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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. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is one of the most common neurodegenerative disorders characterized by progressive decline in cognitive function. Targeted genetic analyses, genome-wide association studies, and imaging genetic analyses have been performed to detect AD risk and protective genes and have successfully identified dozens of AD susceptibility loci. Recently, brain imaging transcriptomics analyses have also been conducted to investigate the relationship between neuroimaging traits and gene expression measures to identify interesting gene-traits associations. These imaging transcriptomic studies typically do not involve the disease outcome in the analysis, and thus the identified brain or transcriptomic markers may not be related or specific to the disease outcome. Results: We propose an innovative two-stage approach to identify genes whose expression profiles are related to diagnosis phenotype via brain transcriptome mapping. Specifically, we first map the effects of a diagnosis phenotype onto imaging traits across the brain using a linear regression model. Then, the gene-diagnosis association is assessed by spatially correlating the brain transcriptome map with the diagnostic effect map on the brain-wide imaging traits. To demonstrate the promise of our approach, we apply it to the integrative analysis of the brain transcriptome data from the Allen Human Brain Atlas (AHBA) and the amyloid imaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Our method identifies 12 genes whose brain-wide transcriptome patterns are highly correlated with six different diagnostic effect maps on the amyloid imaging traits. These 12 genes include four confirmatory findings (i.e., AD genes reported in DisGeNET) and eight novel genes that have not be associated with AD in DisGeNET. Conclusion: We have proposed a novel disease-related brain transcriptomic mapping method to identify genes whose expression profiles spatially correlated with regional diagnostic effects on a studied brain trait. Our empirical study on the AHBA and ADNI data shows the promise of the approach, and the resulting AD gene discoveries provide valuable information for better understanding biological pathways from transcriptomic signatures to intermediate brain traits and to phenotypic disease outcomes. [ABSTRACT FROM AUTHOR]