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Molecular mechanisms underlying Alzheimer's disease (AD) are difficult to investigate, partly because diagnosis lags behind the insidious pathological processes. Therefore, identifying AD neuroimaging markers and their genetic modifiers may help study early mechanisms of neurodegeneration. We aimed to identify brain regions of the highest vulnerability to AD using a data-driven search in the AD Neuroimaging Initiative (ADNI, n = 1,100 subjects), and further explored genetic variants affecting this critical brain trait using both ADNI and the younger UK Biobank cohort (n = 8,428 subjects). Tensor-Based Morphometry (TBM) and Independent Component Analysis (ICA) identified the limbic system and its interconnecting white-matter as the most AD-vulnerable brain feature. Whole-genome analysis revealed a common variant in SHARPIN that was associated with this imaging feature (rs34173062, p = 2.1 × 10-10 ). This genetic association was validated in the UK Biobank, where it was correlated with entorhinal cortical thickness bilaterally (p = .002 left and p = 8.6 × 10-4 right), and with parental history of AD (p = 2.3 × 10-6 ). Our findings suggest that neuroanatomical variation in the limbic system and AD risk are associated with a novel variant in SHARPIN. The role of this postsynaptic density gene product in β1-integrin adhesion is in line with the amyloid precursor protein (APP) intracellular signaling pathway and the recent genome-wide evidence.
Pubmed ID: 32558014 RIS Download
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Open source software suite for processing and analyzing human brain MRI images. Used for reconstruction of brain cortical surface from structural MRI data, and overlay of functional MRI data onto reconstructed surface. Contains automatic structural imaging stream for processing cross sectional and longitudinal data. Provides anatomical analysis tools, including: representation of cortical surface between white and gray matter, representation of the pial surface, segmentation of white matter from rest of brain, skull stripping, B1 bias field correction, nonlinear registration of cortical surface of individual with stereotaxic atlas, labeling of regions of cortical surface, statistical analysis of group morphometry differences, and labeling of subcortical brain structures.Operating System: Linux, macOS.
View all literature mentionsA software package to analyze next-generation resequencing data. The toolkit offers a wide variety of tools, with a primary focus on variant discovery and genotyping as well as strong emphasis on data quality assurance. Its robust architecture, powerful processing engine and high-performance computing features make it capable of taking on projects of any size. This software library makes writing efficient analysis tools using next-generation sequencing data very easy, and second it's a suite of tools for working with human medical resequencing projects such as 1000 Genomes and The Cancer Genome Atlas. These tools include things like a depth of coverage analyzers, a quality score recalibrator, a SNP/indel caller and a local realigner. (entry from Genetic Analysis Software)
View all literature mentionsDatabase of the results of the ADNI study. ADNI is an initiative to develop biomarker-based methods to detect and track the progression of Alzheimer's disease (AD) that provides access to qualified scientists to their database of imaging, clinical, genomic, and biomarker data.
View all literature mentionsA public charity whose mission is to support the NIH in its mission to improve health, by forming and facilitating public-private partnerships for biomedical research and training. Its vision is Building Partnerships for Discovery and Innovation to Improve Health. The FNIH draws together the world''s foremost researchers and resources, pressing the frontier to advance critical discoveries. They are recognized as the number-one medical research charity in the countryleveraging support, and convening high level partnerships, for the greatest impact on the most urgent medical challenges we face today. Grants are awarded as part of a public-private partnership with the National Heart, Lung, and Blood Institute (NHLBI) on behalf of The Heart Truth in support of women''s heart health education and research. Funding for the Community Action Program is provided by the FNIH through donations from individuals and corporations including The Heart Truth partners Belk Department Stores, Diet Coke, and Swarovski. Successful biomedical research relies upon the knowledge, training and dedication of those who conduct it. Bringing multiple disciplines to bear on health challenges requires innovation and collaboration on the part of scientists. Foundation for NIH partnerships operate in a variety of ways and formats to recruit, train, empower and retain their next generation of researchers. From lectures and multi-week courses, to scholarships and awards through fellowships and residential training programs, their programs respond to the needs of scientists at every level and stage in their careers.
View all literature mentionsMarkov chain Monte Carlo program for association in two-dimensional contingency tables, and for testing Hardy-Weinberg equilibrium. (entry from Genetic Analysis Software)
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