[Show abstract][Hide abstract] ABSTRACT: We performed genome-wide meta-analysis of lipid traits on three samples of Mexican and Mexican American ancestry comprising 4,383 individuals, and followed up significant and highly suggestive associations in three additional Hispanic samples comprising 7,876 individuals. Genome-wide significant signals were observed in or near CELSR2, ZNF259/APOA5, KANK2/DOCK6 and NCAN/MAU2 for total cholesterol, LPL, ABCA1, ZNF259/APOA5, LIPC and CETP for HDL cholesterol, CELSR2, APOB and NCAN/MAU2 for LDL cholesterol, and GCKR, TRIB1, ZNF259/APOA5 and NCAN/MAU2 for triglycerides. Linkage disequilibrium and conditional analyses indicate that signals observed at ABCA1 and LIPC for HDL cholesterol and NCAN/MAU2 for triglycerides are independent of previously reported lead SNP associations. Analyses of lead SNPs from the European Global Lipids Genetics Consortium (GLGC) dataset in our Hispanic samples show remarkable concordance of direction of effects as well as strong correlation in effect sizes. A meta-analysis of the European GLGC and our Hispanic datasets identified five novel regions reaching genome-wide significance: two for total cholesterol (FN1 and SAMM50), two for HDL cholesterol (LOC100996634 and COPB1) and one for LDL cholesterol (LINC00324/CTC1/PFAS). The top meta-analysis signals were found to be enriched for SNPs associated with gene expression in a tissue-specific fashion, suggesting an enrichment of tissue-specific function in lipid-associated loci.
Full-text · Article · Feb 2016 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: Methods:
We analyzed influenza surveillance data from nine countries around southern and southeastern Asia spanning latitudinal gradient from equatorial to temperate zones to further characterize influenza type specific seasonality in the region. We calculated proportion of positives by month out of positives during that year and adjust for variation in samples tested and positivity in these countries.
Influenza A epidemics were identified between November-March during winters in areas lying above 30(o) N latitude; during monsoon months of June-November in areas between 10(o) -30(o) N latitude, and no specific seasonality for influenza A virus circulation in areas lying closer to the equator. Influenza B circulation coincided with influenza A circulation in areas lying above 30(o) N latitude; however in areas south of 30(o) N Asia, influenza B circulated year round at 3-8% of annual influenza B positives during most months with less pronounced peaks during post-monsoon period.
Even though influenza B circulates round the year in most areas of the tropical southern and southeastern Asia region, the most appropriate time for influenza vaccination would be prior to the monsoon season conferring protection against influenza A and B peaks using the most recent WHO recommended vaccine. This article is protected by copyright. All rights reserved.
Full-text · Article · Jan 2016 · Influenza and Other Respiratory Viruses
[Show abstract][Hide abstract] ABSTRACT: A unique feature of influenza A virus (IAV) life cycle is replication of the viral genome in the host cell nucleus. The nuclear import of IAV genome is an indispensable step in establishing virus infection. IAV nucleoprotein (NP) is known to mediate the nuclear import of viral genome via its nuclear localization signals. Here, we demonstrate that cellular heat shock protein 40 (Hsp40/DnaJB1) facilitates the nuclear import of incoming IAV viral ribonucleoproteins (vRNPs) and is important for efficient IAV replication. Hsp40 was found to interact with NP component of IAV RNPs during early stages of infection. This interaction is mediated by the J domain of Hsp40 and N-terminal region of NP. Drug or RNAi mediated inhibition of Hsp40 resulted in reduced nuclear import of IAV RNPs, diminished viral polymerase function and attenuates overall viral replication. Hsp40 was also found to be required for efficient association between NP and importin alpha, which is crucial for IAV RNP nuclear translocation. These studies demonstrate an important role for cellular chaperone Hsp40/DnaJB1 in influenza A virus life cycle by assisting nuclear trafficking of viral ribonucleoproteins.
Full-text · Article · Jan 2016 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: Aging is one of the most important biological processes and is a known risk factor for many age-related diseases in human. Studying age-related transcriptomic changes in tissues across the whole body can provide valuable information for a holistic understanding of this fundamental process. In this work, we catalogue age-related gene expression changes in nine tissues from nearly two hundred individuals collected by the Genotype-Tissue Expression (GTEx) project. In general, we find the aging gene expression signatures are very tissue specific. However, enrichment for some well-known aging components such as mitochondria biology is observed in many tissues. Different levels of cross-tissue synchronization of age-related gene expression changes are observed, and some essential tissues (e.g., heart and lung) show much stronger "co-aging" than other tissues based on a principal component analysis. The aging gene signatures and complex disease genes show a complex overlapping pattern and only in some cases, we see that they are significantly overlapped in the tissues affected by the corresponding diseases. In summary, our analyses provide novel insights to the co-regulation of age-related gene expression in multiple tissues; it also presents a tissue-specific view of the link between aging and age-related diseases.
Full-text · Article · Oct 2015 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: On 5-7 May 2014, the World Health Organization (WHO) convened the second integrated meeting on "influenza vaccines that induce broadly protective and long-lasting immune responses". Around 100 invited experts from academia, the vaccine industry, research and development funders, and regulatory and public health agencies attended the meeting. Areas covered included mechanisms of protection in natural influenza-virus infection and vaccine-induced immunity, new approaches to influenza-vaccine design and production, and novel routes of vaccine administration. A timely focus was on how this knowledge could be applied to both seasonal influenza and emerging viruses with pandemic potential such as influenza A (H7N9), currently circulating in China. Special attention was given to the development of possible universal influenza vaccines, given that the Global Vaccine Action Plan calls for at least one licensed universal influenza vaccine by 2020. This report highlights some of the topics discussed and provides an update on studies published since the report of the previous meeting.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified thousands of variants robustly associated with complex traits. However, the biological mechanisms underlying these associations are, in general, not well understood. We propose a gene-based association method called PrediXcan that directly tests the molecular mechanisms through which genetic variation affects phenotype. The approach estimates the component of gene expression determined by an individual's genetic profile and correlates 'imputed' gene expression with the phenotype under investigation to identify genes involved in the etiology of the phenotype. Genetically regulated gene expression is estimated using whole-genome tissue-dependent prediction models trained with reference transcriptome data sets. PrediXcan enjoys the benefits of gene-based approaches such as reduced multiple-testing burden and a principled approach to the design of follow-up experiments. Our results demonstrate that PrediXcan can detect known and new genes associated with disease traits and provide insights into the mechanism of these associations.
[Show abstract][Hide abstract] ABSTRACT: Although predicting which influenza virus subtype will cause the next pandemic is not yet possible, public health authorities must continually assess the pandemic risk associated with animal influenza viruses, particularly those that have caused infections in humans, and determine what resources should be dedicated to mitigating that risk. To accomplish this goal, a risk assessment framework was created in collaboration with an international group of influenza experts. Compared with the previously used approach, this framework, named the Influenza Risk Assessment Tool, provides a systematic and transparent approach for assessing and comparing threats posed primarily by avian and swine influenza viruses. This tool will be useful to the international influenza community and will remain flexible and responsive to changing information.
Preview · Article · Aug 2015 · Emerging Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Despite long-recognized challenges and constraints associated with their updating and manufacture, influenza vaccines remain at the heart of public health preparedness and response efforts against both seasonal and potentially pandemic influenza viruses Globally coordinated virological and epidemiological surveillance is the foundation of the influenza vaccine virus selection and development process. Although national influenza surveillance and reporting capabilities are being strengthened and expanded, sustaining and building upon recent gains has become a major challenge Strengthening the vaccine virus selection process additionally requires the continuation of initiatives to improve the timeliness and representativeness of influenza viruses shared by countries for detailed analysis by the WHO Global Influenza Surveillance and Response System (GISRS)
[Show abstract][Hide abstract] ABSTRACT: One of the important lessons learned from the 2009 H1N1 pandemic is that a high yield influenza vaccine virus is essential for efficient and timely production of pandemic vaccines in eggs. The current seasonal and pre-pandemic vaccine viruses are generated either by classical reassortment or reverse genetics. Both approaches utilize a high growth virus, generally A/Puerto Rico/8/1934 (PR8), as the donor of all or most of the internal genes, and the wild type virus recommended for inclusion in the vaccine to contribute the hemagglutinin (HA) and neuraminidase (NA) genes encoding the surface glycoproteins. As a result of extensive adaptation through sequential egg passaging, PR8 viruses with different gene sequences and high growth properties have been selected at different laboratories in past decades. The effect of these related but distinct internal PR8 genes on the growth of vaccine viruses in eggs has not been examined previously. Here, we use reverse genetics to analyze systematically the growth and HA antigen yield of reassortant viruses with 3 different PR8 backbones. A panel of 9 different HA/NA gene pairs in combination with each of the 3 different lineages of PR8 internal genes (27 reassortant viruses) was generated to evaluate their performance. Virus and HA yield assays showed that the PR8 internal genes influence HA yields in most subtypes. Although no single PR8 internal gene set outperformed the others in all candidate vaccine viruses, a combination of specific PR8 backbone with individual HA/NA pairs demonstrated improved HA yield and consequently the speed of vaccine production. These findings may be important both for production of seasonal vaccines and for a rapid global vaccine response during a pandemic.
[Show abstract][Hide abstract] ABSTRACT: Although there is considerable evidence that individual differences in language development are highly heritable, there have been few genome-wide scans to locate genes associated with the trait. Previous analyses of language impairment have yielded replicable evidence for linkage to regions on chromosomes 16q, 19q, 13q (within lab), and at 13q (between labs). Here we report the first linkage study to screen the continuum of language ability, from normal to disordered, as found in the general population. 383 children from 147 sib-ships (214 sib-pairs) were genotyped on the Illumina® Linkage IVb Marker Panel using three composite language-related phenotypes and a measure of phonological memory (PM). Two regions (10q23.33; 13q33.3) yielded genome-wide significant peaks for linkage with PM. A peak suggestive of linkage was also found at 17q12 for the overall language composite. This study presents two novel genetic loci for the study of language development and disorders, but fails to replicate findings by previous groups. Possible reasons for this are discussed.
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No preview · Article · May 2015 · Genes Brain and Behavior
[Show abstract][Hide abstract] ABSTRACT: The emergence of avian influenza A(H7N9) virus in poultry causing zoonotic human infections was reported on March 31, 2013. Development of A(H7N9) candidate vaccine viruses (CVV) for pandemic preparedness purposes was initiated without delay. Candidate vaccine viruses were derived by reverse genetics using the internal genes of A/Puerto/Rico/8/34 (PR8). The resulting A(H7N9) CVVs needed improvement because they had titers and antigen yields that were suboptimal for vaccine manufacturing in eggs, especially in a pandemic situation.
Two CVVs derived by reverse genetics were serially passaged in embryonated eggs to improve the hemagglutinin (HA) antigen yield. The total viral protein and HA antigen yields of six egg-passaged CVVs were determined by the BCA assay and isotope dilution mass spectrometry (IDMS) analysis, respectively. CVVs were antigenically characterized by hemagglutination inhibition (HI) assays with ferret antisera.
Improvement of total viral protein yield was observed for the six egg-passaged CVVs; HA quantification by IDMS indicated approximately a two-fold increase in yield of several egg-passaged viruses as compared to that of the parental CVV. Several different amino acid substitutions were identified in the HA of all viruses after serial passage; however HI tests indicated that the antigenic properties of two CVVs remained unchanged.
If influenza A(H7N9) viruses were to acquire sustained human to human transmissibility, the improved HA yield of the egg-passaged CVVs generated in this study could expedite vaccine manufacturing for pandemic mitigation. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Preview · Article · May 2015 · Influenza and Other Respiratory Viruses
[Show abstract][Hide abstract] ABSTRACT: Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues.
[Show abstract][Hide abstract] ABSTRACT: Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5x10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
[Show abstract][Hide abstract] ABSTRACT: Motivation: A major focus of current sequencing studies for human genetics is to identify rare variants associated with complex diseases. Aside from reduced power of detecting associated rare variants, controlling for population stratification is particularly challenging for rare variants. Transmission/disequilibrium tests (TDT) based on family designs are robust to population stratification and admixture, and therefore provide an effective approach to rare variant association studies to eliminate spurious associations. To increase power of rare variant association analysis, gene-based collapsing methods become standard approaches for analyzing rare variants. Existing methods that extend this strategy to rare variants in families usually combine TDT statistics at individual variants and therefore lack the flexibility of incorporating other genetic models. Results: In this study, we describe a haplotype-based framework for group-wise TDT (gTDT) that is flexible to encompass a variety of genetic models such as additive, dominant and compound heterozygous (CH) (i.e. recessive) models as well as other complex interactions. Unlike existing methods, gTDT constructs haplotypes by transmission when possible and inherently takes into account the linkage disequilibrium among variants. Through extensive simulations we showed that type I error was correctly controlled for rare variants under all models investigated, and this remained true in the presence of population stratification. Under a variety of genetic models, gTDT showed increased power compared with the single marker TDT. Application of gTDT to an autism exome sequencing data of 118 trios identified potentially interesting candidate genes with CH rare variants.
[Show abstract][Hide abstract] ABSTRACT: Top signals from genome-wide association studies (GWASs) of type 2 diabetes (T2D) are enriched with expression quantitative trait loci (eQTLs) identified in skeletal muscle and adipose tissue. We therefore hypothesized that such eQTLs might account for a dispropor-tionate share of the heritability estimated from all SNPs interrogated through GWASs. To test this hypothesis, we applied linear mixed models to the Wellcome Trust Case Control Consortium (WTCCC) T2D data set and to data sets representing Mexican Americans from Starr County, TX, and Mexicans from Mexico City. We estimated the proportion of phenotypic variance attributable to the additive effect of all variants interrogated in these GWASs, as well as a much smaller set of variants identified as eQTLs in human adipose tissue, skeletal muscle, and lymphoblastoid cell lines. The narrow-sense heritability explained by all interrogated SNPs in each of these data sets was substantially greater than the heritability accounted for by genome-wide-significant SNPs (~10%); GWAS SNPs explained over 50% of phenotypic variance in the WTCCC, Starr County, and Mexico City data sets. The estimate of heritability attributable to cross-tissue eQTLs was greater in the WTCCC data set and among lean Hispanics, whereas adipose eQTLs significantly explained heritability among Hispanics with a body mass index R 30. These results support an important role for regulatory variants in the genetic component of T2D susceptibility, particularly for eQTLs that elicit effects across insulin-responsive peripheral tissues.
Full-text · Article · Oct 2014 · The American Journal of Human Genetics