A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

DNA methylation signatures of aggression and closely related constructs : A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 x 10(-7); Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.Peer reviewe

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.</p

(Des)ubicación: La Lucha por la Vivienda y la Comunidad Después de Echo Park Lake

Elaborado por el Colectivo de Investigación Después de Echo Park Lake, esta monografía analiza desplazamiento encabezado por el estado. Con un enfoque centrado en el desalojo violenta de la comunidad sin vivienda en Echo Park Lake, un parque publico en un barrio gentrificando de la ciudad cerca del centro, eso llama la atencion sobre cómo reclamos políticos de ubicaciónes de viviendas legitiman desubicación pero rara vez resulta en soluciones de la vivienda. A través de investigación etnográfica además de análisis de datos de la gestión de personas sin viviendas, eso expone la artimaña de la vivienda y llama la atención sobre un condición de dezplazabilidad definitiva por los pobres de la ciudad. Un hallazgo clave de la monografía es que en un tiempo de recursos de vivienda ampliados suscrito por fondos federales de emergencia y ayuda económica, tiene un inversión perversa de fondos públicos para la criminalización de pobreza y contención carcelaria de los personas sin viviendas. En marcado contraste con eso carceralidad están infraestructuras comunitarias imaginadas por los organizadores sin viviendas, incluye eso construyó y sostuvo en Echo Park Lake

(Dis)Placement: The Fight for Housing and Community After Echo Park Lake

Authored by the After Echo Park Lake research collective, this monograph analyzes processes of state-led displacement in Los Angeles. With a focus on the violent eviction of the unhoused community at Echo Park Lake, a public park in a gentrifying neighborhood of the city close to downtown, it draws attention to how political claims of housing placements legitimize such displacement but rarely result in housing outcomes. Through ethnographic research as well as analysis of homeless management data, it exposes this ruse of housing and draws attention to a condition of permanent displaceability for the city’s poor. A key finding of the monograph is that at a time of expanded housing resources underwritten by federal and state emergency and economic relief funds, there is a perverse investment of public funds in the criminalization of poverty and in the carceral containment of the unhoused. In sharp contrast to such carcerality are the infrastructures of community envisioned by unhoused organizers, including that which was built and sustained at Echo Park Lake

Blood pressure and heart rate QTL in mice of the B6/D2 lineage: sex differences and environmental influences

A quantitative trait locus (QTL) approach was used to define the genetic architecture underlying variation in systolic blood pressure (SBP) and heart rate (HR), measured indirectly on seven occasions by the tail cuff procedure. The tests were conducted in 395 F2 adult mice (197 males, 198 females) derived from a cross of the C57BL/6J (B6) and DBA/2J (D2) strains and in 22 BXD recombinant-inbred (RI) strains. Interval mapping of F2 data for the first 5 days of measurement nominated one statistically significant and one suggestive QTL for SBP on chromosomes (Chr) 4 and 14, respectively, and two statistically significant QTL for HR on Chr 1 (which was specific to female mice) and Chr 5. New suggestive QTL emerged for SBP on Chr 3 (female-specific) and 8 and for HR on Chr 11 for measurements recorded several weeks after mice had undergone stressful blood sampling procedures. The two statistically significant HR QTL were confirmed by analyses of BXD RI strain means. Male and female F2 mice did not differ in SBP or HR but RI strain analyses showed pronounced strain-by-sex interactions and a negative genetic correlation between the two measures in both sexes. Evidence for a role for mitochondrial DNA was found for both HR and SBP. QTL for HR and SBP may differ in males and females and may be sensitive to different environmental contexts

Malaria in infants below six months of age: retrospective surveillance of hospital admission records in Blantyre, Malawi

<p>Abstract</p> <p>Background</p> <p>Information on the burden of malaria in early infancy is scarce. Young infants are relatively protected against clinical malaria during the first six months of life due to the presence of maternal antibodies and foetal haemoglobin, and have received relatively little attention with respect to research and treatment guidelines. The World Health Organization provides treatment guidelines for children from six months onwards, without specific treatment guidelines for the younger infants. A number of recent reports however suggest that the burden in this young age group may be underestimated.</p> <p>Methods</p> <p>A retrospective review of paediatric hospital records at the Queen Elizabeth Central Hospital in Blantyre from 1998 to 2008 from three data sources was carried out. The number of admitted infants <6 months and ≤ 15 years was obtained from the registry books of the Paediatric-Nursery-Department and the Malaria Research Laboratory. For the period 2001 - 2004, more detailed malaria related admission information was available as part of an ongoing study on severe malaria, allowing a calculation of the proportion of infants < 6 months of age among admissions in children < 5 years.</p> <p>Results</p> <p>Retrospective analysis of hospital records showed that over the course of these years, the average annual proportion of paediatric admissions in children ≤ 15 years with confirmed malaria aged <6 months was 4.8% and ranged between 2.8%-6.7%. This proportion was stable throughout the seasons. Between 2001-2004, 9.9% of admissions with confirmed malaria in children <5 years occurred in infants <6 months, with numbers increasing steadily during the first six months of life.</p> <p>Conclusions</p> <p>These findings are consistent with recent reports suggesting that the burden of malaria during the six first months of life may be substantial, and highlight that more research is needed on dose-optimization, safety and efficacy of anti-malarials that are currently used off-label in this vulnerable patient group.</p