researchers on our application. We will adhere to all data use agreement stipulations through the DSS NIAGADS. We have a secure computational environment called Rosalind within Genentech where we will use these data. We have IT security staff that constantly monitor all our research computing, assuring safety and privacy of all of our stored data. We will not collaborate with researchers at other institutions.

Genetic variation and gene expression data allows us to understand more of the genetic contribution to risk and protection from diseases such as Alzheimer’s and dementia. This information also allows us to identify important biological contributors to disease for developing effective treatment strategies, and identifying groups of individuals that would benefit most from new treatments. Our exploration of this relationship between genotype, disease traits, gene expression, and outcomes, through these datasets will allow us to pursue important new findings for disease treatment.

GWAS, WES and WGS have identified many genes associated with Alzheimer’s Dementia (AD) and its related traits. However, the identified genes thus far collectively explain only a small proportion of disease heritability, suggesting that more genes remained to be identified. Moreover, there is a clear gender and ethnic disparity for AD susceptibility, but little research has been done to identify gender- and ethnic-specific variants associated with AD. Of the many challenges for deciphering AD pathology, lacking of efficient and power statistical methods for genetic association mapping and causal inference represents a major bottleneck. To tackle this challenge, we have developed a set of novel statistical and bioinformatics approaches for genetic association mapping and multi-omics causation inference in large-scale ethnicity-specific epidemiological studies. The goal of this project is to leverage the multi-omics and clinical data archived by the ADSP, ADNI, ADGC as well as other AD-related data repositories to identify novel genes and molecular markers for AD. Specifically, we will (1) validate our novel methods for identifying novel risk and protective genomic variants and multi-omics causal pathways of AD; (2) identify novel ethnicity- and gender-specific genes and molecular causal pathways of AD. We will share our results, statistical methods and computational software with the scientific community.

Although many genes have been associated with Alzheimer’s Dementia (AD), these genes altogether explain only a small fraction of disease etiology, suggesting more genes remained to be identified. Of the many challenges for deciphering AD pathology, lacking of power statistical methods represents a major bottleneck. To tackle this challenge, we have developed a set of novel statistical and bioinformatics approaches for genetic association mapping and multi-omics causation inference in large-scale ethnicity-specific epidemiological studies. The goal of this project is to leverage the rich genetic and other omic data along with clinical data archived by the ADSP, ADNI, ADGC as well as other AD-related data repositories to identify novel genes and molecular markers for AD. Such results will enhance our understanding of AD pathogenesis and may also serve as biomarkers for early diagnosis and therapeutic targets.