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ABSTRACT Mediation analysis is widely utilized in neuroscience to investigate the role of brain image phenotypes in the neurological pathways from genetic exposures to clinical outcomes. However, it is still difficult to conduct mediation analyses with whole genome‐wide exposures and brain subcortical shape mediators due to several challenges including (i) large‐scale genetic exposures, that is, millions of single‐nucleotide polymorphisms (SNPs); (ii) nonlinear Hilbert space for shape mediators; and (iii) statistical inference on the direct and indirect effects. To tackle these challenges, this paper proposes a genome‐wide mediation analysis framework with brain subcortical shape mediators. First, to address the issue caused by the high dimensionality in genetic exposures, a fast genome‐wide association analysis is conducted to discover potential genetic variants with significant genetic effects on the clinical outcome. Second, the square‐root velocity function representations are extracted from the brain subcortical shapes, which fall in an unconstrained linear Hilbert subspace. Third, to identify the underlying causal pathways from the detected SNPs to the clinical outcome implicitly through the shape mediators, we utilize a shape mediation analysis framework consisting of a shape‐on‐scalar model and a scalar‐on‐shape model. Furthermore, the bootstrap resampling approach is adopted to investigate both global and spatial significant mediation effects. Finally, our framework is applied to the corpus callosum shape data from the Alzheimer's Disease Neuroimaging Initiative. 

Large-scale imaging studies often face challenges stemming from heterogeneity arising from differences in geographic location, instrumental setups, image acquisition protocols, study design, and latent variables that remain undisclosed. While numerous regression models have been developed to elucidate the interplay between imaging responses and relevant covariates, limited attention has been devoted to cases where the imaging responses pertain to the domain of shape. This adds complexity to the problem of imaging heterogeneity, primarily due to the unique properties inherent to shape representations, including nonlinearity, high-dimensionality, and the intricacies of quotient space geometry. To tackle this intricate issue, we propose a novel approach: a shape-on-scalar regression model that incorporates confounder adjustment. In particular, we leverage the square root velocity function to extract elastic shape representations which are embedded within the linear Hilbert space of square integrable functions. Subsequently, we introduce a shape regression model aimed at characterizing the intricate relationship between elastic shapes and covariates of interest, all while effectively managing the challenges posed by imaging heterogeneity. We develop comprehensive procedures for estimating and making inferences about the unknown model parameters. Through real-data analysis, our method demonstrates its superiority in terms of estimation accuracy when compared to existing approaches.