Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

BACKGROUND: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. METHODS:We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 0.001).RESULTS:In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. CONCLUSION: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging

Genetic Correlates of Brain Aging on MRI and Cognitive Test Measures: A Genome-Wide Association and Linkage Analysis in the Framingham Study

BACKGROUND: Brain magnetic resonance imaging (MRI) and cognitive tests can identify heritable endophenotypes associated with an increased risk of developing stroke, dementia and Alzheimer's disease (AD). We conducted a genome-wide association (GWA) and linkage analysis exploring the genetic basis of these endophenotypes in a community-based sample. METHODS: A total of 705 stroke- and dementia-free Framingham participants (age 62 +9 yrs, 50% male) who underwent volumetric brain MRI and cognitive testing (1999–2002) were genotyped. We used linear models adjusting for first degree relationships via generalized estimating equations (GEE) and family based association tests (FBAT) in additive models to relate qualifying single nucleotide polymorphisms (SNPs, 70,987 autosomal on Affymetrix 100K Human Gene Chip with minor allele frequency ≥ 0.10, genotypic call rate ≥ 0.80, and Hardy-Weinberg equilibrium p-value ≥ 0.001) to multivariable-adjusted residuals of 9 MRI measures including total cerebral brain (TCBV), lobar, ventricular and white matter hyperintensity (WMH) volumes, and 6 cognitive factors/tests assessing verbal and visuospatial memory, visual scanning and motor speed, reading, abstract reasoning and naming. We determined multipoint identity-by-descent utilizing 10,592 informative SNPs and 613 short tandem repeats and used variance component analyses to compute LOD scores. RESULTS: The strongest gene-phenotype association in FBAT analyses was between SORL1 (rs1131497; p = 3.2 × 10-6) and abstract reasoning, and in GEE analyses between CDH4 (rs1970546; p = 3.7 × 10-8) and TCBV. SORL1 plays a role in amyloid precursor protein processing and has been associated with the risk of AD. Among the 50 strongest associations (25 each by GEE and FBAT) were other biologically interesting genes. Polymorphisms within 28 of 163 candidate genes for stroke, AD and memory impairment were associated with the endophenotypes studied at p < 0.001. We confirmed our previously reported linkage of WMH on chromosome 4 and describe linkage of reading performance to a marker on chromosome 18 (GATA11A06), previously linked to dyslexia (LOD scores = 2.2 and 5.1). CONCLUSION: Our results suggest that genes associated with clinical neurological disease also have detectable effects on subclinical phenotypes. These hypothesis generating data illustrate the use of an unbiased approach to discover novel pathways that may be involved in brain aging, and could be used to replicate observations made in other studies.National Institutes of Health National Center for Research Resources Shared Instrumentation grant (ISI0RR163736-01A1); National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195); National Institute of Aging (5R01-AG08122, 5R01-AG16495); National Institute of Neurological Disorders and Stroke (5R01-NS17950

Geometry and quantum delocalization of interstitial oxygen in silicon

The problem of the geometry of interstitial oxygen in silicon is settled by proper consideration of the quantum delocalization of the oxygen atom around the bond-center position. The calculated infrared absorption spectrum accounts for the 517 and 1136 cm$^{-1}$ bands in their position, character, and isotope shifts. The asymmetric lineshape of the 517 cm$^{-1}$ peak is also well reproduced. A new, non-infrared-active, symmetric-stretching mode is found at 596 cm$^{-1}$. First-principles calculations are presented supporting the nontrivial quantum delocalization of the oxygen atom.Comment: uuencoded, compressed postscript file for the whole. 4 pages (figures included), accepted in PR

Drift Macroalgal Distribution In Northern Gulf of Mexico Seagrass Meadows

Drift macroalgae, often found in clumps or mats adjacent to or within seagrass beds, can increase the value of seagrass beds as habitat for nekton via added food resources and structural complexity. But, as algal biomass increases, it can also decrease light availability, inhibit faunal movements, smother benthic communities, and contribute to hypoxia, all of which can reduce nekton abundance. We quantified the abundance and distribution of drift macroalgae within seagrass meadows dominated by turtle grass Thalassia testudinum across the northern Gulf of Mexico and compared seagrass characteristics to macroalgal biomass and distribution. Drift macroalgae were most abundant in areas with higher seagrass shoot densities and intermediate canopy heights. We did not find significant relationships between algal biomass and point measures of salinity, temperature, or depth. The macroalgal genera Laurencia and Gracilaria were present across the study region, Agardhiella and Digenia were collected in the western Gulf of Mexico, and Acanthophora was collected in the eastern Gulf of Mexico. Our survey revealed drift algae to be abundant and widespread throughout seagrass meadows in the northern Gulf of Mexico, which likely influences the habitat value of seagrass ecosystems

Fire and Forage: Variability in Elk Forage on a Landscape of Wildfire and Changing Fire Management

Forest management practices can modify ungulate nutritional resources through landscape-scale processes such as prescribed fire and wildfire. The resulting availability and distribution of nutritional resources can affect ungulate survival, reproduction, and distribution. Our primary goals were to evaluate how landscapes with varying post-fire successional stages influence elk summer nutritional resources and to quantify the variability of nutritional resources associated with varying fire histories and management practices during 1900–2015. Within 3 elk population ranges located in the Bitterroot Valley, Montana, we measured elk forage quality across a range of land cover types and fire histories and developed a landscape-scale forage quality model. Based on historical wildfire and prescribed fire data, we reconstructed decadal land cover models and used our forage models to predict fire-related variations in forage quality each decade within the elk summer ranges. Forage quality was predicted to decrease with successional stage. The area burned by wildfire increased 242–1,772% during 1990–2015 as compared to 1900–1990, resulting in firerelated variations of predicted nutritional resources. The area of highest forage quality varied, increasing 31.3–48.5% in 2 ranges and decreasing 2.4% in 1 range, from 1900–1990 to 1990–2015. These results highlight the important effect of wildfire on the distribution of ungulate nutritional resources and demonstrate that ungulate nutritional resources likely vary over time with variation in fire history and management practices

Collaboration between local health and local government agencies for health improvement (Review)

Background: In many countries, national, regional and local inter- and intra-agency collaborations have been introduced to improve health outcomes. Evidence is needed on the effectiveness of locally developed partnerships which target changes in health outcomes and behaviours. Objectives: To evaluate the effects of interagency collaboration between local health and local government agencies on health outcomes in any population or age group. Search methods: We searched the Cochrane Public Health Group Specialised Register, AMED, ASSIA, CENTRAL, CINAHL, DoPHER, EMBASE, ERIC, HMIC, IBSS, MEDLINE, MEDLINE In-Process, OpenGrey, PsycINFO, Rehabdata, Social Care Online, Social Services Abstracts, Sociological Abstracts, TRoPHI andWeb of Science from 1966 through to January 2012. ’Snowballing’ methods were used, including expert contact, citation tracking, website searching and reference list follow-up. Selection criteria: Randomized controlled trials (RCTs), controlled clinical trials (CCTs), controlled before-and-after studies (CBAs) and interrupted time series (ITS) where the study reported individual health outcomes arising from interagency collaboration between health and local government agencies compared to standard care. Studies were selected independently in duplicate, with no restriction on population subgroup or disease. Data collection and analysis: Two authors independently conducted data extraction and assessed risk of bias for each study

Alpha-fetoprotein detection of hepatocellular carcinoma leads to a standardized analysis of dynamic AFP to improve screening based detection

Detection of hepatocellular carcinoma (HCC) through screening can improve outcomes. However, HCC surveillance remains costly, cumbersome and suboptimal. We tested whether and how serum Alpha-Fetoprotein (AFP) should be used in HCC surveillance. Record linkage, dedicated pathways for management and AFP data-storage identified i) consecutive highly characterised cases of HCC diagnosed in 2009-14 and ii) a cohort of ongoing HCC-free patients undergoing regular HCC surveillance from 2009. These two well-defined Scottish patient cohorts enabled us to test the utility of AFP surveillance. Of 04 cases of HCC diagnosed over 6 years, 42% (129) were identified by a dedicated HCC surveillance programme. Of these 129, 47% (61) had a detectable lesion first identified by screening ultrasound (US) but 38% (49) were prompted by elevated AFP. Despite pre-HCC diagnosis AFP >20kU/L being associated with poor outcome, 'AFP-detected' tumours were offered potentially curative management as frequently as 'US-detected' HCCs; and had comparable survival. Linearity of serial log10 -transformed AFPs in HCC cases and in the screening 'HCC-free' cohort (n = 1509) provided indicators of high-risk AFP behaviour in HCC cases. An algorithm was devised in static mode, then tested dynamically. A case/control series in hepatitis C related disease demonstrated highly significant detection (p-5) of patients at high risk of developing HCC. These data support the use of AFP in HCC surveillance. We show proof-of-principle that an automated and further refineable algorithmic interpretation of AFP can identify patients at higher risk of HCC. This approach could provide a cost-effective, user-friendly and much needed addition to US surveillance

The postdigital challenge of redefining academic publishing from the margins

This paper explores relationships between knowledge production and academic publication and shows that the current political economy of mainstream academic publishing has resulted from a complex interplay between large academic publishers, academics, and hacker-activists. The process of publishing is a form of ‘social production’ that takes place across the economy, politics and culture, all of which are in turn accommodating both old and new technology in our postdigital age. Technologies such as software cannot be separated from human labour, academic centres cannot be looked at in isolation from their margins, and the necessity of transdisciplinary approaches does not imply the disappearance of traditional disciplines. In the postdigital age, the concept of the margins has not disappeared, but it has become somewhat marginal in its own right. We need to develop a new language of describing what we mean by ‘marginal voices’ in the social relations between knowledge production and academic publication. Universities require new strategies for cohabitation of, and collaboration between, various socio-technological actors, and new postdigital politics and practice of knowledge production and academic publishing

Genetic Correlates of Longevity and Selected Age-related Phenotypes: A Genome-wide Association Study in the Framingham Study

Background: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. Methods: We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate ≥80%, minor allele frequency ≥10%, Hardy-Weinberg test p ≥ 0.001). Results: In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10^-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. Conclusion: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging