Background. The Shingles Prevention Study (SPS) demonstrated zoster vaccine efficacy through 4 years postvaccination. A Short-Term Persistence Substudy (STPS) demonstrated persistence of vaccine ...efficacy for at least 5 years. A Long-Term Persistence Substudy (LTPS) was undertaken to further assess vaccine efficacy in SPS vaccine recipients followed for up to 11 years postvaccination. Study outcomes were assessed for the entire LTPS period and for each year from 7 to 11 years postvaccination. Methods. Surveillance, case determination, and follow-up were comparable to those in SPS and STPS. Because SPS placebo recipients were offered zoster vaccine before the LTPS began, there were no unvaccinated controls. Instead, SPS and STPS placebo results were used to model reference placebo groups. Results. The LTPS enrolled 6867 SPS vaccine recipients. Compared to SPS, estimated vaccine efficacy in LTPS decreased from 61.1% to 37.3% for the herpes zoster (HZ) burden of illness (BOI), from 66.5% to 35.4% for incidence of postherpetic neuralgia, and from 51.3% to 21.1% for incidence of HZ, and declined for all 3 outcome measures from 7 through 11 years postvaccination. Vaccine efficacy for the HZ BOI was significantly greater than zero through year 10 postvaccination, whereas vaccine efficacy for incidence of HZ was significantly greater than zero only through year 8. Conclusions. Estimates of vaccine efficacy decreased over time in the LTPS population compared with modeled control estimates. Statistically significant vaccine efficacy for HZ BOI persisted into year 10 postvaccination, whereas statistically significant vaccine efficacy for incidence of HZ persisted only through year 8.
Over 8 million babies have been born following IVF (in vitro fertilisation) and other artificial reproductive technology (ART) procedures since Louise Brown's birth 40 years ago. New innovations have ...added much complexity to both clinical and laboratory procedures over the last four decades. Translation of novel approaches from basic science into clinical practice continues unabated, widening the applicability of ART to new groups of people and helping improve both chances of healthy live birth and patient acceptability. However, the impact of ART on the health of both patients and their offspring continues to cause concern, and many ethical challenges created by new scientific developments in this field attract widely differing opinions. What is undeniable is that there will be a sustained global growth in utilisation of ART and that reproductive tourism will allow many people to access the treatment they desire notwithstanding national regulations that may forbid some approaches. The greatest challenge is to expand access to ART to those living in the less wealthy nations who are equally deserving of its benefits.
Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study ...(TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS.
As studies of DNA methylation increase in scope, it has become evident that methylation has a complex relationship with gene expression, plays an important role in defining cell types, and is ...disrupted in many diseases. We describe large-scale single-base resolution DNA methylation profiling on a diverse collection of 82 human cell lines and tissues using reduced representation bisulfite sequencing (RRBS). Analysis integrating RNA-seq and ChIP-seq data illuminates the functional role of this dynamic mark. Loci that are hypermethylated across cancer types are enriched for sites bound by NANOG in embryonic stem cells, which supports and expands the model of a stem/progenitor cell signature in cancer. CpGs that are hypomethylated across cancer types are concentrated in megabase-scale domains that occur near the telomeres and centromeres of chromosomes, are depleted of genes, and are enriched for cancer-specific EZH2 binding and H3K27me3 (repressive chromatin). In noncancer samples, there are cell-type specific methylation signatures preserved in primary cell lines and tissues as well as methylation differences induced by cell culture. The relationship between methylation and expression is context-dependent, and we find that CpG-rich enhancers bound by EP300 in the bodies of expressed genes are unmethylated despite the dense gene-body methylation surrounding them. Non-CpG cytosine methylation occurs in human somatic tissue, is particularly prevalent in brain tissue, and is reproducible across many individuals. This study provides an atlas of DNA methylation across diverse and well-characterized samples and enables new discoveries about DNA methylation and its role in gene regulation and disease.
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially ...to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.
Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based ...in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
Mapping DNase I hypersensitive (HS) sites is an accurate method of identifying the location of genetic regulatory elements, including promoters, enhancers, silencers, insulators, and locus control ...regions. We employed high-throughput sequencing and whole-genome tiled array strategies to identify DNase I HS sites within human primary CD4
+ T cells. Combining these two technologies, we have created a comprehensive and accurate genome-wide open chromatin map. Surprisingly, only 16%–21% of the identified 94,925 DNase I HS sites are found in promoters or first exons of known genes, but nearly half of the most open sites are in these regions. In conjunction with expression, motif, and chromatin immunoprecipitation data, we find evidence of cell-type-specific characteristics, including the ability to identify transcription start sites and locations of different chromatin marks utilized in these cells. In addition, and unexpectedly, our analyses have uncovered detailed features of nucleosome structure.
Schizophrenia genome-wide association studies have identified >150 regions of the genome associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. ...To explore the mechanism of non-coding regulatory elements in schizophrenia, we performed ATAC-seq on adult prefrontal cortex brain samples from 135 individuals with schizophrenia and 137 controls, and identified 118,152 ATAC-seq peaks. These accessible chromatin regions in the brain are highly enriched for schizophrenia SNP heritability. Accessible chromatin regions that overlap evolutionarily conserved regions exhibit an even higher heritability enrichment, indicating that sequence conservation can further refine functional risk variants. We identify few differences in chromatin accessibility between cases and controls, in contrast to thousands of age-related differential accessible chromatin regions. Altogether, we characterize chromatin accessibility in the human prefrontal cortex, the effect of schizophrenia and age on chromatin accessibility, and provide evidence that our dataset will allow for fine mapping of risk variants.
Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this ...association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity.
To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference.
This 2-sample mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes-self-reported (n = 377 234) and objective accelerometer-based (n = 91 084)-and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in diverse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR-Pleiotropy Residual Sum and Outlier PRESSO) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018.
MDD and physical activity.
GWAS summary data were available for a combined sample size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio OR, 0.74 for MDD per 1-SD increase in mean acceleration; 95% CI, 0.59-0.92; P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (β = -0.08 in mean acceleration per MDD vs control status; 95% CI, -0.47 to 0.32; P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity; 95% CI, 0.57-3.37; P = .48), or between MDD and self-reported activity (β = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status; 95% CI, -0.008 to 0.05; P = .15).
Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed-but not self-reported-physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression.
Regulatory elements recruit transcription factors that modulate gene expression distinctly across cell types, but the relationships among these remains elusive. To address this, we analyzed matched ...DNase-seq and gene expression data for 112 human samples representing 72 cell types. We first defined more than 1800 clusters of DNase I hypersensitive sites (DHSs) with similar tissue specificity of DNase-seq signal patterns. We then used these to uncover distinct associations between DHSs and promoters, CpG islands, conserved elements, and transcription factor motif enrichment. Motif analysis within clusters identified known and novel motifs in cell-type-specific and ubiquitous regulatory elements and supports a role for AP-1 regulating open chromatin. We developed a classifier that accurately predicts cell-type lineage based on only 43 DHSs and evaluated the tissue of origin for cancer cell types. A similar classifier identified three sex-specific loci on the X chromosome, including the XIST lincRNA locus. By correlating DNase I signal and gene expression, we predicted regulated genes for more than 500K DHSs. Finally, we introduce a web resource to enable researchers to use these results to explore these regulatory patterns and better understand how expression is modulated within and across human cell types.
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