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Abstract Background Alzheimer’s disease (AD) is a complex neurodegenerative disorder and the most common type of dementia. AD is characterized by a decline of cognitive function and brain atrophy, and is highly heritable with estimated heritability ranging from 60 to 80 $$\%$$ % . The most straightforward and widely used strategy to identify AD genetic basis is to perform genome-wide association study (GWAS) of the case-control diagnostic status. These GWAS studies have identified over 50 AD related susceptibility loci. Recently, imaging genetics has emerged as a new field where brain imaging measures are studied as quantitative traits to detect genetic factors. Given that many imaging genetics studies did not involve the diagnostic outcome in the analysis, the identified imaging or genetic markers may not be related or specific to the disease outcome. Results We propose a novel method to identify disease-related genetic variants enriched by imaging endophenotypes, which are the imaging traits associated with both genetic factors and disease status. Our analysis consists of three steps: (1) map the effects of a genetic variant (e.g., single nucleotide polymorphism or SNP) onto imaging traits across the brain using a linear regression model, (2) map the effects of a diagnosis phenotype onto imaging traits across the brain using a linear regression model, and (3) detect SNP-diagnosis association via correlating the SNP effects with the diagnostic effects on the brain-wide imaging traits. We demonstrate the promise of our approach by applying it to the Alzheimer’s Disease Neuroimaging Initiative database. Among 54 AD related susceptibility loci reported in prior large-scale AD GWAS, our approach identifies 41 of those from a much smaller study cohort while the standard association approaches identify only two of those. Clearly, the proposed imaging endophenotype enriched approach can reveal promising AD genetic variants undetectable using the traditional method. Conclusion We have proposed a novel method to identify AD genetic variants enriched by brain-wide imaging endophenotypes. This approach can not only boost detection power, but also reveal interesting biological pathways from genetic determinants to intermediate brain traits and to phenotypic AD outcomes. 

Brain imaging genetics examines associations between imaging quantitative traits (QTs) and genetic factors such as single nucleotide polymorphisms (SNPs) to provide important insights into the pathogenesis of Alzheimer’s disease (AD). The individual level SNP-QT signals are high dimensional and typically have small effect sizes, making them hard to be detected and replicated. To overcome this limitation, this work proposes a new approach that identifies high-level imaging genetic associations through applying multigraph clustering to the SNP-QT association maps. Given an SNP set and a brain QT set, the association between each SNP and each QT is evaluated using a linear regression model. Based on the resulting SNP-QT association map, five SNP–SNP similarity networks (or graphs) are created using five different scoring functions, respectively. Multigraph clustering is applied to these networks to identify SNP clusters with similar association patterns with all the brain QTs. After that, functional annotation is performed for each identified SNP cluster and its corresponding brain association pattern. We applied this pipeline to an AD imaging genetic study, which yielded promising results. For example, in an association study between 54 AD SNPs and 116 amyloid QTs, we identified two SNP clusters with one responsible for amyloid beta clearances and the other regulating amyloid beta formation. These high-level findings have the potential to provide valuable insights into relevant genetic pathways and brain circuits, which can help form new hypotheses for more detailed imaging and genetics studies in independent cohorts. 

Brain imaging genetics aims to reveal genetic effects on brain phenotypes, where most studies examine phenotypes defined on anatomical or functional regions of interest (ROIs) given their biologically meaningful annotation and modest dimensionality compared with voxel-wise approaches. Typical ROI-level measures used in these studies are summary statistics from voxel-wise measures in the region, without making full use of individual voxel signals. In this paper, we propose a flexible and powerful framework for mining regional imaging genetic associations via voxel-wise enrichment analysis, which embraces the collective effect of weak voxel-level signals within an ROI. We demonstrate our method on an imaging genetic analysis using data from the Alzheimers Disease Neuroimaging Initiative, where we assess the collective regional genetic effects of voxel-wise FDG-PET measures between 116 ROIs and 19 AD candidate SNPs. Compared with traditional ROI-wise and voxel-wise approaches, our method identified 102 additional significant associations, some of which were further supported by evidences in brain tissue-specific expression analysis. This demonstrates the promise of the proposed method as a flexible and powerful framework for exploring imaging genetic effects on the brain. 

Brain imaging genetics aims to reveal genetic effects on brain phenotypes, where most studies examine phenotypes defined on anatomical or functional regions of interest (ROIs) given their biologically meaningful interpretation and modest dimensionality compared with voxelwise approaches. Typical ROI-level measures used in these studies are summary statistics from voxelwise measures in the region, without making full use of individual voxel signals.

In this article, we propose a flexible and powerful framework for mining regional imaging genetic associations via voxelwise enrichment analysis, which embraces the collective effect of weak voxel-level signals and integrates brain anatomical annotation information. Our proposed method achieves three goals at the same time: (i) increase the statistical power by substantially reducing the burden of multiple comparison correction; (ii) employ brain annotation information to enable biologically meaningful interpretation and (iii) make full use of fine-grained voxelwise signals. We demonstrate our method on an imaging genetic analysis using data from the Alzheimer’s Disease Neuroimaging Initiative, where we assess the collective regional genetic effects of voxelwise FDG-positron emission tomography measures between 116 ROIs and 565 373 single-nucleotide polymorphisms. Compared with traditional ROI-wise and voxelwise approaches, our method identified 2946 novel imaging genetic associations in addition to 33 ones overlapping with the two benchmark methods. In particular, two newly reported variants were further supported by transcriptome evidences from region-specific expression analysis. This demonstrates the promise of the proposed method as a flexible and powerful framework for exploring imaging genetic effects on the brain.

The R code and sample data are freely available at https://github.com/lshen/RIGEA.

Supplementary data are available at Bioinformatics online.

 

Genetic interactions have been recognized as a potentially important contributor to the heritability of complex diseases. Nevertheless, due to small effect sizes and stringent multiple‐testing correction, identifying genetic interactions in complex diseases is particularly challenging. To address the above challenges, many genomic research initiatives collaborate to form large‐scale consortia and develop open access to enable sharing of genome‐wide association study (GWAS) data. Despite the perceived benefits of data sharing from large consortia, a number of practical issues have arisen, such as privacy concerns on individual genomic information and heterogeneous data sources from distributed GWAS databases. In the context of large consortia, we demonstrate that the heterogeneously appearing marginal effects over distributed GWAS databases can offer new insights into genetic interactions for which conventional methods have had limited success. In this paper, we develop a novel two‐stage testing procedure, namedphylogenY‐based effect‐size tests for interactions using first 2 moments(YETI2), to detect genetic interactions through bothpooled marginal effects, in terms of averaging site‐specific marginal effects, andheterogeneity in marginal effectsacross sites, using a meta‐analytic framework. YETI2 can not only be applied to large consortia without shared personal information but also can be used to leverage underlyingheterogeneity in marginal effectsto prioritize potential genetic interactions. We investigate the performance of YETI2 through simulation studies and apply YETI2 to bladder cancer data from dbGaP.