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We propose in this paper a unified approach for testing the association between rare variants and phenotypes in sequencing association studies. This approach maximizes power by adaptively using the data to optimally combine the burden test and the nonburden sequence kernel association test (SKAT). Burden tests are more powerful when most variants in a(More)
It is well established that the progression to human cancer is characterized by the evolution of clones of cells with accumulated genetic abnormalities. However, technical difficulties limit the ability to study this process in some premalignant and malignant conditions. For example, the progression to esophageal adenocarcinoma in the premalignant condition(More)
The chromosome 8p11-12 Werner syndrome (WRN ) locus encodes a RecQ helicase protein of unknown function that possesses both 3' --> 5' helicase and 3' --> 5' exonuclease activities. We show that WRN cell lines display a marked reduction in cell proliferation following mitotic recombination, and generate few viable gene conversion-type recombinants. These(More)
To determine the role of reactive oxygen species in mammalian longevity, we generated transgenic mice that overexpress human catalase localized to the peroxisome, the nucleus, or mitochondria (MCAT). Median and maximum life spans were maximally increased (averages of 5 months and 5.5 months, respectively) in MCAT animals. Cardiac pathology and cataract(More)
Exome sequencing - the targeted sequencing of the subset of the human genome that is protein coding - is a powerful and cost-effective new tool for dissecting the genetic basis of diseases and traits that have proved to be intractable to conventional gene-discovery strategies. Over the past 2 years, experimental and analytical approaches relating to exome(More)
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) of unknown etiology. Introduction of acid into the respiratory tree can produce pulmonary fibrosis. Gastroesophageal reflux (GER) has previously been associated with several other respiratory conditions, including pneumonia, bronchitis, and asthma. To investigate(More)
Ulcerative colitis, a chronic inflammatory disease of the colon, is associated with a high risk of colorectal carcinoma that is thought to develop through genomic instability. We considered that the rapid cell turnover and oxidative injury observed in ulcerative colitis might accelerate telomere shortening, thereby increasing the potential of chromosomal(More)
High frequency allelic loss of chromosome 9p21 has been reported in a number of human cancers, including those of the esophagus. The CDKN2 gene on chromosome 9p21 that encodes the p16 inhibitor of cyclinD/Cdk4 complexes is a target of allelic loss and inactivation in a variety of human cancers and cell lines. However, the roles of 9p21 allelic losses and(More)
BACKGROUND Patients with ulcerative colitis and primary sclerosing cholangitis are at high risk for colonic dysplasia and cancer. This risk approaches 50% after 25 years of colitis. Ursodiol has been shown to protect against development of colorectal neoplasia in animal models. OBJECTIVE To assess the relationship between ursodiol use and colonic(More)
Werner syndrome (WRN) is an uncommon autosomal recessive disease whose phenotype includes features of premature aging, genetic instability, and an elevated risk of cancer. We used three different experimental strategies to show that WRN cellular phenotypes of limited cell division potential, DNA damage hypersensitivity, and defective homologous(More)