Dataset Information

Whole genome sequencing-based copy number variations reveal novel pathways and targets in Alzheimer's disease.

ABSTRACT:

Introduction

A few copy number variations (CNVs) have been reported for Alzheimer's disease (AD). However, there is a lack of a systematic investigation of CNVs in AD based on whole genome sequencing (WGS) data.

Methods

We used four methods to identify consensus CNVs from the WGS data of 1,411 individuals and further investigated their functional roles in AD using the matched transcriptomic and clinicopathological data.

Results

We identified 3,012 rare AD-specific CNVs whose residing genes are enriched for cellular glucuronidation and neuron projection pathways. Genes whose mRNA expressions are significantly correlated with common CNVs are involved in major histocompatibility complex class II receptor activity. Integration of CNVs, gene expression, and clinical and pathological traits further pinpoints a key CNV that potentially regulates immune response in AD.

Discussion

We identify CNVs as potential genetic regulators of immune response in AD. The identified CNVs and their downstream gene networks reveal novel pathways and targets for AD.

SUBMITTER: Ming C

PROVIDER: S-EPMC9264340 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Whole genome sequencing-based copy number variations reveal novel pathways and targets in Alzheimer's disease.

Ming Chen C Wang Minghui M Wang Qian Q Neff Ryan R Wang Erming E Shen Qi Q Reddy Joseph S JS Wang Xue X Allen Mariet M Ertekin-Taner Nilüfer N De Jager Philip L PL Bennett David A DA Haroutunian Vahram V Schadt Eric E Zhang Bin B

Alzheimer's & dementia : the journal of the Alzheimer's Association 20211217 10

<h4>Introduction</h4>A few copy number variations (CNVs) have been reported for Alzheimer's disease (AD). However, there is a lack of a systematic investigation of CNVs in AD based on whole genome sequencing (WGS) data.<h4>Methods</h4>We used four methods to identify consensus CNVs from the WGS data of 1,411 individuals and further investigated their functional roles in AD using the matched transcriptomic and clinicopathological data.<h4>Results</h4>We identified 3,012 rare AD-specific CNVs whos ...[more]

PMID: 34918867

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Project description:BackgroundWhole genome sequencing enables a high resolution view of the human genome and provides unique insights into genome structure at an unprecedented scale. There have been a number of tools to infer copy number variation in the genome. These tools, while validated, also include a number of parameters that are configurable to genome data being analyzed. These algorithms allow for normalization to account for individual and population-specific effects on individual genome CNV estimates but the impact of these changes on the estimated CNVs is not well characterized. We evaluate in detail the effect of normalization methodologies in two CNV algorithms FREEC and CNV-seq using whole genome sequencing data from 8 individuals spanning four populations.MethodsWe apply FREEC and CNV-seq to a sequencing data set consisting of 8 genomes. We use multiple configurations corresponding to different read-count normalization methodologies in FREEC, and statistically characterize the concordance of the CNV calls between FREEC configurations and the analogous output from CNV-seq. The normalization methodologies evaluated in FREEC are: GC content, mappability and control genome. We further stratify the concordance analysis within genic, non-genic, and a collection of validated variant regions.ResultsThe GC content normalization methodology generates the highest number of altered copy number regions. Both mappability and control genome normalization reduce the total number and length of copy number regions. Mappability normalization yields Jaccard indices in the 0.07 - 0.3 range, whereas using a control genome normalization yields Jaccard index values around 0.4 with normalization based on GC content. The most critical impact of using mappability as a normalization factor is substantial reduction of deletion CNV calls. The output of another method based on control genome normalization, CNV-seq, resulted in comparable CNV call profiles, and substantial agreement in variable gene and CNV region calls.ConclusionsChoice of read-count normalization methodology has a substantial effect on CNV calls and the use of genomic mappability or an appropriately chosen control genome can optimize the output of CNV analysis.

Dataset Information

Whole genome sequencing-based copy number variations reveal novel pathways and targets in Alzheimer's disease.

Introduction

Methods

Results

Discussion

Publications

Whole genome sequencing-based copy number variations reveal novel pathways and targets in Alzheimer's disease.

Similar Datasets

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