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Background: Human brain structural connectivity is an important imaging quantitative trait for brain development and aging. Mapping the network connectivity to the phenotypic variation provides fundamental insights in understanding the relationship between detailed brain topological architecture, function, and dysfunction. However, the underlying neurobiological mechanism from gene to brain connectome, and to phenotypic outcomes, and whether this mechanism changes over time, remain unclear. Methods: This study analyzes diffusion-weighted imaging data from two age-specific neuroimaging cohorts, extracts structural connectome topological network measures, performs genome-wide association studies of the measures, and examines the causality of genetic influences on phenotypic outcomes mediated via connectivity measures. Results: Our empirical study has yielded several significant findings: 1) It identified genetic makeup underlying structural connectivity changes in the human brain connectome for both age groups. Specifically, it revealed a novel association between the minor allele (G) of rs7937515 and the decreased network segregation measures of the left middle temporal gyrus across young and elderly adults, indicating a consistent genetic effect on brain connectivity across the lifespan. 2) It revealed rs7937515 as a genetic marker for body mass index in young adults but not in elderly adults. 3) It discovered brain network segregation alterations as a potential neuroimaging biomarker for obesity. 4) It demonstrated the hemispheric asymmetry of structural network organization in genetic association analyses and outcome-relevant studies. Discussion: These imaging genetic findings underlying brain connectome warrant further investigation for exploring their potential influences on brain-related complex diseases, given the significant involvement of altered connectivity in neurological, psychiatric and physical disorders. 

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.