New Entries in the Lottery of Facial GWAS Discovery.
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ABSTRACT:
SUBMITTER: Claes P
PROVIDER: S-EPMC4999261 | biostudies-literature | 2016 Aug
REPOSITORIES: biostudies-literature
Publications
New Entries in the Lottery of Facial GWAS Discovery.
Claes Peter P Shriver Mark D MD
PLoS genetics 20160825 8
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Project description:We have applied a GWAS to 40 consanguineous families segregating cases of non-syndromic cleft lip with or without cleft palate (NS CL/P) (a total of 160 affected and unaffected individuals) in order to trace potential recessive loci that confer susceptibility to this common facial malformation. Pedigree-based association test (PBAT) analyses reported nominal evidence of association and linkage over SNP markers located at 11q25 (rs4937877, P = 2.7 × 10(-6)), 19p12 (rs4324267, P = 1.6 × 10(-5)), 5q14.1 (rs4588572, P-value = 3.36 × 10(-5)), and 15q21.1 (rs4774497, P = 1.08 × 10(-4)). Using the Versatile Gene-Based Association Study to complement the PBAT results, we found clusters of markers located at chromosomes 19p12, 11q25, and 8p23.2 overcome the threshold for GWAS significance (P < 1 × 10(-7)). From this study, new recessive loci implicated in NS CL/P include: B3GAT1, GLB1L2, ZNF431, ZNF714, and CSMD1, even though the functional association with the genesis of NS CL/P remains to be elucidated. These results emphasize the importance of using homogeneous populations, phenotypes, and family structures for GWAS combined with gene-based association analyses, and should encourage. other researchers to evaluate these genes on independent patient samples affected by NS CL/P.
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Project description:The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs). These studies were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders. We start by giving a number of quotes from scientists and journalists about perceived problems with GWASs. We will then briefly give the history of GWASs and focus on the discoveries made through this experimental design, what those discoveries tell us and do not tell us about the genetics and biology of complex traits, and what immediate utility has come out of these studies. Rather than giving an exhaustive review of all reported findings for all diseases and other complex traits, we focus on the results for auto-immune diseases and metabolic diseases. We return to the perceived failure or disappointment about GWASs in the concluding section.
| S-EPMC3257326 | biostudies-literature
Project description:The past decade has witnessed an explosion in trial data on JAK inhibitors (JAKi). These small molecules target the Janus kinase - signal transducer and activator of transcription (JAK-STAT) pathway, blocking crucial cytokines across a septum of rheumatic diseases. As a class, JAKi are beginning to demonstrate efficacy on par, if not superior to biologics. Two first generation JAKi are licensed for use in inflammatory arthritis; tofacitinib and baricitinib. Next-generation JAKi have been designed with selective affinity for one JAK enzymes, the aim to reduce unwanted adverse effects without declining clinical efficacy. Emerging data with selective JAK1 inhibitors upadacitinib and filgotinib looks very promising. Despite differences in selectivity between JAKi, an overlap exists in their safety profiles. Across the class, a characteristic safety signal is emerging with viral opportunistic infections, particularly herpes zoster. Post marketing drug surveillance will be essential in evaluating the long-term risk with these agents.
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Project description:It has been 15 years since the advent of the genome-wide association study (GWAS) era. Here, we review how this experimental design has realized its promise by facilitating an impressive range of discoveries with remarkable impact on multiple fields, including population genetics, complex trait genetics, epidemiology, social science, and medicine. We predict that the emergence of large-scale biobanks will continue to expand to more diverse populations and capture more of the allele frequency spectrum through whole-genome sequencing, which will further improve our ability to investigate the causes and consequences of human genetic variation for complex traits and diseases.
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Project description:The patterning of the facial midline involves early specification of neural crest cells to form skeletal tissues that support the upper jaw . In order to understand the molecular mechanisms involved we have taken advantage of a beak duplication model developed in the chicken embryo. Here we can induce the transformation of the side of the beak into a second midline that is easily identifiable by the formation of a supernumerary egg tooth. The phenotype is induced by implanting two microscopic beads, one soaked in retinoic acid and the other soaked in Noggin into the side of the head of the chicken embryo. Here we use microarrays to profile expression of maxillary mesenchyme 16h after placing the beads. A subset of genes were validated using in situ hybridization and QPCR. The aims of the study are to test the function of these genes using retroviral transgenesis, knockdown with morpholinos or expression of secreted proteins and their application to the embryo. Embryos were incubated at 38 degrees C until they reached Hamburger Hamilton Stage 15 or 25 somites. Four different treatments were carried out consisting of two beads simultaneously implanted into the side of the head between the eye and mandibular arch. The beads were either Noggin+retinoic acid, Tris+retinoic acid, Noggin+DMSO or the control, Tris+DMSO. Embryos were reincubated for another 16h until they reached stage 18. Embryos were dissected on ice in Hanks Buffered Salt Solution and batches of 12-15 maxillary pieces were snap frozen in liquid Nitrogen. These pooled facial prominences comprised one biological replicate. A total of three biological replicates were generated for each treatment.
2014-02-28 | E-GEOD-52227 | biostudies-arrayexpress
Project description:The patterning of the facial midline involves early specification of neural crest cells to form skeletal tissues that support the upper jaw . In order to understand the molecular mechanisms involved we have taken advantage of a beak duplication model developed in the chicken embryo. Here we can induce the transformation of the side of the beak into a second midline that is easily identifiable by the formation of a supernumerary egg tooth. The phenotype is induced by implanting two microscopic beads, one soaked in retinoic acid and the other soaked in Noggin into the side of the head of the chicken embryo. Here we use microarrays to profile expression of maxillary mesenchyme 16h after placing the beads. A subset of genes were validated using in situ hybridization and QPCR. The aims of the study are to test the function of these genes using retroviral transgenesis, knockdown with morpholinos or expression of secreted proteins and their application to the embryo.
2014-02-28 | GSE52227 | GEO
Project description:Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.
| S-EPMC5501872 | biostudies-literature
Project description:Importance:Poor health and unhealthy lifestyles are substantially more prevalent among individuals with low income than among individuals with high income, but the underlying mechanisms are not well understood. Objective:To evaluate whether changes to unearned wealth from lotteries are associated with long-term health behaviors and overall health. Design, Setting, and Participants:In this quasi-experimental cohort study, 4820 participants (aged 18-70 years at the time of winning) in 3 Swedish lotteries were surveyed from September 1, 2016, to November 11, 2016, between 5 and 22 years after a lottery event. Outcomes of participants in the same lottery who were randomly assigned prizes of different magnitudes by the lotteries but were ex ante identical in terms of their probability of winning different prizes were compared. Data were analyzed from December 22, 2016, to November 21, 2019. Exposures:Lottery prizes ranged from $0 for nonwinning players to $1.6 million. Main Outcomes and Measures:Four lifestyle factors (smoking, alcohol consumption, physical activity, and a healthy diet index) and 2 measures of overall health (subjective health and an index of total health derived from responses to questions about 35 health conditions). Results:The survey was returned by 3344 of 4820 individuals (69%; 1722 [51.5%] male), which corresponded to 3362 observations. The mean (SD) age was 48 (11.8) years in the year of the lottery win and 60 (11.0) years at the time of the survey. There were no statistically significant associations between prize amount won and any of the 6 long-term health outcomes. Estimated associations expressed in SD units per $100 000 won were as follows: smoking (-0.006, 95% CI, -0.038 to 0.026); alcohol consumption (0.003, 95% CI, -0.027 to 0.033); physical activity (0.001, 95% CI, -0.029 to 0.032); dietary quality (-0.007, 95% CI, -0.040 to 0.026); subjective health (0.013, 95% CI, -0.017 to 0.043); and index of total health (-0.003, 95% CI, -0.033 to 0.027). Conclusions and Relevance:In this study of Swedish lottery players, unearned wealth from random lottery prize winnings was not associated with subsequent healthy lifestyle factors or overall health. The findings suggest that large, random transfers of unearned wealth are unlikely to be associated with large, long-term changes in health habits or overall health.
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Project description: Not available
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