Lai S.-L.,U.S. National Institute on Aging |
Lai S.-L.,University College London |
Lai S.-L.,Chang Gung University |
Abramzon Y.,U.S. National Institute on Aging |
And 31 more authors.
Neurobiology of Aging | Year: 2011
Mutations in the FUS gene have recently been described as a cause of familial amyotrophic lateral sclerosis (ALS), but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of all coding exons of FUS in 228 sporadic ALS cases, and, as previous reports suggest that exon 15 represents a mutational hotspot, we sequenced this exon in an additional 1295 sporadic cases. Six variants in six different cases were found, indicating that FUS mutations can underlie apparently sporadic ALS, but account for less than 1% of this form of disease. © 2010 .
Yoon B.-J.,Texas A&M University |
Qian X.,University of South Florida |
Dougherty E.R.,Texas A&M University |
Dougherty E.R.,Translational Genomics Institute TGen
IEEE Transactions on Signal Processing | Year: 2013
Real-world problems often involve complex systems that cannot be perfectly modeled or identified, and many engineering applications aim to design operators that can perform reliably in the presence of such uncertainty. In this paper, we propose a novel Bayesian framework for objective-based uncertainty quantification (UQ), which quantifies the uncertainty in a given system based on the expected increase of the operational cost that it induces. This measure of uncertainty, called MOCU (mean objective cost of uncertainty), provides a practical way of quantifying the effect of various types of system uncertainties on the operation of interest. Furthermore, the proposed UQ framework provides a general mathematical basis for designing robust operators, and it can be applied to diverse applications, including robust filtering, classification, and control. We demonstrate the utility and effectiveness of the proposed framework by applying it to the problem of robust structural intervention of gene regulatory networks, an important application in translational genomics. © 1991-2012 IEEE.
Ramanan V.K.,Indiana University |
Risacher S.L.,Indiana University |
Nho K.,Indiana University |
Kim S.,Indiana University |
And 13 more authors.
Molecular Psychiatry | Year: 2014
Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir (18 F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10 -14) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10 -8) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum. © 2014 Macmillan Publishers Limited.