Genome-wide linkage analysis for human longevity: Genetics of healthy aging study

Clear evidence exists for heritability of humanlongevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/ APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10). By combined modeling of linkage and association, we showed that association of longevity with APOEe4 and APOEe2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

Haplotype association analysis of genes within the WNT signalling pathways in diabetic nephropathy

Background: Renal interstitial fibrosis and glomerular sclerosis are hallmarks of diabetic nephropathy (DN) and several studies have implicated members of the WNT pathways in these pathological processes. This study comprehensively examined common genetic variation within the WNT pathway for association with DN.

Methods: Genes within the WNT pathways were selected on the basis of nominal significance and consistent direction of effect in the GENIE meta-analysis dataset. Common SNPs and common haplotypes were examined within the selected WNT pathway genes in a white population with type 1 diabetes, discordant for DN (cases: n = 718; controls: n = 749). SNPs were genotyped using Sequenom or Taqman assays. Association analyses were performed using PLINK, to compare allele and haplotype frequencies in cases and controls. Correction for multiple testing was performed by either permutation testing or using false discovery rate.

Results: A logistic regression model including collection centre, duration of diabetes, and average HbA1c as covariates highlighted three SNPs in GSK3B (rs17810235, rs17471, rs334543), two in DAAM1 (rs1253192, rs1252906) and one in NFAT5 (rs17297207) as being significantly (P< 0.05) associated with DN, however these SNPs did not remain significant after correction for multiple testing. Logistic regression of haplotypes, with ESRD as the outcome, and pairwise interaction analyses did not yield any significant results after correction for multiple testing.

Conclusions: These results indicate that both common SNPs and common haplotypes of WNT pathway genes are not strongly associated with DN. However, this does not completely exclude these or the WNT pathways from association with DN, as unidentified rare genetic or copy number variants could still contribute towards the genetic architecture of DN.© 2013 Kavanagh et al.; licensee BioMed Central Ltd.

Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

The role of adiposity in cardiometabolic traits:a Mendelian randomization analysis

The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.

Individual Participant Data (IPD) Meta-analyses of Randomised Controlled Trials: Guidance on Their Use

Jayne Tierney and colleagues offer guidance on how to spot a well-designed and well-conducted individual participant data meta-analysis.

Summary Points 

• Systematic reviews are most commonly based on aggregate data extracted from publications or obtained from trial investigators. 

• Systematic reviews involving the central collection and analysis of individual participant data (IPD) usually are larger-scale, international, collaborative projects that can bring about substantial improvements to the quantity and quality of data, give greater scope in the analyses, and provide more detailed and robust results. 

• The process of collecting, checking, and analysing IPD is more complex than for aggregate data, and not all IPD meta-analyses are done to the same standard, making it difficult for researchers, clinicians, patients, policy makers, funders, and publishers to judge their quality. 

• Following our step-by-step guide will help reviewers and users of IPD meta-analyses to understand them better and recognise those that are well designed and conducted and so help ensure that policy, practice, and research are informed by robust evidence about the effects of interventions.

Accumulating research: a systematic account of how cumulative meta-analyses would have provided knowledge, improved health, reduced harm and saved resources

BACKGROUND: "Cumulative meta-analysis" describes a statistical procedure to calculate, retrospectively, summary estimates from the results of similar trials every time the results of a further trial in the series had become available. In the early 1990 s, comparisons of cumulative meta-analyses of treatments for myocardial infarction with advice promulgated through medical textbooks showed that research had continued long after robust estimates of treatment effects had accumulated, and that medical textbooks had overlooked strong, existing evidence from trials. Cumulative meta-analyses have subsequently been used to assess what could have been known had new studies been informed by systematic reviews of relevant existing evidence and how waste might have been reduced.

METHODS AND FINDINGS: We used a systematic approach to identify and summarise the findings of cumulative meta-analyses of studies of the effects of clinical interventions, published from 1992 to 2012. Searches were done of PubMed, MEDLINE, EMBASE, the Cochrane Methodology Register and Science Citation Index. A total of 50 eligible reports were identified, including more than 1,500 cumulative meta-analyses. A variety of themes are illustrated with specific examples. The studies showed that initially positive results became null or negative in meta-analyses as more trials were done; that early null or negative results were over-turned; that stable results (beneficial, harmful and neutral) would have been seen had a meta-analysis been done before the new trial; and that additional trials had been much too small to resolve the remaining uncertainties.

CONCLUSIONS: This large, unique collection of cumulative meta-analyses highlights how a review of the existing evidence might have helped researchers, practitioners, patients and funders make more informed decisions and choices about new trials over decades of research. This would have led to earlier uptake of effective interventions in practice, less exposure of trial participants to less effective treatments, and reduced waste resulting from unjustified research.

A HuGE Review and Meta-Analyses of Genetic Associations in New Onset Diabetes after Kidney Transplantation

PURPOSE: New onset diabetes after transplantation (NODAT) is a serious complication following solid organ transplantation. There is a genetic contribution to NODAT and we have conducted comprehensive meta-analysis of available genetic data in kidney transplant populations.

METHODS: Relevant articles investigating the association between genetic markers and NODAT were identified by searching PubMed, Web of Science and Google Scholar. SNPs described in a minimum of three studies were included for analysis using a random effects model. The association between identified variants and NODAT was calculated at the per-study level to generate overall significance values and effect sizes.

RESULTS: Searching the literature returned 4,147 citations. Within the 36 eligible articles identified, 18 genetic variants from 12 genes were considered for analysis. Of these, three were significantly associated with NODAT by meta-analysis at the 5% level of significance; CDKAL1 rs10946398 p = 0.006 OR = 1.43, 95% CI = 1.11-1.85 (n = 696 individuals), KCNQ1 rs2237892 p = 0.007 OR = 1.43, 95% CI = 1.10-1.86 (n = 1,270 individuals), and TCF7L2 rs7903146 p = 0.01 OR = 1.41, 95% CI = 1.07-1.85 (n = 2,967 individuals).

CONCLUSION: Evaluating cumulative evidence for SNPs associated with NODAT in kidney transplant recipients has revealed three SNPs associated with NODAT. An adequately powered, dense genome-wide association study will provide more information using a carefully defined NODAT phenotype.

Utilidade dos exames de ressonância magnética no diagnóstico da doença de Parkinson : revisão sistemática e meta análise

Tese de mestrado, Neurociências, Faculdade de Medicina, Universidade de Lisboa, 2014

Quality control and conduct of genome-wide association meta-analyses.

Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.

Social physique anxiety across physical activity settings : a meta-analytical review

The purpose of this meta-analytic investigation was to review the empirical evidence specific to the effect of physical activity context on social physique anxiety (SP A). English language studies were located from computer and manual literature searches. A total of 146 initial studies were coded. Studies included in the meta-analysis presented at least one empirical effect for SPA between physical activity participants (i.e., athletes or exercisers) and non-physical activity participants. The final sample included thirteen studies, yielding 14 effect sizes, with a total sample size of 2846. Studies were coded for mean SPA between physical activity participants and non-physical activity participants. Moderator variables related to demographic and study characteristics were also coded. Using Hunter and Schmidt's (2004) protocol, statistical artifacts were corrected. Results indicate that, practically speaking, those who were physically active reported lower levels of SPA than the comparison group (dcorr = -.12; SDeorr.-=-;22). Consideration of the magnitude of the ES, the SDeorr, and confidence interval suggests that this effect is not statistically significant. While most moderator analyses reiterated this trend, some differences were worth noting. Previous research has identified SPA to be especially salient for females compared to males, however, in the current investigation, the magnitude of the ES' s comparing physical activity participants to the comparison group was similar (deorr = -.24 for females and deorr = -.23 for males). Also, the type of physical activity was investigated, and results showed that athletes reported lower levels of SP A than the comparison group (deorr = -.19, SDeorr = .08), whereas exercisers reported higher levels of SPA than the comparison group (deorr = .13, SDeorr = .22). Results demonstrate support for the dispositional nature of SP A. Consideration of practical significance suggests that those who are involved in physical activity may experience slightly lower levels of SPA than those not reporting physical activity participation. Results potentially offer support for the bi-directionality of the relationship between physical activity and SP A; however, a causality may not be inferred. More information about the type of physical activity (i.e., frequency/nature of exercise behaviour, sport classificationllevel of athletes) may help clarify the role of physical activity contexts on SPA.

Asociación del HLA Clase II con la Hepatitis Autoinmune en Latinoamérica: Meta-análisis

Introducción: La Hepatitis Autoinmune (AIH) es una enfermedad hepática crónica en la cual se han asociado diferentes alelos de susceptibilidad del antígeno leucocitario humano (HLA) de acuerdo a grupos étnicos, geográficos afectados, así como edad de presentación pronóstico y perfil serológico. El objetivo de este trabajo es identificar alelos del HLA de Clase II que contribuyen a la susceptibilidad de la HAI en pacientes latinoamericanos. Metodología: El presente desarrolló una revisión sistemática de la literatura seguida por un meta-análisis de 694 casos y 1769 controles de estudios del tipo casos y controles que brindaron información suficiente para calcular el odds ratio y el intervalo de confianza del 95% desarrollados en América Latina Resultados: El grupo serológico DQ2 fue encontrado como factor de riesgo, mientras los grupos DR5 y DQ3 fueron encontrados como factores protectores en esta población. En el nivel alélico, el DQB1*02, DQB1*0603, DRB1*0405, y DRB1*1301, se encontraron como factores de riesgo, mientras que los alelos DRB1*1302 y DQB1*0301 fueron factores protectores. Las similitudes físico químicas de los aminoácidos críticos que codifican los péptidos de la fosa de anclaje en los bolsillos P1, P4, y P6 de estas moléculas del HLA, permiten dilucidar su influencia en el desarrollo de la enfermedad. Conclusión: El presente estudio fortalece el conocimiento del componente del HLA en el desarrollo de la HAI en Latinoamérica y su relación con otras poblaciones a nivel mundial.

Eficacia de la n-acetilcisteína en nefropatía inducida por contraste en pacientes con alteración renal previa: meta-análisis. (METACIAKI)

INTRODUCCIÓN: Se define lesión renal aguda inducida por contraste (CIAKI), al deterioro de la función renal en las 48 horas posteriores a la administración de radiofármacos. Para prevenir este evento se han estudiado diversas intervenciones clínicas, como la administración de N-Acetilcisteina (NAC), previa al procedimiento diagnóstico. Meta-análisis anteriores comparan diferentes intervenciones clínicas para prevenir CIAKI sin resultados concluyentes. El presente meta-análisis analiza la evidencia de la eficacia la administración de NAC previa al procedimiento diagnóstico para prevenir CIAKI en pacientes con nefropatía previa. METODOLOGÍA: Se analizaron por 3 revisores independientes estudios ECCA, en población con nefropatía, en inglés, español, portugués, italiano, alemán y francés tanto publicados como de literatura gris, en donde se comparara NAC versus hidratación o placebo. RESULTADOS: Los estudios encontrados fueron publicados entre el año 2000 y 2010. Se analizaron 37 reportes con 6.022 pacientes. La correlación intraclase para tres observadores fue kappa r=0.97 [IC95% 0.93-0.99]). Los pacientes con nefropatía a quienes se les administró NAC previo al procedimiento tuvieron un 34% menos de probabilidad de hacer falla renal aguda, con OR ajustado por sesgo de publicación de 0.66 [IC95% 0.50-0.88] con un p de 0.002. Al realizar análisis de sensibilidad por la escala de Jadad, se encuentra que los resultados en los estudios con baja calidad no son significativos (p=0.202). CONCLUSION: Los resultados soportan la asociación entre el tratamiento preventivo con N-Acetilcisteina y una menor frecuencia de lesión renal aguda inducida por medio de contraste en pacientes nefrópatas.

Solventes orgánicos factor de riesgo para enfermedades autoinmunes: revisión sistemática de la literatura y meta-análisis

Introducción: A través de los años se ha reconocido como la principal causa de enfermedades complejas, como lo son las enfermedades autoinmunes (EAI), la interacción entre los factores genéticos, los epigenéticos y el ambiente. Dentro de los factores ambientales están los solventes orgánicos (SO), compuestos químicos ampliamente utilizados en lavanderías (ej. tetracloroetileno, percloroetileno), pinturas (ej. tolueno y turpentina), removedores de esmalte para uñas, pegamentos (ej. acetona, metil acetato, etil acetato), removedores de manchas (ej. hexano, petróleo, eter), detergentes (ej. citrus terpeno), perfumes (etanol), y en la síntesis de esmaltes, entre otros. Teniendo en cuenta la controversia que existe aún sobre la asociación entre los SO y las EAI, evaluamos la evidencia a través de una revisión sistemática de la literatura y un meta-análisis. Métodos y resultados: La búsqueda sistemática se hizo en el PubMed, SCOPUS , SciELO y LILACS con artículos publicados hasta febrero de 2012. Se incluyó cualquier tipo de estudio que utilizara criterios aceptados para la definición de EAI y que tuvieran información sobre la exposición SO. De un total de 103 artículos, 33 fueron finalmente incluidos en el meta -análisis. Los OR e intervalos de confianza del 95 % (IC) se obtuvieron mediante el modelo de efectos aleatorios. Un análisis de sensibilidad confirmó que los resultados no son susceptibles a la limitación de los datos incluidos. El sesgo de publicación fue trivial. La exposición a SO se asoció a esclerosis sistémica, vasculitis primaria y esclerosis múltiple de forma individual y también para todas las EAI consideradas como un rasgo común (OR: 1.54 , IC 95 % : 1,25 a 1,92 ; valor de p 0.001). Conclusión: La exposición a SO es un factor de riesgo para el desarrollo de EAI. Como corolario, los individuos con factores de riesgo no modificables (es decir, autoinmunidad familiar o con factores genéticos identificados) deben evitar toda exposición a SO con el fin de evitar que aumente su riesgo de desarrollar una EAI.

Prevalencia de enfermedad celiaca en Latinoamérica: revisión sistemática de la literatura y meta-análisis

Introducción: La enfermedad celiaca (EC) es una enfermedad autoinmune (EA) intestinal desencadenada por la ingesta de gluten. Por la falta de información de la presencia de EC en Latinoamérica (LA), nosotros investigamos la prevalencia de la enfermedad en esta región utilizando una revisión sistemática de la literatura y un meta-análisis. Métodos y resultados: Este trabajo fue realizado en dos fases: La primera, fue un estudio de corte transversal de 300 individuos Colombianos. La segunda, fue una revisión sistemática y una meta-regresión siguiendo las guías PRSIMA. Nuestros resultados ponen de manifiesto una falta de anti-transglutaminasa tisular (tTG) e IgA anti-endomisio (EMA) en la población Colombiana. En la revisión sistemática, 72 artículos cumplían con los criterios de selección, la prevalencia estimada de EC en LA fue de 0,46% a 0,64%, mientras que la prevalencia en familiares de primer grado fue de 5,5 a 5,6%, y en los pacientes con diabetes mellitus tipo 1 fue de 4,6% a 8,7% Conclusión: Nuestro estudio muestra que la prevalencia de EC en pacientes sanos de LA es similar a la notificada en la población europea.

La influencia del tabaquismo en la actividad de la artritis reumatoide y progresión de erosiones articulares: Una revision sistemática y meta-análisis.

Objetivos: Sintetizar a través de una revisión sistemática y un meta-análisis los datos disponibles en la literatura sobre el tabaquismo y la artritis reumatoide (AR), teniendo en cuenta su efecto sobre la actividad de la enfermedad y la progresión radiográfica de erosiones. Métodos: Se realizo una revisión sistemática usando las guías PRISMA en las bases de datos de MEDLINE hasta Julio 2013. Los términos de búsqueda incluían tabaquismo, tabaco, humo, cigarrillo y artritis reumatoide. Se consideró incluir cualquier tipo de de estudio realizado con casos de AR, definida por criterios aceptados de clasificación y que incluyeran información que indicara la relación entre tabaquismo y DAS28 o por lo menos un puntaje de erosión. Un tamaño común del efecto se calculó usando un modelo de efectos aleatorios. Resultados: De un total de 2215 artículos obtenidos, 45 cumplían los criterios de inclusión. De estos 27 fueron incluidos en el meta-análisis. Doce contenían información sobre la relación con DAS28 y 17 acerca del efecto en progresión radiográfica. Se encontró una asociación negativa entre tabaquismo y respuesta EULAR (OR: 0.72; 95% CI:0.57-0.91; p=0.005) y Remisión definida por DAS28 (OR:0.78; 95%CI:0.63-0.96; p=0.023). EL puntaje de DAS28 era significativamente mas alto en fumadores actuales (MD:0.29; 95% CI:0.12-0.44;p<0.001) de igual forma el puntaje de erosión era mas alto en fumadores actuales (SMD:0.38;95% CI:0.04-0.72; p=0.028). Los datos para progresión de erosiones eran ambiguos (OR: 0.93; 95% CI: 0.72-1,2; p=0.59). Un análisis de sensibilidad confirmo que los resultados no eran sensibles a la restricción de los datos incluidos. El sesgo de publicación fue mínimo. Conclusiones: El tabaquismo se encuentra asociado a una respuesta disminuida a tratamiento (definido por criterios EULAR) y un puntaje de erosión, pero no se logro demostrar una mayor progresión radiográfica en los pacientes fumadores.