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1.  Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease 
Escott-Price, Valentina | Bellenguez, Céline | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Jones, Lesley | Holmans, Peter | Gerrish, Amy | Vedernikov, Alexey | Richards, Alexander | DeStefano, Anita L. | Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A. | Naj, Adam C. | Sims, Rebecca | Jun, Gyungah | Bis, Joshua C. | Beecham, Gary W. | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A. | Denning, Nicola | Smith, Albert V. | Chouraki, Vincent | Thomas, Charlene | Ikram, M. Arfan | Zelenika, Diana | Vardarajan, Badri N. | Kamatani, Yoichiro | Lin, Chiao-Feng | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L. | Vronskaya, Maria | Johnson, Andrew D. | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L. | Buxbaum, Joseph D. | Campion, Dominique | Crane, Paul K. | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L. | De Jager, Philip L. | Deramecourt, Vincent | Johnston, Janet A. | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Hernández, Isabel | Rubinsztein, David C. | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M. | Fiévet, Nathalie | Huentelman, Matthew J. | Gill, Michael | Brown, Kristelle | Kamboh, M. Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B. | Myers, Amanda J. | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W. | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick C. | Hardy, John | Naranjo, Maria Candida Deniz | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Scarpini, Elio | Bonuccelli, Ubaldo | Mancuso, Michelangelo | Siciliano, Gabriele | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Frank-García, Ana | Panza, Francesco | Solfrizzi, Vincenzo | Caffarra, Paolo | Nacmias, Benedetta | Perry, William | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M. | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G. | Coto, Eliecer | Hamilton-Nelson, Kara L. | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J. | Faber, Kelley M. | Jonsson, Palmi V. | Combarros, Onofre | O'Donovan, Michael C. | Cantwell, Laura B. | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H. | Bennett, David A. | Harris, Tamara B. | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F. A. G. | Passmore, Peter | Montine, Thomas J. | Bettens, Karolien | Rotter, Jerome I. | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M. | Kukull, Walter A. | Hannequin, Didier | Powell, John F. | Nalls, Michael A. | Ritchie, Karen | Lunetta, Kathryn L. | Kauwe, John S. K. | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R. | Schmidt, Reinhold | Rujescu, Dan | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M. | Graff, Caroline | Psaty, Bruce M. | Haines, Jonathan L. | Lathrop, Mark | Pericak-Vance, Margaret A. | Launer, Lenore J. | Van Broeckhoven, Christine | Farrer, Lindsay A. | van Duijn, Cornelia M. | Ramirez, Alfredo | Seshadri, Sudha | Schellenberg, Gerard D. | Amouyel, Philippe | Williams, Julie
PLoS ONE  2014;9(6):e94661.
Background
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal Findings
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
doi:10.1371/journal.pone.0094661
PMCID: PMC4055488  PMID: 24922517
2.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease 
Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A | Harold, Denise | Naj, Adam C | Sims, Rebecca | Bellenguez, Céline | Jun, Gyungah | DeStefano, Anita L | Bis, Joshua C | Beecham, Gary W | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A | Jones, Nicola | Smith, Albert V | Chouraki, Vincent | Thomas, Charlene | Ikram, M Arfan | Zelenika, Diana | Vardarajan, Badri N | Kamatani, Yoichiro | Lin, Chiao-Feng | Gerrish, Amy | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Choi, Seung-Hoan | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Ramirez, Alfredo | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L | De Jager, Philip L | Deramecourt, Vincent | Johnston, Janet A | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Morón, Francisco J | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Brown, Kristelle | Kamboh, M Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B | Green, Robert | Myers, Amanda J | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | St George-Hyslop, Peter | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petroula | Collinge, John | Sorbi, Sandro | Sanchez-Garcia, Florentino | Fox, Nick C | Hardy, John | Deniz Naranjo, Maria Candida | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Matthews, Fiona | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J | Faber, Kelley M | Jonsson, Palmi V | Combarros, Onofre | O’Donovan, Michael C | Cantwell, Laura B | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H | Bennett, David A | Harris, Tamara B | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F A G | Passmore, Peter | Montine, Thomas J | Bettens, Karolien | Rotter, Jerome I | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M | Kukull, Walter A | Hannequin, Didier | Powell, John F | Nalls, Michael A | Ritchie, Karen | Lunetta, Kathryn L | Kauwe, John S K | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Schmidt, Reinhold | Rujescu, Dan | Wang, Li-san | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M | Graff, Caroline | Psaty, Bruce M | Jones, Lesley | Haines, Jonathan L | Holmans, Peter A | Lathrop, Mark | Pericak-Vance, Margaret A | Launer, Lenore J | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broeckhoven, Christine | Moskvina, Valentina | Seshadri, Sudha | Williams, Julie | Schellenberg, Gerard D | Amouyel, Philippe
Nature genetics  2013;45(12):1452-1458.
Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease.
doi:10.1038/ng.2802
PMCID: PMC3896259  PMID: 24162737
3.  Genetic variation associated with circulating monocyte count in the eMERGE Network 
Human Molecular Genetics  2013;22(10):2119-2127.
With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value = 2.78×10(−16), β = −0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(−7), β = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(−16), β = −0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value = 2.29×10(−7), β = 0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value = 5.68×10(−17), β = −0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.
doi:10.1093/hmg/ddt010
PMCID: PMC3633369  PMID: 23314186
4.  Neuropathology in the Adult Changes in Thought Study: A Review 
The neuropathology underlying dementia syndromes in older populations is complex. The contributions of Alzheimer’s and Lewy body pathology are well appreciated. Recent studies with brain autopsies have highlighted the high prevalence of vascular disease as an independent, but often co-morbid contributor to dementia. The Adult Changes in Thought Study is a community-based, longitudinal study of brain aging and cognitive decline which has recently confirmed cerebral microinfarcts as a strong correlate of cognitive impairment and dementia. This study examines correlations between clinical characteristics including extensive, longitudinal medication histories, and longitudinal cognitive testing against structural and biochemical features of disease. Keywords: Aging, community-based, microinfarct, longitudinal, neuropathology.
doi:10.3233/JAD-2009-1180
PMCID: PMC4008877  PMID: 19661627
Aging; community-based; microinfarct; longitudinal; neuropathology
5.  Genome- and Phenome-Wide Analysis of Cardiac Conduction Identifies Markers of Arrhythmia Risk 
Circulation  2013;127(13):1377-1385.
Background
Electrocardiographic QRS duration, a measure of cardiac intraventricular conduction, varies ~2-fold in individuals without cardiac disease. Slow conduction may promote reentrant arrhythmias.
Methods and Results
We performed a genome-wide association study (GWAS) to identify genomic markers of QRS duration in 5,272 individuals without cardiac disease selected from electronic medical record (EMR) algorithms at five sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the CHARGE consortium QRS GWAS meta-analysis. Twenty-three single nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE samples; 18 SNPs were in the chromosome 3 SCN5A and SCN10A loci, where the most significant SNPs were rs1805126 in SCN5A with p=1.2×10−8 (eMERGE) and p=2.5×10−20 (CHARGE) and rs6795970 in SCN10A with p=6×10−6 (eMERGE) and p=5×10−27 (CHARGE). The other loci were in NFIA, near CDKN1A, and near C6orf204. We then performed phenome-wide association studies (PheWAS) on variants in these five loci in 13,859 European Americans to search for diagnoses associated with these markers. PheWAS identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5,272 “heart-healthy” study population.
Conclusions
We conclude that DNA biobanks coupled to EMRs provide a platform not only for GWAS but may also allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The PheWAS approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias.
doi:10.1161/CIRCULATIONAHA.112.000604
PMCID: PMC3713791  PMID: 23463857
cardiac conduction; QRS duration; atrial fibrillation; genome-wide association study; phenome-wide association study; electronic medical records
6.  Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data 
Nature biotechnology  2013;31(12):1102-1110.
Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10−6 (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.
doi:10.1038/nbt.2749
PMCID: PMC3969265  PMID: 24270849
7.  Glucose Levels and Risk of Dementia 
The New England journal of medicine  2013;369(6):540-548.
BACKGROUND
Diabetes is a risk factor for dementia. It is unknown whether higher glucose levels increase the risk of dementia in people without diabetes.
METHODS
We used 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2067 participants without dementia to examine the relationship between glucose levels and the risk of dementia. Participants were from the Adult Changes in Thought study and included 839 men and 1228 women whose mean age at baseline was 76 years; 232 participants had diabetes, and 1835 did not. We fit Cox regression models, stratified according to diabetes status and adjusted for age, sex, study cohort, educational level, level of exercise, blood pressure, and status with respect to coronary and cerebrovascular diseases, atrial fibrillation, smoking, and treatment for hypertension.
RESULTS
During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia (P = 0.01); with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18 (95% confidence interval [CI], 1.04 to 1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (P = 0.002); with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40 (95% CI, 1.12 to 1.76).
CONCLUSIONS
Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes. (Funded by the National Institutes of Health.)
doi:10.1056/NEJMoa1215740
PMCID: PMC3955123  PMID: 23924004
8.  Validation sampling can reduce bias in healthcare database studies: an illustration using influenza vaccination effectiveness 
Journal of clinical epidemiology  2013;66(8 0):S110-S121.
Objective
Estimates of treatment effectiveness in epidemiologic studies using large observational health care databases may be biased due to inaccurate or incomplete information on important confounders. Study methods that collect and incorporate more comprehensive confounder data on a validation cohort may reduce confounding bias.
Study Design and Setting
We applied two such methods, imputation and reweighting, to Group Health administrative data (full sample) supplemented by more detailed confounder data from the Adult Changes in Thought study (validation sample). We used influenza vaccination effectiveness (with an unexposed comparator group) as an example and evaluated each method’s ability to reduce bias using the control time period prior to influenza circulation.
Results
Both methods reduced, but did not completely eliminate, the bias compared with traditional effectiveness estimates that do not utilize the validation sample confounders.
Conclusion
Although these results support the use of validation sampling methods to improve the accuracy of comparative effectiveness findings from healthcare database studies, they also illustrate that the success of such methods depends on many factors, including the ability to measure important confounders in a representative and large enough validation sample, the comparability of the full sample and validation sample, and the accuracy with which data can be imputed or reweighted using the additional validation sample information.
doi:10.1016/j.jclinepi.2013.01.015
PMCID: PMC3911878  PMID: 23849144
aged; bias (epidemiologic); comparative effectiveness research; confounding factors (epidemiology); influenza vaccines; propensity score
9.  APOE ε4 Increases Risk for Dementia in Pure Synucleinopathies 
JAMA neurology  2013;70(2):223-228.
Objective
To test for an association between the apolipoprotein E (APOE) ε4 allele and dementias with synucleinopathy.
Design
Genetic case-control association study.
Setting
Academic research.
Patients
Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269).
Main Outcome Measure
The APOE allele frequencies.
Results
The APOE ε4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ42=185.25; P=5.56×10−39), and it was higher in the pDLB group than the PDD group (P=.01). In an age-adjusted and sex-adjusted dominant model, ε4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4–15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1–19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5–10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7–5.6).
Conclusions
The APOE ε4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ε4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ε4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.
doi:10.1001/jamaneurol.2013.600
PMCID: PMC3580799  PMID: 23407718
10.  Neuropathologic correlates of cognition in a population-based sample 
Many cognitively normal older adults have underlying neuropathologic changes of Alzheimer’s disease (AD), vascular brain injury (VBI), or Lewy body disease (LBD), which confer an increased risk of dementia. The current study focused on the association between multiple neuropathologic indices and performance on specific cognitive domains in a community sample of older adults. Of 438 participants in the Adult Changes in Thought population-based study of brain aging who were autopsied, 363 subjects had cognitive testing at their final study visit and were included. Associations were measured between performance on the Cognitive Abilities Screening Instrument prior to death and neuropathologic endpoints, including AD neuropathologic changes, LBD, cerebral amyloid angiopathy, and measures of VBI. Braak stage for neurofibrillary tangles, lower brain weight, and VBI as measured by cerebral cortical microvascular lesions (μVBI) explained a significant proportion of the variance associated with global cognitive test performance (R2=0.31, p< 0.0001) both in the entire sample and when analysis was restricted to non-demented subjects (R2= 0.23, p< 0.0001). Specific cognitive domains were differentially related to neuropathologic lesion type: memory and executive function with AD pathologic changes and cortical μVBI, executive function with subcortical μVBI, and visuospatial construction with LBD. Thus, neuropathologic lesions of LBD and μVBI are associated with poorer cognitive performance over and above AD neuropathologic changes in subjects without dementia in this cohort. These findings underscore that cognitive impairment is a complex convergent trait that has important implications for clinical investigation and medical management of older adults.
doi:10.3233/JAD-130281
PMCID: PMC3737376  PMID: 23666176
Alzheimer’s disease; brain; cerebrovascular disorders; cognition; dementia; Lewy bodies; pathologic processes
11.  Mechanistic Phenotypes: An Aggregative Phenotyping Strategy to Identify Disease Mechanisms Using GWAS Data 
PLoS ONE  2013;8(12):e81503.
A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with “mechanistic phenotypes”, comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03), driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10−5, FDR p = 0.03) (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L) while the additive model showed enrichment related to chromatid segregation (p = 4×10−6, FDR p = 0.005) (KIF25, PINX1). We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.
doi:10.1371/journal.pone.0081503
PMCID: PMC3861317  PMID: 24349080
12.  Relationship Between Longitudinal Measures of Renal Function and Onset of Dementia Among a Community Cohort of Older Adults 
Background
Prior studies have described a higher incidence of dementia or worsening cognitive function in patients with lower levels of kidney function at a single point in time.
Objectives
To evaluate the association between dynamic measures of renal function ascertained over time with onset of dementia.
Design
prospective community cohort study.
Setting and Participants
2,968 adults aged 65 and older followed for the development of dementia over a median of 6.0 years (interquartile range 3.1–10.1 years).
Measurements
Time varying measures of renal function were constructed based on a total of 49,340 serum creatinine measurements and included: the average level of estimated glomerular filtration rate (eGFR), eGFR trajectory and variability in eGFR around this trajectory over 5-year exposure windows. The association between these three eGFR exposure measures and risk of dementia was estimated using a Cox regression model adjusted for other patient characteristics. In sensitivity analyses, we also adjusted for time-varying measures of urine protein by dipstick.
Results
Patients with lower levels of eGFR had a higher incidence of dementia but this did not reach statistical significance in adjusted analyses (omnibus p value=0.14). There were trends toward a higher adjusted incidence of dementia in patients with positive eGFR trajectories (omnibus p value=0.07) and greater variability in eGFR (omnibus p value=0.04) over time. The results of sensitivity analyses, including those in which we included time-varying measures of proteinuria, were consistent with those of the primary analysis.
Conclusion
Among a community cohort of older adults followed for a median of 6 years, we did not find strong associations between measures of kidney disease severity and progression and incident dementia.
doi:10.1111/j.1532-5415.2012.04238.x
PMCID: PMC3531894  PMID: 23231548
dementia; renal function; eGFR; variability; trajectory
13.  Insulin and Sex Interactions in Older Adults with Mild Cognitive Impairment 
Alzheimer’s disease (AD) and other dementias are likely preceded by a protracted preclinical state. Thus, identification of biomarkers that signal potential points of intervention during this prodromal phase (during which patients are largely able to compensate for their cognitive deficits) is of paramount importance. Insulin is a pancreatic hormone with potent central nervous system effects, and insulin dysregulation has been implicated in the pathogenesis of both AD and vascular dementia. The aim of the current study was to determine whether circulating insulin differs as a function of mild cognitive impairment (MCI) diagnosis, and whether this relationship is mediated by sex and apolipoprotein E (APOE) genotype. A sample of 549 nondemented participants aged 65 and over from the Adult Changes in Thought community-based cohort underwent cognitive testing and blood draw to determine fasting levels of plasma insulin. Subjects were categorized as having normal cognitive functioning, amnestic MCI, or nonamnestic MCI. Results showed that the relationship between insulin and diagnostic category is moderated by sex, such that men with nonamnestic or amnestic MCI have higher fasting plasma insulin than cognitively normal men, while women with amnestic MCI have lower fasting plasma insulin than cognitively normal women. Exploratory analyses suggest that APOE ε4 genotype may further influence the relationship between sex and insulin. Future research will help determine whether insulin dysregulation results in differential effects on vascular function and AD pathology as a function of sex and/or APOE genotype.
doi:10.3233/JAD-2012-120202
PMCID: PMC3798013  PMID: 22571978
Age-related memory disorders; aging; Alzheimer’s disease; cognition; dementia; hyperinsulinemia; insulin; vascular
14.  The Electronic Medical Records and Genomics (eMERGE) Network: Past, Present and Future 
The Electronic Medical Records and Genomics (eMERGE) Network is a National Human Genome Research Institute (NHGRI)-funded consortium engaged in the development of methods and best-practices for utilizing the Electronic Medical Record (EMR) as a tool for genomic research. Now in its sixth year, its second funding cycle and comprising nine research groups and a coordinating center, the network has played a major role in validating the concept that clinical data derived from EMRs can be used successfully for genomic research. Current work is advancing knowledge in multiple disciplines at the intersection of genomics and healthcare informatics, particularly electronic phenotyping, genome-wide association studies, genomic medicine implementation and the ethical and regulatory issues associated with genomics research and returning results to study participants. Here we describe the evolution, accomplishments, opportunities and challenges of the network since its inception as a five-group consortium focused on genotype-phenotype associations for genomic discovery to its current form as a nine-group consortium pivoting towards implementation of genomic medicine.
doi:10.1038/gim.2013.72
PMCID: PMC3795928  PMID: 23743551
electronic medical records; personalized medicine; genome-wide association studies; genetics and genomics; collaborative research
15.  Impact on Seniors of the Patient-Centered Medical Home: Evidence From a Pilot Study 
The Gerontologist  2012;52(5):703-711.
Purpose: To assess the impact on health care cost and quality among seniors of a patient-centered medical home (PCMH) pilot at Group Health Cooperative, an integrated health care system in Washington State. Design and Methods: A prospective before-and-after evaluation of the experience of seniors receiving primary care services at 1 pilot clinic compared with seniors enrolled at the remaining 19 primary care clinics owned and operated by Group Health. Analyses of secondary data on quality and cost were conducted for 1,947 seniors in the PCMH clinic and 39,396 seniors in the 19 control clinics. Patient experience with care was based on survey data collected from 487 seniors in the PCMH clinic and of 668 in 2 specific control clinics that were selected for their similarities in organization and patient composition to the pilot clinic.Results: After adjusting for baseline, seniors in the PCMH clinic reported higher ratings than controls on 3 of 7 patient experience scales. Seniors in the PCMH clinic had significantly greater quality outcomes over time, but this difference was not significant relative to control. PCMH patients used more e-mail, phone, and specialist visits but fewer emergency services and inpatient admissions for ambulatory care sensitive conditions. At 1 and 2 years, the PCMH and control clinics did not differ significantly in overall costs. Implications: A PCMH redesign can be associated with improvements in patient experience and quality without increasing overall cost.
doi:10.1093/geront/gnr158
PMCID: PMC3605940  PMID: 22421916
PCMH; Medicare; Geriatric health care
16.  Risk for late-life re-injury, dementia and death among individuals with traumatic brain injury: a population-based study 
Objectives
To determine the association of self-reported traumatic brain injury (TBI) with loss of consciousness (LOC) with late-life re-injury, dementia diagnosis and mortality.
Design
Ongoing longitudinal population-based prospective cohort study.
Setting
Seattle-area integrated health system.
Participants
4225 dementia-free individuals age 65 and older were randomly selected and enrolled between 1994 and 2010. Participants were seen every 2 years, with mean (range) follow-up of 7.4 (0–16) years. 606 (14%) participants reported a lifetime history of TBI with LOC at enrolment. 3466 participants provided information regarding lifetime history of TBI and completed at least one follow-up visit.
Main outcome measures
Self-reported TBI with LOC after study entry, incident all-cause dementia and Alzheimer’s disease (AD), and all-cause mortality.
Results
There were 25 567 person-years of follow-up. History of TBI with LOC reported at study enrolment was associated with increased risk for TBI with LOC during follow-up, with adjusted HRs ranging from 2.54 (95% CI 1.42 to 4.52) for those reporting first injury before age 25 to 3.79 (95% CI 1.89 to 7.61) for those with first injury after age 55. History of TBI with LOC was not associated with elevated risk for developing dementia or AD. There was no association between baseline history of TBI with LOC and mortality, though TBI with LOC since the previous study visit (‘recent TBI’) was associated with increased mortality (HR 2.12, 95% CI 1.62 to 2.78).
Conclusions
Individuals aged 65 or older who reported a history of TBI with LOC at any time in their lives were at elevated risk of subsequent re-injury. Recent TBI with LOC sustained in older adulthood was associated with increased risk for mortality. Findings support the need for close clinical monitoring of older adults who sustain a TBI with LOC.
doi:10.1136/jnnp-2012-303938
PMCID: PMC3752841  PMID: 23172868
17.  A “virtually minimal” visuo-haptic training of attention in severe traumatic brain injury 
Background
Although common during the early stages of recovery from severe traumatic brain injury (TBI), attention deficits have been scarcely investigated. Encouraging evidence suggests beneficial effects of attention training in more chronic and higher functioning patients. Interactive technology may provide new opportunities for rehabilitation in inpatients who are earlier in their recovery.
Methods
We designed a “virtually minimal” approach using robot-rendered haptics in a virtual environment to train severely injured inpatients in the early stages of recovery to sustain attention to a visuo-motor task. 21 inpatients with severe TBI completed repetitive reaching toward targets that were both seen and felt. Patients were tested over two consecutive days, experiencing 3 conditions (no haptic feedback, a break-through force, and haptic nudge) in 12 successive, 4-minute blocks.
Results
The interactive visuo-haptic environments were well-tolerated and engaging. Patients typically remained attentive to the task. However, patients exhibited attention loss both before (prolonged initiation) and during (pauses during motion) a movement. Compared to no haptic feedback, patients benefited from haptic nudge cues but not break-through forces. As training progressed, patients increased the number of targets acquired and spontaneously improved from one day to the next.
Conclusions
Interactive visuo-haptic environments could be beneficial for attention training for severe TBI patients in the early stages of recovery and warrants further and more prolonged clinical testing.
doi:10.1186/1743-0003-10-92
PMCID: PMC3750632  PMID: 23938101
Virtual reality; Robotics; Attention; Rehabilitation; TBI
18.  Novel antibody capture assay for paraffin-embedded tissue detects wide-ranging amyloid beta and paired helical filament–tau accumulation in cognitively normal older adults 
Quantifying antigens in formalin-fixed tissue is challenging and limits investigation in population-based studies of brain aging. To address this major limitation, we have developed a new technique that we call “Histelide”: immunohistochemistry (HIST-) and ELISA (-EL-) performed on a glass slide (-IDE). We validated Histelide in sections of prefrontal cortex from 20 selected cases: 12 subjects with clinically and neuropathologically diagnosed Alzheimer’s disease (AD), either autosomal dominant or late-onset forms, and 8 clinical and neuropathologic Controls. AD cases had significantly increased amyloid beta (Aβ) peptide and paired helical filament– (PHF-) tau per area of neocortex that was proteinase K-sensitive, and significantly decreased amount of synaptophysin. We next investigated prefrontal cortex from 81 consecutive cases of high cognitive performers from the Adult Changes in Thought (ACT) study, a population-based study of brain aging and incident dementia. As expected, latent AD was common in this group; however, our results quantified widely individually-varying levels of Aβ peptides and PHF-tau among these high cognitive performers. This novel approach obtains quantitative data from population-based studies, and our initial studies with high cognitive performers provide important quantitative insights into latent AD that should help guide expectations from neuroimaging and prevention studies.
doi:10.1111/j.1750-3639.2011.00542.x
PMCID: PMC3295908  PMID: 21999410
19.  Adult Changes in Thought Study: Dementia is an Individually Varying Convergent Syndrome with Prevalent Clinically Silent Diseases that may be Modified by Some Commonly Used Therapeutics 
Current Alzheimer research  2012;9(6):718-723.
The Adult Changes in Thought (ACT) study is a longitudinal population-based prospective cohort study of brain aging and incident dementia in the Seattle metropolitan area. Observational studies using autopsies from ACT indicate that dementia is a convergent syndrome that commonly derives from Alzheimer’s disease (AD), microvascular brain injury (μVBI), and Lewy body disease (LBD), and that these diseases have prevalent subclinical forms that also are commonly co-morbid. The existence of subclinical diseases highlights potential opportunities to intervene before the development of clinically apparent impairments. Our observations suggest that some such interventions already may exist to suppress processes of AD (statin therapy) or μVBI (treatment of hypertension). Reduced burden of LBD is associated with cigarette smoking; although smoking is not recommended as an intervention, these exposure data may provide clues to alternative neuroprotective mechanisms. Self reported anti-oxidant supplementation was without apparent effect in this cohort on indices of AD, μVBI, or LBD. Continued observational studies of brain aging will provide further insight into the convergent complexity of the dementia syndrome and its subclinical forms as well as highlight potential interventions that will require validation in clinical trials.
PMCID: PMC3409333  PMID: 22471861
20.  Informed Consent in Genome-Scale Research: What Do Prospective Participants Think? 
AJOB primary research  2012;3(3):3-11.
Background
To promote effective genome-scale research, genomic and clinical data for large population samples must be collected, stored, and shared.
Methods
We conducted focus groups with 45 members of a Seattle-based integrated healthcare delivery system to learn about their views and expectations for informed consent in genome-scale studies.
Results
Participants viewed information about study purpose, aims, and how and by whom study data could be used to be at least as important as information about risks and possible harms. They generally supported a tiered consent approach for specific issues, including research purpose, data sharing, and access to individual research results. Participants expressed a continuum of opinions with respect to the acceptability of broad consent, ranging from completely acceptable to completely unacceptable. Older participants were more likely to view the consent process in relational – rather than contractual – terms, compared with younger participants. The majority of participants endorsed seeking study subjects’ permission regarding material changes in study purpose and data sharing.
Conclusions
Although this study sample was limited in terms of racial and socioeconomic diversity, our results suggest a strong positive interest in genomic research on the part of at least some prospective participants and indicate a need for increased public engagement, as well as strategies for ongoing communication with study participants.
doi:10.1080/21507716.2012.662575
PMCID: PMC3593675  PMID: 23493836
Informed consent; participant views; genomic research; biobank; research ethics
21.  Enhancing the Power of Genetic Association Studies through the Use of Silver Standard Cases Derived from Electronic Medical Records 
PLoS ONE  2013;8(6):e63481.
The feasibility of using imperfectly phenotyped “silver standard” samples identified from electronic medical record diagnoses is considered in genetic association studies when these samples might be combined with an existing set of samples phenotyped with a gold standard technique. An analytic expression is derived for the power of a chi-square test of independence using either research-quality case/control samples alone, or augmented with silver standard data. The subset of the parameter space where inclusion of silver standard samples increases statistical power is identified. A case study of dementia subjects identified from electronic medical records from the Electronic Medical Records and Genomics (eMERGE) network, combined with subjects from two studies specifically targeting dementia, verifies these results.
doi:10.1371/journal.pone.0063481
PMCID: PMC3677889  PMID: 23762230
22.  Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ε4, and the Risk of Late-Onset Alzheimer Disease in African Americans 
Importance
Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment.
Objective
To identify genetic loci associated with late-onset Alzheimer disease in African Americans.
Design, Setting, and Participants
The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance–weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci.
Main Outcomes and Measures
Presence of Alzheimer disease according to standardized criteria.
Results
Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10–9), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8
Conclusions and Relevance
In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.
doi:10.1001/jama.2013.2973
PMCID: PMC3667653  PMID: 23571587
International psychogeriatrics / IPA  2010;22(8):1196-1202.
Worldwide, lifespan is lengthening. Concomitantly, late-life dementias are increasingly common, challenging both personal and public health internationally. After age 65, rates of dementia tend to double every five years in developed countries and every seven in developing ones. The late-life dementias, particularly Alzheimer’s disease, have profound effects on aging individuals and their caregivers. Multidisciplinary research has explored the potential for various approaches to prevent or delay the onset of late-life dementias. Outlining that research, including our team’s Adult Changes in Thought and Kame studies, this review concludes that delaying these dementias’ onset appears feasible, although absolute prevention may not be. Today the most promising methods appear to include controlling vascular risk factors like hypertension and engaging in physical exercise—and possibly mental exercise—on and off the job. If people can delay the onset of dementias, they can lead more fulfilling lives for longer—spending less time suffering from dementia and letting their families spend less time coping with the disease. It is possible that trends toward more knowledge-based societies, where cognitive health is so vital, may increasingly exert evolutionary pressure favoring larger and healthier brains—and a “compression of cognitive morbidity”—well into old age. Public health’s great triumph, increased lifespan, should give more of the world’s people the reward of many years of dementia-free life—rather than the personal difficulties and public health burdens of many years of functional impairment, dependency, and suffering with dementia some interventions may delay the onset of Alzheimer’s disease and other dementias.
doi:10.1017/S1041610210001080
PMCID: PMC3164829  PMID: 20594386
Alzheimer’s disease; prevention; lifestyle risk factors; aging; exercise; demographics; evolution
ABSTRACT
Improving health literacy is one key to buoying our nation’s troubled health care system. As system-level health literacy improvement strategies take the stage among national priorities for health care, the patient-centered medical home (PCMH) model of care emerges as a compelling avenue for their widespread implementation. With a shared focus on effective communication and team-based care organized around patient needs, health literacy principles and the PCMH are well aligned. However, their synergy has received little attention, even as PCMH demonstration projects and health literacy interventions spring up nationwide. While many health literacy interventions are limited by their focus on a single point along the continuum of care, creating a “room” for health literacy within the PCMH may finally provide a multi-dimensional, system-level approach to tackling the full range of health literacy challenges. Increasing uptake coupled with federal support and financial incentives further boosts the model’s potential for advancing health literacy. On the journey toward a revitalized health care system, integrating health literacy into the PCMH presents a promising opportunity that deserves consideration.
doi:10.1007/s11606-011-1964-6
PMCID: PMC3326113  PMID: 22215273
communication; health literacy; patient-centered care; medical home
Background
Little is known about patterns of kidney function decline leading up to initiation of chronic dialysis.
Study Design
Retrospective cohort study.
Setting and Participants
5,606 VA patients who initiated chronic dialysis in 2001–2003. Predictor: Trajectory of estimated glomerular filtration rate (eGFR) during the two year period before dialysis initiation.
Outcomes and Measurements
Patient characteristics and care practices before and at the time of dialysis initiation and survival after initiation.
Results
We identified four distinct trajectories of eGFR during the two year period before dialysis initiation: 62.8% of patients had persistently low levels of eGFR below 30 ml/min/1.73 m2 (mean eGFR slope 7.7 ±4.7 (SD) ml/min/1.73 m2 per year); 24.6% had progressive loss of eGFR from levels around 30–59 ml/min/1.73 m2 (mean eGFR slope 16.3 ±7.6 ml/min/1.73 m2 per year); 9.5% had accelerated loss of eGFR from levels above 60 ml/min/1.73 m2 (mean eGFR slope 32.3 ±13.4 ml/min/1.73 m2 per year); and 3.1% experienced catastrophic loss of eGFR within six months or less from levels above 60 ml/min/1.73 m2. Patients with steeper eGFR trajectories were more likely to have been hospitalized and to have an inpatient diagnosis of acute kidney injury. They were less likely to have received recommended pre-dialysis care and had a higher risk of death in the first year after dialysis initiation.
Conclusions
There is substantial heterogeneity in patterns of kidney function loss leading up to initiation of chronic dialysis, perhaps calling for a more flexible approach toward preparing for end-stage renal disease.
doi:10.1053/j.ajkd.2011.11.044
PMCID: PMC3312937  PMID: 22305760

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