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Background Inflammatory bowel disease (IBD) is associated with an increased risk of osteoporosis and bone fracture. The aims of this study were to (1) confirm the association between IBD and low bone density and (2) test for shared risk variants across diseases. Methods The study cohort included patients from the Michigan Genomics Initiative. Student’s t tests (continuous) and chi-square tests (categorical) were used for univariate analyses. Multivariable logistic regression was performed to test the effect of IBD on osteoporosis or osteopenia. Publicly available genome-wide association summary statistics were used to identify variants that alter the risk of IBD and bone density, and Mendelian randomization (MR) was used to identify causal effects of genetically predicted IBD on bone density. Results There were 51 405 individuals in the Michigan Genomics Initiative cohort including 10 378 (20.2%) cases of osteoporosis or osteopenia and 1404 (2.7%) cases of IBD. Patients with osteoporosis or osteopenia were more likely to be older (64 years of age vs 56 years of age; P < .001), female (67% vs 49%; P < .001), and have a lower body mass index (29 kg/m2 vs 30 kg/m2; P < .001). IBD patients with (odds ratio, 4.60; 95% confidence interval, 3.93-5.37) and without (odds ratio, 1.77; 95% confidence interval, 1.42-2.21) steroid use had a significantly higher risk of osteoporosis or osteopenia. Twenty-one IBD variants associated with reduced bone mineral density at P ≤ .05 and 3 IBD risk variants associated with reduced bone mineral density at P ≤ 5 × 10-8. Of the 3 genome-wide significant variants, 2 increased risk of IBD (rs12568930-T: MIR4418;ZBTB40; rs7236492-C: NFATC1). MR did not reveal a causal effect of genetically predicted IBD on bone density (MR Egger, P = .30; inverse variance weighted, P = .63). Conclusions Patients with IBD are at increased risk for low bone density, independent of steroid use. Variants in or near ZBTB40 and NFATC1 are associated with an increased risk of IBD and low bone density.

Finding of light inhibition of hydrogenation reactions and the development of a plasmonic switcher for reaction control, performed through interfacial electron transfer in a hybrid nanoparticle reversed by the plasmonic effect.

To derive and validate a polygenic risk score (PRS) to predict the occurrence and severity of diverticulitis and to understand the potential for incorporation of a PRS in current decision-making.PRS quantifies genetic variation into a continuous measure of risk. There is a need for improved risk stratification to guide surgical decision-making that could be fulfilled by PRS. It is unknown how surgeons might integrate PRS in decision-making.We derived a PRS with 44 SNPs associated with diverticular disease in the United Kingdom Biobank and validated this score in the Michigan Genomics Initiative (MGI). We performed a discrete choice experiment of practicing colorectal surgeons. Surgeons rated the influence of clinical factors and a hypothetical polygenic risk prediction tool.Among 2,812 MGI participants with diverticular disease, 1,964 were asymptomatic, 574 had mild disease, and 274 had severe disease. PRS was associated with occurrence and severity. Patients in the highest PRS decile were more likely to have diverticulitis (OR=1.84 (95%CI 1.42-2.38)) and more likely to have severe diverticulitis (OR=1.61 (95% CI 1.04-2.51)) than the bottom 50%. Among 213 surveyed surgeons, extreme disease-specific factors had the largest utility (3 episodes in the last year, +74.4; percutaneous drain, + 69.4). Factors with strongest influence against surgery included 1 lifetime episode (-63.3), outpatient management (-54.9), and patient preference (-39.6) PRS was predicted to have high utility, (+71).A PRS derived from a large national biobank was externally validated, and found to be associated with the incidence and severity of diverticulitis. Surgeons have clear guidance at clinical extremes, but demonstrate equipoise in intermediate scenarios. Surgeons are receptive to PRS, which may be most useful in marginal clinical situations. Given the current lack of accurate prognostication in recurrent diverticulitis, PRS may provide a novel approach for improving patient counseling and decision-making.

Human genome-wide association studies found single-nucleotide polymorphisms (SNPs) near LYPLAL1 (Lysophospholipase-like protein 1) that have sex-specific effects on fat distribution and metabolic traits. To determine whether altering LYPLAL1 affects obesity and metabolic disease, we created and characterized a mouse knockout (KO) of Lyplal1. We fed the experimental group of mice a high-fat, high-sucrose (HFHS) diet for 23 weeks, and the controls were fed regular chow diet. Here, we show that CRISPR-Cas9 whole-body Lyplal1 KO mice fed an HFHS diet showed sex-specific differences in weight gain and fat accumulation as compared to chow diet. Female, not male, KO mice weighed less than WT mice, had reduced body fat percentage, had white fat mass, and had adipocyte diameter not accounted for by changes in the metabolic rate. Female, but not male, KO mice had increased serum triglycerides, decreased aspartate, and decreased alanine aminotransferase. Lyplal1 KO mice of both sexes have reduced liver triglycerides and steatosis. These diet-specific effects resemble the effects of SNPs near LYPLAL1 in humans, suggesting that LYPLAL1 has an evolutionary conserved sex-specific effect on adiposity. This murine model can be used to study this novel gene-by-sex-by-diet interaction to elucidate the metabolic effects of LYPLAL1 on human obesity.

Nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) represent a genetically and phenotypically diverse entity with no approved therapy, making it imperative to define the spectrum of pathways contributing to its pathogenesis. Rare variants in genes encoding nuclear envelope proteins cause lipodystrophy that includes early-onset NASH; we hypothesized that common variants in nuclear envelope-related genes might also contribute to hepatic steatosis and NASH. In an association meta-analysis of nuclear envelope-related coding variants in three large cohorts (N>120,000 participants), rs6461378 (SUN1H118Y) was the top steatosis-associated variant (PLay SummaryA common genetic variant that leads to an amino acid change in the nuclear envelope protein SUN1 was found to positively associate with hepatic steatosis in a meta-analysis of genomic data from multiple large cohorts. Follow-up studies in separate validation cohorts demonstrated strong positive associations with metabolic traits that are linked to nonalcoholic fatty liver disease, including insulin resistance, type 2 diabetes, hypertension, and cardiovascular disease. Testing of this variant in cell culture demonstrated biochemical differences from wild-type SUN1, with increased proteasomal degradation of the H118Y variant, decreased sensitivity to insulin, and increased lipid accumulation, suggesting that this is a functional variant with a potential causal role in human disease.

Objective. To study the regional cerebral blood flow (rCBF) in important brain functional areas and the metabolic levels of these brain functional areas in patients with primary hypothyroidism by using arterial spin labeling (ASL) and magnetic resonance spectroscopy (MRS) techniques to explain the possible causes of brain dysfunction in patients with primary hypothyroidism. Methods. Twenty-five patients with primary hypothyroidism (newly diagnosed and not treated) who were treated in the endocrinology department of our hospital were selected as the research group, and 25 healthy patients with normal thyroid function who came to our hospital during the same period with matched gender and age were selected as the control group. ASL and MRS techniques were used to detect and calculate regional cerebral blood flow (rCBF) in the frontal lobe, hippocampus, and posterior cingulate gyrus, as well as N-acetylaspartate/creatine (NAA/Cr), choline/creatine (Cho) in the brain/Cr, and inositol/creatine (mI/Cr) ratio. The correlations between metabolite ratios measured by rCBF, MRS, and serum TSH, FT3, and FT4 levels were analyzed. Results. Compared with the control group, the rCBF in the frontal lobe, hippocampus, and posterior cingulate gyrus of the dominant hemisphere of the hypothyroid patients in the study group decreased significantly ( P < 0.05 ). The comparison of metabolite ratios showed that compared with the control group, the NAA/Cr ratio of the frontal lobe and posterior cingulate gyrus of the study group was significantly decreased, and the Cho/Cr ratio of the posterior cingulate gyrus of the study group was significantly increased. The MI/Cr ratio of the hippocampus was significantly decreased (all P values < 0.05). Correlation analysis showed that rCBF and NAA/Cr in posterior cingulate gyrus were significantly negatively correlated with serum TSH levels ( P < 0.05 ). Conclusion. The changes of rCBF and metabolite ratios in the frontal lobe, hippocampus, and posterior cingulate gyrus of patients with primary hypothyroidism can be detected using ASL and MRS techniques. The changes of rCBF and metabolite ratio and their negative correlation with serum TSH level are helpful to explain the causes of brain dysfunction in patients with primary hypothyroidism.

Chemoradiotherapy (CRT) is the most accepted treatment for locally advanced pancreatic ductal adenocarcinoma (PDAC) and can significantly improve the R0 resection rate. However, there are few long-term survivors after CRT. Although some polymer nanoparticles have shown potential in alleviating the dose-limiting toxicity and assisting the chemotherapy of PDAC, there are few efficient nanosensitizers (NS) available for CRT of this malignancy, especially in the context of its hypoxic nature. Herein, based on the biological features of PDAC, a γ-glutamyl transpeptidase (GGT)/glutathione (GSH)/hypoxia triple-responsive prodrug NS to overcome the biological barrier and microenvironmental limitations confronted by CRT in PDAC is developed. Due to triple-responsiveness, deep tumor penetration, GSH/hypoxia-responsive drug release/activation, and hypoxia-induced chemoradio-sensitization can be simultaneously achieved with this NS. As a result, tumor shrinkage after CRT with this NS can be observed in both subcutaneous and orthotopic PDAC models, foreshadowing its potential in clinical neoadjuvant CRT.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P

Serum liver enzyme concentrations are the most frequently-used laboratory markers of liver disease, a major cause of mortality. We conduct a meta-analysis of genome-wide association studies of liver enzymes from UK BioBank and BioBank Japan. We identified 160 previously-unreported independent alanine aminotransferase, 190 aspartate aminotransferase, and 199 alkaline phosphatase genome-wide significant associations, with some affecting multiple different enzymes. Associated variants implicate genes that demonstrate diverse liver cell type expression and promote a range of metabolic and liver diseases. These findings provide insight into the pathophysiology of liver and other metabolic diseases that are associated with serum liver enzyme concentrations., Serum liver enzymes are used as markers of liver disease, their concentration influenced in part by genetic factors. Here the authors meta-analyse genome-wide association studies on the UK Biobank and BioBank Japan to evaluate the association of three liver enzymes with liver and other metabolic diseases.

Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome‐wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome‐wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30–1.73), p = 2.1 × 10−8) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16–1.36), p = 4.3 × 10−8). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13–1.43), p = 5 × 10−5) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97–1.09), p = .37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.

Background Inflammatory bowel disease is associated with an increased risk of skin cancer. The aims of this study were to determine whether IBD susceptibility variants are also associated with skin cancer susceptibility and if such risk is augmented by use of immune-suppressive therapy. Methods The discovery cohort included participants in the UK Biobank. The validation cohort included participants in the Michigan Genomics Initiative. The primary outcome of interest was skin cancer, subgrouped into nonmelanoma skin cancers (NMSC) and melanoma skin cancers (MSC). Multivariable logistic regression with matched controls (3 controls:1 case) was performed to identify genomic predictors of skin malignancy in the discovery cohort. Variants with P Results The discovery cohort included 10,247 cases of NMSC and 1883 cases of MSC. The validation cohort included 7334 cases of NMSC and 3304 cases of MSC. Twenty-nine variants were associated with risk of NMSC in the discovery cohort, of which 5 replicated in the validation cohort (increased risk, rs7773324-A [DUSP22; IRF4], rs2476601-G [PTPN22], rs1847472-C [BACH2], rs72810983-A [CPEB4]; decreased risk, rs6088765-G [PROCR; MMP24]). Twelve variants were associated with risk of MSC in the discovery cohort, of which 4 were replicated in the validation cohort (increased risk, rs61839660-T [IL2RA]; decreased risk, rs17391694-C [GIPC2; MGC27382], rs6088765-G [PROCR; MMP24], and rs1728785-C [ZFP90]). No effect modification was observed. Conclusions The results of this study highlight shared genetic susceptibility across IBD and skin cancer, with increased risk of NMSC in those who carry risk variants in IRF4, PTPN22, CPEB4, and BACH2 and increased risk of MSC in those who carry a risk variant in IL2RA.

The nanoparticle-polymer composite is a widely used electronic packaging material. To satisfy the miscibility of nanoparticles with polymer, the surface of nanoparticles needs to be modified. The particle surface modification has been widely studied. However, the interaction between the silane coupling agent (SCA) and the nanoparticle surface is not clear yet. This article aims to investigate the surface modification impact on the nano-SiO 2 particle surface and to clarify the interaction between chemical reagent and the particle surface. In this investigation nano-SiO 2 was characterized by thermal gravity analysis (TGA), Fourier transform infrared spectroscopy (FT - IR), and nano- IR. The FT - IR results showed that the specific peak of SCA appears in the synthesized nano-silica. The TGA experiments were carried out to test the weight loss of SCA modified nano-SiO 2 as well as the grafting efficiency of the surface modification. The FT-IR and TGA results confirmed the SCA chemical grafting onto the nanoparticle surfaces. The nano-IR test provided detailed information for nano-silica surface. It could not only show the topographical AFM images but also the corresponding nanoscale IR adsorption spectra of the nano-silica surface. The topographic image distinguished the nanoparticle from the substrate. The discrete domains spectra shows the existence of SCA on the silica surface, which indicated that the SCA was grafted onto the silica surface with chemical bonding.

The introduction of inorganic nanoparticles into polymer matrix improves the performance of the underfill in flip-chip packaging, for example it improves the mechanical properties of the polymer and reduces the coefficient of thermal expansion (CTE). However, the nanoparticles are not always compatible with the polymer resin and hard to be well dispersed in the colloidal suspension. The phenomenon is caused by the very small diameter, the large specific surface area, and the outstanding surface energy of nanoparticles. As a result, nanoparticles are easy to interact with each other and form agglomerates in the colloid, and lead to mobility problem. To resolve this problem, this paper investigated the particle interaction for raw nanoparticles and surface modified nanoparticles in epoxy resin, and distinguished the functional group impact on the particle interactions. The Fourier transform infrared spectroscopy (FT - IR) is used to characterize the specific chemical groups of modified nanoparticles. The FI-IR result verified that silane coupling agents (SCA) were grafted onto the nanoparticles. Raw nanoparticles and surface modified nanoparticles were suspended into epoxy resin to investigate the rheological behaviour. The rheological flow curves were well fitted by the Herschel-Bulkley model. The dynamic rheology of these colloidal suspensions was examined as well. According to the frequency spectrum, the elastic modulus (G') dominants over the whole angular frequency range for raw nanoparticle epoxy resin colloidal suspension. N anoparticles interact with each other via hydrogen bonding and van der Waals attraction strongly in the suspension. However, surface modification for nanoparticles reduced the fluidity according to the rheological flow curves. The dynamic rheological property demonstrates that surface modification improves the elasticity of the suspension, which means van der Waals attraction between nano-silica particles becomes stronger while the particle-resin interaction is weaker for the SCA modified nano-silica suspension.

The miniaturization of the electronic devices requires smaller packaged chips, and the distance between the chip and the substrate becomes smaller, which make it necessary to introduce the nano-silica in the filler for advanced packaging. However, the nano-silica is easy to settle in the underfill and block the packing, because it tends to agglomerate due to its large specific area. Unfortunately, the addition of nano-silica in the underfill could also largely improve the viscosity, giving rise to the unacceptable low flowability. Therefore, it is necessary to investigate the key factors that could influence the dispersion of nano-silica in the epoxy resin. In this paper, the time domain nuclear magnetic resonance spectrometer (NMR) technique was used to study the dispersion of silica fillers. This research studied the nano-silica particle size impact and the surface modification impact on the dispersion of nano-silica in epoxy resin. The shape and size distribution of three types of particles were characterized before studying the relaxation property. The three types of particles were then modified with silane coupling agents. The results of time domain NMR relaxation rate showed that the surface modified nano-silica particles have lower relaxation time, meaning the better dispersity in the epoxy. Meanwhile, after surface modification, larger fillers obtained better dispersity compared with smaller fillers, which result in the uniform dispersion in the resin.

Non-alcoholic fatty liver disease (NAFLD) is caused by excess lipid accumulation in hepatocytes. Genome-wide association studies have identified a strong association of NAFLD with non-synonymous E167K amino acid mutation in the transmembrane 6 superfamily member 2 (TM6SF2) protein. The E167K mutation reduces TM6SF2 stability, and its carriers display increased hepatic lipids and lower serum triglycerides. However, the effects of TM6SF2 on hepatic lipid metabolism are not completely understood. We overexpressed wild-type or E167K variant of TM6SF2 or knocked down TM6SF2 expression in lipid-treated Huh-7 cells and used untargeted lipidomic analysis, RNAseq transcriptome analysis, and fluorescent imaging to determine changes in hepatic lipid metabolism. Both TM6SF2 knockdown and E167K overexpression increased hepatic lipid accumulation, while wild-type overexpression decreased acylglyceride levels. We also observed lipid chain remodeling for acylglycerides by TM6SF2 knockdown, leading to a relative increase in species with shorter, more saturated side chains. RNA-sequencing revealed differential expression of several lipid metabolizing genes, including genes belonging to AKR1 family and lipases, primarily in cells with TM6SF2 knockdown. Taken together, our data show that overexpression of TM6SF2 gene or its loss-of-function changes hepatic lipid species composition and expression of lipid metabolizing genes. Additionally, our data further confirms a loss-of-function effect for the E167K variant.

Human genome-wide association studies found SNPs near LYPLAL1 that have sex-specific effects on fat distribution and metabolic traits. To determine whether altering LYPLAL1 affects obesity and metabolic disease we created and characterized a mouse knockout of Lyplal1. Here we show that CRISPR-Cas9 whole-body Lyplal1 knockout (KO) mice fed a high fat, high sucrose (HFHS) diet showed sex-specific differences in weight gain and fat accumulation. Female, not male, KO mice weighed less than WT mice, had reduced body fat percentage, white fat mass, and adipocyte diameter not accounted for by changes in metabolic rate. Female, but not male, KO mice had increased serum triglycerides, decreased aspartate, and alanine aminotransferase. Lyplal1 KO mice of both sexes have reduced liver triglycerides and steatosis. These diet-specific effects resemble the effects of SNPs near LYPLAL1 in humans, suggesting that LYPLAL1 has an evolutionary conserved sex-specific effect on adiposity. This murine model can be used to study this novel gene-by-sex-by-diet interaction to elucidate the metabolic effects of LYPLAL1 on human obesity.

BackgroundNonalcoholic fatty liver disease (NAFLD) is caused by accumulation of excess lipids in hepatocytes. Genome wide association studies have identified strong association of NAFLD with non-synonymous E167K amino acid mutation in transmembrane 6 superfamily member 2 (TM6SF2) protein. The E167K mutation affects TM6SF2 stability and its carriers display increased hepatic lipids levels and lower serum triglycerides. While similar phenotype is evident in mice with TM6SF2 knockdown, effects of TM6SF2 on hepatic lipid metabolism is not completely understood.MethodsHere, we overexpressed wild-type or E167K variant of TM6SF2 or knocked down TM6SF2 expression in lipid-treated Huh-7 cells and used biochemical assays, untargeted lipidomic analysis, RNAseq transcriptome analysis and high-throughput fluorescent imaging to determine changes in lipid metabolism.ResultsBoth knockdown and E167K overexpression increased acylglyceride levels which was decreased by wild-type TM6SF2 overexpression. Further, mean intensity of individual lipid droplets was increased by E167K overexpression and knockdown while wild-type TM6SF2 had no effects. We also observed lipid chain remodeling for acylglycerides by TM6SF2 knockdown leading to a relative increase in species with shorter and more saturated side chains. RNA sequencing revealed differential expression of several lipid metabolizing genes, including genes belonging to AKR1 family and lipases, primarily in cells with TM6SF2 knockdown.ConclusionTaken together, our data shows that overexpression of TM6SF2 gene or its loss-of-function changes hepatic lipid species composition and expression of lipid metabolizing genes. Further, overexpression of E167K variant and TM6SF2 knockdown similarly increased hepatic lipid accumulation and lipid droplets profile further confirming a loss-of-function effect for variant.

Purpose Impulse buying has been the focus of attention in the marketing. With the rise of online shopping, online impulse buying phenomenon becomes increasingly serious. Whereas, the impulse buying behavior in an online environment is rarely discussed in relevant literature. The purpose of this paper is to explore the impact of the type of product and time pressure on consumer online impulse buying intention; this is a relatively new issue of marketing academia in China. Design/methodology/approach In this paper, the experimental methodology was adopted to explore the impact of consumer online impulse buying tendencies, the departure from the type of product and the time pressure. Findings Results show that low-involvement feeling products stimulate consumer online impulse buying tendencies. Simultaneously, there is an interaction effect between time pressure and product type, which is, under the influence of time pressure, the enhancement of low-involvement feeling products on consumer online impulse buying tendency is more significant. Originality/value This study discusses the interaction between time pressure and product type on consumers’ online impulse buying tendency, which has not been studied before. While discussing the impact of product types on consumers’ impulse buying tendency on the internet, this paper considers the impact of time pressure on consumers’ impulsive buying tendency, and applies the term of time pressure, a psychological research term, to the field of marketing research, so as to make the cross-links between disciplines closer.

Up to 25% of patients with nonalcoholic fatty liver disease (NAFLD) are not obese but may have a fat or muscle composition that predisposes them to NAFLD. Our aim was to determine whether body composition parameters associate with NAFLD and to identify genetic contributors to this association. This study included two cohorts. The first included 2,249 participants from the Framingham Heart Study who underwent a computed tomography scan to evaluate hepatic steatosis, dual‐energy x‐ray absorptiometry testing to assess body composition, and clinical examination. Body composition parameters were normalized to total body weight. A subset of participants underwent genotyping with an Affymetrix 550K single‐nucleotide polymorphism array. The second cohort, Michigan Genomics Initiative, included 19,239 individuals with genotyping on the Illumina HumanCoreExome v.12.1 array and full electronic health record data. Using sex‐stratified multivariable linear regression, greater central body fat associated with increased hepatic steatosis while greater lower extremity body fat associated with decreased hepatic steatosis. Greater appendicular lean mass was associated with decreased hepatic steatosis in men but not in women. A polygenic risk score for lipodystrophy (regional or global loss of adipose tissue) was associated with increased hepatic steatosis, increased liver fibrosis, and decreased lower extremity fat mass. Conclusion: Greater central body fat associated with increased hepatic steatosis, while greater lower extremity body fat and, in men, greater appendicular lean mass were associated with decreased hepatic steatosis. A genetic risk score for lipodystrophy was associated with NAFLD and liver fibrosis. Our results suggest that buffering of excess energy by peripheral fat and muscle may protect against NAFLD and liver fibrosis in the general population.

BACKGROUND AND AIMS: Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS: We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS: Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS: We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.

Diverticular disease is common and has a high morbidity. Treatments are limited owing to the poor understanding of its pathophysiology. Here, to elucidate its etiology, we performed a genome-wide association study of diverticular disease (27,444 cases; 382,284 controls) from the UK Biobank and tested for replication in the Michigan Genomics Initiative (2,572 cases; 28,649 controls). We identified 42 loci associated with diverticular disease; 39 of these loci are novel. Using data-driven expression-prioritized integration for complex traits (DEPICT), we show that genes in these associated regions are significantly enriched for expression in mesenchymal stem cells and multiple connective tissue cell types and are co-expressed with genes that have a role in vascular and mesenchymal biology. Genes in these associated loci have roles in immunity, extracellular matrix biology, cell adhesion, membrane transport and intestinal motility. Phenome-wide association analysis of the 42 variants shows a common etiology of diverticular disease with obesity and hernia. These analyses shed light on the genomic landscape of diverticular disease. Genome-wide analyses identify 42 risk loci for diverticular disease, 39 of which are new. Genes in associated regions are enriched for expression in connective tissue cell types and are coexpressed with genes involved in vascular and mesenchymal biology.

Although keyword auctions are often studied in the context of a single keyword in the literature, firms generally have to participate in multiple keyword auctions at the same time. Advertisers purchase a variety of keywords that can be categorized as generic-relevant, focal-brand, and competing-brand keywords. At the same time, firms also have to choose how the keywords can be matched to search queries: exact, phrase, or broad. This study empirically examines how keyword categories and match types influence the performance of advertising campaigns. We build a hierarchical Bayesian model to address the endogeneity problem contained in the simultaneous equations of the click-through rate, the conversion rate, cost per click, and rank, and we use the Markov Chain Monte Carlo method to identify the parameters. Our results suggest that it is important to differentiate among the various bidding strategies for various keyword categories and match types. We also report results related to financial performance such as number of sales, profit, and return on investment for different keywords. These findings shed light on the practice of sponsored search advertising by offering insights into how to manage ad campaigns when advertisers have to bid on multiple keywords. The online appendix is available at https://doi.org/10.1287/isre.2017.0724 .

Non-alcoholic fatty liver disease (NAFLD) is caused by excess lipid accumulation in hepatocytes. Genome-wide association studies have identified a strong association of NAFLD with non-synonymous E167K amino acid mutation in the transmembrane 6 superfamily member 2 (TM6SF2) protein. The E167K mutation reduces TM6SF2 stability, and its carriers display increased hepatic lipids and lower serum triglycerides. However, the effects of TM6SF2 on hepatic lipid metabolism are not completely understood. We overexpressed wild-type or E167K variant of TM6SF2 or knocked down TM6SF2 expression in lipid-treated Huh-7 cells and used untargeted lipidomic analysis, RNAseq transcriptome analysis, and fluorescent imaging to determine changes in hepatic lipid metabolism. Both TM6SF2 knockdown and E167K overexpression increased hepatic lipid accumulation, while wild-type overexpression decreased acylglyceride levels. We also observed lipid chain remodeling for acylglycerides by TM6SF2 knockdown, leading to a relative increase in species with shorter, more saturated side chains. RNA-sequencing revealed differential expression of several lipid metabolizing genes, including genes belonging to AKR1 family and lipases, primarily in cells with TM6SF2 knockdown. Taken together, our data show that overexpression of TM6SF2 gene or its loss-of-function changes hepatic lipid species composition and expression of lipid metabolizing genes. Additionally, our data further confirms a loss-of-function effect for the E167K variant.

Context Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. Objective Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. Design Genetics of Obesity-associated Liver Disease Consortium. Setting Population-based. Main Outcome Computed tomography measured liver attenuation. Results Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. Conclusions These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.