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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.
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A structured brain‐wide and genome‐wide association study using ADNI PET images
Abstract A multistage variable selection method is introduced for detecting association signals in structured brain‐wide and genome‐wide association studies (brain‐GWAS). Compared to conventional methods that link one voxel to one single nucleotide polymorphism (SNP), our approach is more efficient and powerful in selecting the important signals by integrating anatomic and gene grouping structures in the brain and the genome, respectively. It avoids resorting to a large number of multiple comparisons while effectively controlling the false discoveries. Validity of the proposed approach is demonstrated by both theoretical investigation and numerical simulations. We apply our proposed method to a brain‐GWAS using Alzheimer's Disease Neuroimaging Initiative positron emission tomography (ADNI PET) imaging and genomic data. We confirm previously reported association signals and also uncover several novel SNPs and genes that are either associated with brain glucose metabolism or have their association significantly modified by Alzheimer's disease status.
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- Award ID(s):
- 1915711
- PAR ID:
- 10452753
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Canadian Journal of Statistics
- Volume:
- 49
- Issue:
- 1
- ISSN:
- 0319-5724
- Format(s):
- Medium: X Size: p. 182-202
- Size(s):
- p. 182-202
- Sponsoring Org:
- National Science Foundation
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