Patricia L Kramer

Publications (10)59.87 Total impact

• Source

  Available from: Hiroko Hayama Dodge

  Article: Review of selected databases of longitudinal aging studies.

  Deniz Erten-Lyons, Lena O Sherbakov, Andrea M Piccinin, Scott M Hofer, Hiroko H Dodge, Joseph F Quinn, Randy L Woltjer, Patricia L Kramer, Jeffrey A Kaye
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  ABSTRACT: One of the recommendations of the 2010 Leon Thal Symposium, organized to develop strategies to prevent Alzheimer's disease, was to build a global database of longitudinal aging studies. Although several databases of longitudinal aging studies exist, none of these are comprehensive or complete. In this article, we review selected databases of longitudinal aging studies. We also make recommendations on future steps to create a comprehensive database. Additionally, we discuss issues related to data harmonization.
  Alzheimer's & dementia: the journal of the Alzheimer's Association 11/2012; 8(6):584-9. · 5.90 Impact Factor
• Article: Variants in ASB10 are associated with open-angle glaucoma.

  Francesca Pasutto, Kate E Keller, Nicole Weisschuh, Heinrich Sticht, John R Samples, Yong-Feng Yang, Matthias Zenkel, Ursula Schlötzer-Schrehardt, Christian Y Mardin, Paolo Frezzotti, Beth Edmunds, Patricia L Kramer, Eugen Gramer, André Reis, Ted S Acott, Mary K Wirtz
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  ABSTRACT: The molecular events responsible for obstruction of aqueous humor outflow and the loss of retinal ganglion cells in glaucoma, one of the main causes of blindness worldwide, remain poorly understood. We identified a synonymous variant, c.765C>T (Thr255Thr), in ankyrin repeats and suppressor of cytokine signaling box-containing protein 10 (ASB10) in a large family with primary open angle glaucoma (POAG) mapping to the GLC1F locus. This variant affects an exon splice enhancer site and alters mRNA splicing in lymphoblasts of affected family members. Systematic sequence analysis in two POAG patient groups (195 US and 977 German) and their respective controls (85 and 376) lead to the identification of 26 amino acid changes in 70 patients (70 of 1172; 6.0%) compared with 9 in 13 controls (13 of 461; 2.8%; P = 0.008). Molecular modeling suggests that these missense variants change ASB10 net charge or destabilize ankyrin repeats. ASB10 mRNA and protein were found to be strongly expressed in trabecular meshwork, retinal ganglion cells and ciliary body. Silencing of ASB10 transcripts in perfused anterior segment organ culture reduced outflow facility by ∼50% compared with control-infected anterior segments (P = 0.02). In conclusion, genetic and molecular analyses provide evidence for ASB10 as a glaucoma-causing gene.
  Human Molecular Genetics 12/2011; 21(6):1336-49. · 7.64 Impact Factor
• Article: Functional screening of Alzheimer pathology genome-wide association signals in Drosophila.

  Joshua M Shulman, Portia Chipendo, Lori B Chibnik, Cristin Aubin, Dong Tran, Brendan T Keenan, Patricia L Kramer, Julie A Schneider, David A Bennett, Mel B Feany, Philip L De Jager
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  ABSTRACT: We have leveraged a Drosophila model relevant to Alzheimer disease (AD) for functional screening of findings from a genome-wide scan for loci associated with a quantitative measure of AD pathology in humans. In six of the 15 genomic regions evaluated, we successfully identified a causal gene for the association, on the basis of in vivo interactions with the neurotoxicity of Tau, which forms neurofibrillary tangles in AD. Among the top results, rs10845990 within SLC2A14, encoding a glucose transporter, showed evidence of replication for association with AD pathology, and gain and loss of function in glut1, the Drosophila ortholog, was associated with suppression and enhancement of Tau toxicity, respectively. Our strategy of coupling genome-wide association in humans with functional screening in a model organism is likely to be a powerful approach for gene discovery in AD and other complex genetic disorders.
  The American Journal of Human Genetics 02/2011; 88(2):232-8. · 10.60 Impact Factor
• Article: Association of POAG risk factors and the Thr377Met MYOC mutation in an isolated Greek population.

  Mary K Wirtz, John R Samples, Victoria Toumanidou, Jac Charlesworth, Dimitrios G Mikropoulos, Konstantinos Kaltsos, Athanasios Economou, Antonios Dimopoulos, Irene N Georgiadou, Georgios Moumtzis, Athanasios Papanastasiou, Patricia L Kramer, Tom Dyer, John Blangero, Anastasios G P Konstas
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  ABSTRACT: To characterize the MYOC genotype correlation with phenotypes in an isolated Greek population with a high incidence of glaucoma. Five hundred thirty-one villagers were enrolled in the study. Participants underwent a comprehensive ophthalmic examination. All three exons of myocilin were bidirectionally sequenced. Power calculations and measured genotype analysis was conducted using the genetic variance analysis program, SOLAR version 4.2, to account for the relatedness between individuals. The participants, 376 of whom were linked in a single 11-generation pedigree, ranged in age from 10 to 95 years with a mean age of 49. Sixty-five individuals had POAG, and 27 of those carried the Thr377Met MYOC mutation. Both peak intraocular pressure and vertical cup-to dis- ratio were significantly associated with the MYOC Thr377Met variant (P = 9 x 10(-14) and P = 9 x 10(-8), respectively), whereas central corneal thickness showed no significant association (P < 0.7). This village had a high frequency of glaucoma, with 12% of the participants aged 10 to 95 years having the disease. In this cohort, the Thr377Met MYOC mutation was significantly associated with both high intraocular pressures and high vertical cup-to-disc ratios. No association was found with central corneal thickness.
  Investigative ophthalmology & visual science 06/2010; 51(6):3055-60. · 3.43 Impact Factor
• Source

  Available from: Raymond Scott Turner

  Article: Alzheimer disease pathology in cognitively healthy elderly: a genome-wide study.

  Patricia L Kramer, Haiyan Xu, Randall L Woltjer, Shawn K Westaway, David Clark, Deniz Erten-Lyons, Jeffrey A Kaye, Kathleen A Welsh-Bohmer, Juan C Troncoso, William R Markesbery, Ronald C Petersen, R Scott Turner, Walter A Kukull, David A Bennett, Douglas Galasko, John C Morris, Jurg Ott
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  ABSTRACT: Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.
  Neurobiology of aging 05/2010; 32(12):2113-22. · 5.94 Impact Factor
• Article: The path to open-angle glaucoma gene discovery: endophenotypic status of intraocular pressure, cup-to-disc ratio, and central corneal thickness.

  Jac Charlesworth, Patricia L Kramer, Tom Dyer, Victor Diego, John R Samples, Jamie E Craig, David A Mackey, Alex W Hewitt, John Blangero, Mary K Wirtz
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  ABSTRACT: PURPOSE. Primary open-angle glaucoma (POAG) is a complex disease with a genetic architecture that can be simplified through the investigation of individual traits underlying disease risk. It has been well studied in twin models, and this study was undertaken to investigate the heritability of some of these key endophenotypes in extended pedigrees. METHODS. These data are derived from a large, multicenter study of extended, Caucasian POAG families from Australia and the United States. The study included 1181 people from 22 extended pedigrees. Variance components modeling was used to determine the heritabilities of maximum intraocular pressure (IOP), maximum vertical cup-to-disc ratio (VCDR), and mean central corneal thickness (CCT). Bivariate quantitative genetic analysis between these eye-related phenotypes and POAG itself was performed to determine whether any of these traits represent true endophenotypes. RESULTS. Heritability estimates for IOP, VCDR, and CCT (0.42, 0.66, and 0.72, respectively) were significant and show strong concordance with data in previous studies. Bivariate analysis revealed that both IOP (RhoG = 0.80; P = 9.6 x 10(-6)) and VCDR (RhoG = 0.76; P = 4.8 x 10(-10)) showed strong evidence of genetic correlation with POAG susceptibility. These two traits also correlated genetically with each other (RhoG = 0.45; P = 0.0012). Alternatively, CCT did not correlate genetically with risk of POAG. CONCLUSIONS. All the proposed POAG-related traits have genetic components. However, the significant genetic correlations observed between IOP, VCDR, and POAG itself suggest that they most likely represent true endophenotypes that could aid in the identification of genes underlying POAG susceptibility. CCT did not correlate genetically with disease and is unlikely to be a useful surrogate endophenotype for POAG.
  Investigative ophthalmology & visual science 03/2010; 51(7):3509-14. · 3.43 Impact Factor
• Source

  Available from: pnas.org

  Article: A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia.

  Wei Tian, Yi Fu, Anna Garcia-Elias, José M Fernández-Fernández, Rubén Vicente, Patricia L Kramer, Robert F Klein, Robert Hitzemann, Eric S Orwoll, Beth Wilmot, Shannon McWeeney, Miguel A Valverde, David M Cohen
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  ABSTRACT: Disorders of water balance are among the most common and morbid of the electrolyte disturbances, and are reflected clinically as abnormalities in the serum sodium concentration. The transient receptor potential vanilloid 4 (TRPV4) channel is postulated to comprise an element of the central tonicity-sensing mechanism in the mammalian hypothalamus, and is activated by hypotonic stress in vitro. A nonsynonymous polymorphism in the TRPV4 gene gives rise to a Pro-to-Ser substitution at residue 19. We show that this polymorphism is significantly associated with serum sodium concentration and with hyponatremia (serum sodium concentration < or =135 mEq/L) in 2 non-Hispanic Caucasian male populations; in addition, mean serum sodium concentration is lower among subjects with the TRPV4(P19S) allele relative to the wild-type allele. Subjects with the minor allele were 2.4-6.4 times as likely to exhibit hyponatremia as subjects without the minor allele (after inclusion of key covariates). Consistent with these observations, a human TRPV4 channel mutated to incorporate the TRPV4(P19S) polymorphism showed diminished response to hypotonic stress (relative to the wild-type channel) and to the osmotransducing lipid epoxyeicosatrienoic acid in heterologous expression studies. These data suggest that this polymorphism affects TRPV4 function in vivo and likely influences systemic water balance on a population-wide basis.
  Proceedings of the National Academy of Sciences 09/2009; 106(33):14034-9. · 9.68 Impact Factor
• Article: Translational gene mapping of cognitive decline.

  Beth Wilmot, Shannon K McWeeney, Randal R Nixon, Thomas J Montine, Jamie Laut, Christina A Harrington, Jeffrey A Kaye, Patricia L Kramer
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  ABSTRACT: The ability to maintain cognitive function during aging is a complex process subject to genetic and environmental influences. Alzheimer's disease (AD) is the most common disorder causing cognitive decline among the elderly. Among those with AD, there is broad variation in the relationship between AD neuropathology and clinical manifestations of dementia. Differences in expression of genes involved in neural processing pathways may contribute to individual differences in maintenance of cognitive function. We performed whole genome expression profiling of RNA obtained from frontal cortex of clinically non-demented and AD subjects to identify genes associated with brain aging and cognitive decline. Genetic mapping information and biological function annotation were incorporated to highlight genes of particular interest. The candidate genes identified in this study were compared with those from two other studies in different tissues to identify common underlying transcriptional profiles. In addition to confirming sweeping transcriptomal differences documented in previous studies of cognitive decline, we present new evidence for up-regulation of actin-related processes and down-regulation of translation, RNA processing and localization, and vesicle-mediated transport in individuals with cognitive decline.
  Neurobiology of aging 05/2008; 29(4):524-41. · 5.94 Impact Factor
• Article: The role of the WDR36 gene on chromosome 5q22.1 in a large family with primary open-angle glaucoma mapped to this region.

  Patricia L Kramer, John R Samples, Sharareh Monemi, Renee Sykes, Mansoor Sarfarazi, Mary K Wirtz
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  ABSTRACT: To determine whether mutations in the WD40-repeat 36 (WDR36) gene are responsible for primary open-angle glaucoma (POAG) that maps to the GLC1G locus in a family with 16 affected family members. Ninety-two family members underwent clinical evaluation for POAG on the basis of intraocular pressures, cupping of discs, and visual fields after informed consent was obtained. All 23 exons of WDR36 were sequenced in DNA from 5 affected and 2 unaffected family members. Sixteen family members showed evidence of POAG. A number of sequence variations were identified in family members; most of the variations were previously described single-nucleotide polymorphisms also present in the general population. The 3 new sequence changes were all intronic; 2 were found in only 1 of the family members undergoing screening. Several polymorphisms, including known single-nucleotide polymorphisms, were identified; however, none of these were consistent with disease-causing mutations. A mutation in a noncoding region of WDR36 may be responsible for POAG in this family, or another gene in this region may be the actual cause of glaucoma in this family. The finding that the WDR36 gene is probably not the responsible gene in this family further documents the genetic heterogeneity of POAG.
  Archives of Ophthalmology 10/2006; 124(9):1328-31. · 3.71 Impact Factor
• Article: A large GLC1C Greek family with a myocilin T377M mutation: inheritance and phenotypic variability.

  Michael B Petersen, George Kitsos, John R Samples, N Donna Gaudette, Effrosini Economou-Petersen, Renée Sykes, Kristal Rust, Maria Grigoriadou, George Aperis, Dongseok Choi, Konstantinos Psilas, Jamie E Craig, Patricia L Kramer, David A Mackey, Mary K Wirtz
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  ABSTRACT: POAG is a complex disease; therefore, families in which a glaucoma gene has been mapped may carry additional POAG genes. The goal of this study was to determine whether mutations in the myocilin (MYOC) gene on chromosome 1 are present in two POAG families, which have previously been mapped to the GLC1C locus on chromosome 3. The three exons of MYOC were screened by denaturing (d)HPLC. Samples with heteroduplex peaks were sequenced. Clinical findings were compared with genotype status in all available family members over the age of 20 years. A T377M coding sequence change in MYOC was identified in family members of the Greek GLC1C family but not in the Oregon GLC1C family. Individuals carrying both the MYOC T377M variant and the GLC1C haplotype were more severely affected at an earlier age than individuals with just one of the POAG genes, suggesting that these two genes interact or that both contribute to the POAG phenotype in a cumulative way.
  Investigative Ophthalmology &amp Visual Science 03/2006; 47(2):620-5. · 3.60 Impact Factor