Structurally divergent and recurrently mutated regions of primate genomes.

We sequenced and assembled using multiple long-read sequencing technologies the genomes of chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, owl monkey, and marmoset. We identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. We estimate that 819.47 Mbp or ∼27% of the genome has been affected by SVs across primate evolution. We identify 1,607 structurally divergent regions wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (e.g., CARD, C4, and OLAH gene families) and additional lineage-specific genes are generated (e.g., CKAP2, VPS36, ACBD7, and NEK5 paralogs), becoming targets of rapid chromosomal diversification and positive selection (e.g., RGPD gene family). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species.

DROEG: a method for cancer drug response prediction based on omics and essential genes integration.

Predicting therapeutic responses in cancer patients is a major challenge in the field of precision medicine due to high inter- and intra-tumor heterogeneity. Most drug response models need to be improved in terms of accuracy, and there is limited research to assess therapeutic responses of particular tumor types. Here, we developed a novel method DROEG (Drug Response based on Omics and Essential Genes) for prediction of drug response in tumor cell lines by integrating genomic, transcriptomic and methylomic data along with CRISPR essential genes, and revealed that the incorporation of tumor proliferation essential genes can improve drug sensitivity prediction. Concisely, DROEG integrates literature-based and statistics-based methods to select features and uses Support Vector Regression for model construction. We demonstrate that DROEG outperforms most state-of-the-art algorithms by both qualitative (prediction accuracy for drug-sensitive/resistant) and quantitative (Pearson correlation coefficient between the predicted and actual IC50) evaluation in Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopedia datasets. In addition, DROEG is further applied to the pan-gastrointestinal tumor with high prevalence and mortality as a case study at both cell line and clinical levels to evaluate the model efficacy and discover potential prognostic biomarkers in Cisplatin and Epirubicin treatment. Interestingly, the CRISPR essential gene information is found to be the most important contributor to enhance the accuracy of the DROEG model. To our knowledge, this is the first study to integrate essential genes with multi-omics data to improve cancer drug response prediction and provide insights into personalized precision treatment.

A Polynesian-specific copy number variant encompassing the MICA gene associates with gout.

Gout is of particularly high prevalence in the Maori and Pacific (Polynesian) populations of Aotearoa New Zealand (NZ). Here, we investigated the contribution of common population-specific copy number variation (CNV) to gout in the Aotearoa NZ Polynesian population. Microarray-generated genome-wide genotype data from Aotearoa NZ Polynesian individuals with (n = 1196) and without (n = 1249) gout were analyzed. Comparator population groups were 552 individuals of European ancestry and 1962 of Han Chinese ancestry. Levels of circulating major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) were measured by enzyme-linked immunosorbent assay. Fifty-four CNV regions (CNVRs) appearing in at least 10 individuals were detected, of which seven common (>2%) CNVRs were specific to or amplified in Polynesian people. A burden test of these seven revealed associations of insertion/deletion with gout (odds ratio (OR) 95% confidence interval [CI] = 1.80 [1.01; 3.22], P = 0.046). Individually testing of the seven CNVRs for association with gout revealed nominal association of CNVR1 with gout in Western Polynesian (Chr6: 31.36-31.45 Mb, OR = 1.72 [1.03; 2.92], P = 0.04), CNVR6 in the meta-analyzed Polynesian sample sets (Chr1: 196.75-196.92 Mb, OR = 1.86 [1.16; 3.00], P = 0.01) and CNVR9 in Western Polynesian (Chr1: 189.35-189.54 Mb, OR = 2.75 [1.15; 7.13], P = 0.03). Analysis of European gout genetic association data demonstrated a signal of association at the CNVR1 locus that was an expression quantitative trait locus for MICA. The most common CNVR (CNVR1) includes deletion of the MICA gene, encoding an immunomodulatory protein. Expression of MICA was reduced in the serum of individuals with the deletion. In summary, we provide evidence for the association of CNVR1 containing MICA with gout in Polynesian people, implicating class I MHC-mediated antigen presentation in gout.

Epidemiologic and genetic associations between primary biliary cholangitis and extrahepatic rheumatic diseases.

Patients with primary biliary cholangitis (PBC) commonly experience extrahepatic rheumatic diseases. However, the epidemiologic and genetic associations as well as causal relationship between PBC and these extrahepatic conditions remain undetermined. In this study, we first conducted systematic review and meta-analyses by analyzing 73 studies comprising 334,963 participants across 17 countries and found strong phenotypic associations between PBC and rheumatic diseases. Next, we utilized large-scale genome-wide association study summary data to define the shared genetic architecture between PBC and rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Sjögren's syndrome (SS). We observed significant genetic correlations between PBC and each of the four rheumatic diseases. Pleiotropy and heritability enrichment analysis suggested the involvement of humoral immunity and interferon-associated processes for the comorbidity. Of note, we identified four variants shared between PBC and RA (rs80200208), SLE (rs9843053), and SSc (rs27524, rs3873182) using cross-trait meta-analysis. Additionally, several pleotropic loci for PBC and rheumatic diseases were found to share causal variants with gut microbes possessing immunoregulatory functions. Finally, Mendelian randomization revealed consistent evidence for a causal effect of PBC on RA, SLE, SSc, and SS, but no or inconsistent evidence for a causal effect of extrahepatic rheumatic diseases on PBC. Our study reveals a profound genetic overlap and causal relationships between PBC and extrahepatic rheumatic diseases, thus providing insights into shared biological mechanisms and novel therapeutic interventions.

The role of gut microbiota in chronic restraint stress-induced cognitive deficits in mice.

BACKGROUND: Chronic stress induces cognitive deficits. There is a well-established connection between the enteric and central nervous systems through the microbiota-gut-brain (MGB) axis. However, the effects of the gut microbiota on cognitive deficits remain unclear. The present study aimed to elucidate the microbiota composition in cognitive deficits and explore its potential in predicting chronic stress-induced cognitive deficits. METHODS: Mice were randomly divided into control and chronic restraint stress (CRS) groups. The mice subjected to CRS were further divided into cognitive deficit (CRS-CD) and non-cognitive deficit (CRS-NCD) groups using hierarchical cluster analysis of novel object recognition test results. The composition and diversity of the gut microbiota were analyzed. RESULTS: After being subjected to chronic restraint distress, the CRS-CD mice travelled shorter movement distances (p = 0.034 vs. CRS-NCD; p < 0.001 vs. control) and had a lower recognition index than the CRS-NCD (p < 0.0001 vs. CRS-NCD; p < 0.0001 vs. control) and control mice. The results revealed that 5 gut bacteria at genus levels were significantly different in the fecal samples of mice in the three groups. Further analyses demonstrated that Muricomes were not only significantly enriched in the CRS-CD group but also correlated with a decreased cognitive index. The area under the receiver operating curve of Muricomes for CRS-induced cognitive deficits was 0.96. CONCLUSIONS: Our study indicates that the composition of the gut microbiota is involved in the development of cognitive deficits induced by chronic restraint stress. Further analysis revealed that Muricomes have the potential to predict the development of chronic stress-induced cognitive deficits in mice.

Transport Pathways of Nitrate in Stormwater Runoff Inferred from High-Frequency Sampling and Stable Water Isotopes.

Storm events can mobilize nitrogen species from landscapes into streams, exacerbating eutrophication and threatening aquatic ecosystems as well as human health. However, the transport pathways and storm responses of different nitrogen forms remain elusive. We used high-frequency chemical and isotopic sampling to partition sources of stormwater runoff and determine transport pathways of multiple nitrogen forms in an agricultural catchment. Bayesian mixing modeling reveals shallow subsurface water as the dominant source of stormwater runoff, contributing 74% of the water flux and 72, 71, and 79% of total nitrogen (TN), total dissolved nitrogen (TDN), and nitrate (NO3-N), respectively. Groundwater, by contrast, contributed 11% of stormwater runoff and 21, 22, and 17% of TN, TDN, and NO3-N, respectively. The remaining 14% of stormwater runoff can be attributed to rainwater, which contains much less TN, TDN, and NO3-N. Surprisingly, during storm events, the dominant nitrogen form was NO3-N rather than dissolved organic nitrogen. Antecedent conditions and runoff characteristics have an important influence on nitrogen loads during storm events. Our results provide insight into hydrological mechanisms driving nitrogen transport during storm events and may help in developing catchment management practices for reducing nitrogen pollution in aquatic ecosystems.

Effects of Dexmedetomidine on Systemic Inflammation and Postoperative Complications in Laparoscopic Pancreaticoduodenectomy: A Double-blind Randomized Controlled Trial.

BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) may induce intense inflammatory response which might be related to the patient's outcomes. Clinical dexmedetomidine (DEX) has been widely used for opioid-sparing anesthesia and satisfactory sedation. The objective of this study was to investigate the influence of DEX on inflammatory response and postoperative complications in LPD. METHODS: Ninety-nine patients undergoing LPD were randomly assigned to two groups: normal saline (NS) and DEX. The primary outcome was the neutrophil-to-lymphocyte ratio (NLR) differences postoperatively within 48 h. Secondary outcomes were postoperative complications, the length of postoperative hospital stay and the incidence of ICU admission. Other outcomes included anesthetics consumption and intraoperative vital signs. RESULTS: NLR at postoperative day 2 to baseline ratio decreased significantly in the DEX group (P = 0.032). Less major complications were observed in the DEX group such as pancreatic fistula, delayed gastric emptying and intra-abdominal infection (NS vs. DEX, 21.7% vs. 13.6%, P = 0.315; 10.9% vs. 2.3%, P = 0.226; 17.4% vs. 11.4%, P = 0.416, respectively) though there were no statistical differences. Three patients were transferred to the ICU after surgery in the NS group, while there was none in the DEX group (P = 0.242). The median postoperative hospital stay between groups were similar (P = 0.313). Both intraoperative propofol and opioids were less in the DEX group (P < 0.05). CONCLUSIONS: Intraoperative DEX reduced the early postoperative inflammatory response in LPD. It also reduced the use of narcotics that may related to reduced major complications, which need additional research further.

Genome-Wide Association Study of Obstructive Sleep Apnea and Objective Sleep-related Traits Identifies Novel Risk Loci in Han Chinese Individuals.

Rationale: Previous genetic studies of obstructive sleep apnea (OSA) have limitations in terms of precise case definition, integrated quantitative traits, and interpretation of genetic functions; thus, the heritability of OSA remains poorly explained. Objectives: To identify novel genetic variants associated with OSA and objective sleep-related traits and to explore their functional roles. Methods: A genome-wide association study was performed in 20,590 Han Chinese individuals (5,438 OSA and 15,152 control samples). Human samples and point mutation knockin mice were used for follow-up investigation of gene functions. Measurements and Main Results: Two characteristic study-wide significant loci (P < 2.63 × 10-9) for OSA were identified: the PACRG intronic variant rs6455893 on 6q26 (odds ratio [OR] = 1.62; 95% confidence interval [CI], 1.39-1.89; P = 6.98 × 10-10) and the missense variant rs3746804 (p.Pro267Leu) in the riboflavin transporter SLC52A3 on 20p13 (OR = 0.83; 95% CI, 0.79-0.88; P = 7.57 × 10-10). In addition, 18 genome-wide significant loci associated with quantitative OSA and objective sleep-related traits were identified, 5 of which exceeded the study-wide significance threshold. Rs3746804 was associated with elevated serum riboflavin concentrations, and the corresponding mutation in mice increased riboflavin concentrations, suggesting that this variant may facilitate riboflavin uptake and riboflavin-dependent physiological activity. Conclusions: We identified several novel genome-wide significant loci associated with OSA and objective sleep-related traits. Our findings provide insight into the genetic architecture of OSA and suggest that SLC52A3 might be a therapeutic target, whereas riboflavin might be a therapeutic agent.

Effects of Propofol on Perioperative Sleep Quality in Patients Undergoing Gastrointestinal Endoscopy: A Prospective Cohort Study.

PURPOSE: Some patients experience sleep disturbances after endoscopy performed under sedation. This study aimed to evaluate the effects of propofol on sleep quality after gastrointestinal endoscopy (GE). DESIGN: This study was a prospective cohort study. METHODS: This study enrolled 880 patients who underwent GE. Patients who chose to undergo GE under sedation received intravenous propofol, whereas the control group did not. The Pittsburgh Sleep Quality Index (PSQI) was measured before GE (PSQI-1) and 3 weeks (PSQI-2) after GE. The Groningen Sleep Score Scale (GSQS) was used before GE (GSQS-1) and 1 (GSQS-2) and 7 days (GSQS-3) after GE. FINDINGS: There was a significant increase in GSQS scores from baseline to days 1 and 7 after GE (GSQS-2 vs GSQS-1, P < .001, GSQS-3 vs GSQS-1, P = .008). However, no significant changes were observed in the control group (GSQS-2 vs GSQS-1, P = .38, GSQS-3 vs GSQS-1, P = .66). On day 21, there were no significant changes in the baseline PSQI scores over time in either group (sedation group, P = .96; control group, P = .95). CONCLUSIONS: GE with propofol sedation negatively affected sleep quality for 7 days after GE but not 3 weeks after GE.

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control.

High serum urate is a prerequisite for gout and associated with metabolic disease. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control; however, there has been little progress in understanding the molecular basis of the associated loci. Here, we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify 10 new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new candidate loci. By cis- and trans-eQTL colocalization analysis, we identified 34 and 20 genes, respectively, where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was SLC22A9 that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane; MLXIP that, with the previously identified MLXIPL, is a transcription factor that may regulate serum urate via the pentose-phosphate pathway and MRPS7 and IDH2 that encode proteins necessary for mitochondrial function. Functional fine mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1 and HNF4G) with colocalized eQTL containing putative causal SNPs. This systematic analysis of serum urate GWAS loci identified candidate causal genes at 24 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis.

BACKGROUND & AIMS: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). CONCLUSIONS: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Colchicine prophylaxis is associated with fewer gout flares after COVID-19 vaccination.

OBJECTIVES: COVID-19 vaccination often triggers a constellation of transitory inflammatory symptoms. Gout is associated with several comorbidities linked to poor outcomes in COVID-19, and gout flares can be triggered by some vaccinations. We analysed the risk of gout flares in the first 3 months after COVID-19 vaccination with inactivated virus, and whether colchicine can prevent gout flares following post-COVID-19 vaccination. METHODS: A clinical delivery population-based cross-sectional study was conducted in the Gout Clinic at the Affiliated Hospital of Qingdao University between February and October 2021. Study participants were selected using a systematic random sampling technique among follow-up patients with gout. We collected data, including vaccinations and potential risk factors, using a combination of interviews, health QR codes and medical records. Logistic regression was used to adjust for covariates. RESULTS: We enrolled 549 gout participants (median age 39 years, 84.2% vaccinated). For the 462 patients who received COVID-19 vaccine, 203 (43.9%) developed at least one gout flare in the 3 months after vaccination. Most of these flares were experienced within 1 month after the first (99/119 (83.2%)) or second (70/115 (60.9%)) dose of vaccine. Compared with unvaccinated participants, COVID-19 vaccination was associated with higher odds of gout flare within 3 months (adjusted OR 6.02; 95% CI 3.00 to 12.08). Colchicine use was associated with 47% less likelihood of postvaccine gout flare. CONCLUSION: COVID-19 vaccination was associated with increased odds of gout flare, which developed mainly in month 1 after each vaccine dose, and was negatively associated with colchicine prophylaxis.

Effects of lidocaine administration via the perforated outer cuff of a dual-cuff endotracheal tube and remifentanil administration on recovery from general anaesthesia for female patients undergoing thyroidectomy: a single centre, double-blind, randomised study.

BACKGROUND: Cough caused by endotracheal tube (ETT) placement is ubiquitous and correlates with adverse outcomes. Remifentanil administration via target-controlled infusion (TCI) is one of the cough prevention measures used during recovery. In a pilot study, lidocaine administered via the perforated outer cuff of a dual-cuff endotracheal tube was also found to prevent cough due to ETT placement. We therefore compared these two cough prevention approaches during recovery after thyroidectomy in a single-centre, double-blind, randomised study conducted in China during the period from 09/10/2020 to 30/04/2021. METHODS: Ninety-eight female patients aged 18-65 years with American Society of Anaesthesiologists Physical Status scores of I and II were scheduled to undergo thyroidectomy. The ETT contained an internal cuff covered by a perforated outer cuff to allow for lidocaine delivery. Patients were randomised to receive either 4 ml of saline solution (Group R, n = 49) or 4 ml of 2% lidocaine in the outer cuff (Group L, n = 49) at the beginning of skin suturing. Remifentanil (2 ng/ml) was maintained in Group R until extubation, while remifentanil was maintained in Group L until the end of skin suturing. The primary outcome was cough during patient transfer, at 1 min before extubation, and at extubation. The secondary outcomes were haemodynamics and other recovery parameters. RESULTS: Primary outcomes were compared between remifentanil vs. lidocaine application, namely, the incidence of cough during patient transfer (0% in Group R vs. 0% in Group L), at 1 min before extubation (22.45% in Group R vs. 4.08% in Group L; P = 0.015), and at extubation (61.22% in Group R vs. 20.41% in Group L; P < 0.001). Compared with remifentanil, lidocaine more effectively decreased heart rate elevation and hypoxemia at 5 min after extubation, the spontaneous respiration recovery time, the extubation time, the duration of post-anaesthesia care unit (PACU) stay, Richmond Agitation-Sedation Scale scores in the agitated range and Critical-Care Pain Observation Tool scores. CONCLUSION: Lidocaine administered via the perforated outer cuff of the ETT significantly improved recovery from general anaesthesia compared to remifentanil in female patients after thyroidectomy. TRIAL REGISTRATION: Chinese Clinical Trial Registry (No. ChiCTR2000038653), registered on 27/09/2020.

Curcumin Ameliorates the Experimental Diabetic Peripheral Neuropathy through Promotion of NGF Expression in Rats.

Increasing evidence suggested that inhibiting the apoptosis of Schwann cells (SCs) and promoting nerve growth factor (NGF) expression in sciatic nerves play key roles in preventing the onset of diabetic peripheral neuropathy (DPN). Curcumin, a primary bioactive substance in turmeric with multiple characteristics, has been shown to have many therapeutic effects in a variety of diseases. However, curcumin is poorly studied in the DPN models. We aimed to explore the therapeutic benefits and underlying mechanism of curcumin in high fat/sugar diets joint streptozotocin (STZ)-induced DPN rat models. Sprague-Dawley (SD) rats were divided into five groups (6 rats per group), control group, DPN group, Curcumin groups (50, 100, and 150 mg/kg). Curcumin was administered intragastrically once per day for 4 continuous weeks. Body weight (BW) and fasting blood glucose (FBG) were monitored in all groups. The mechanical withdraw threshold (MWT) was measured. We also assessed neuropathic change by testing nerve conductance velocity (NCV) in sciatic nerves. TEM was applied to observe the sciatic nerves ultrastructure. The SCs apoptosis in sciatic nerves was stained using TUNEL kit. NGF contents in sciatic nerves and serum were detected using western blotting and ELISA analysis. The results showed curcumin had no obvious effect on the BW and FBG change. Curcumin (100 and 150 mg/kg) attenuated the MWT, NCV, and sciatic nerves ultrastructure in DPN rats. Curcumin (50, 100 and 150 mg/kg) reduced SCs apoptosis in sciatic nerves. In addition, curcumin at 150 mg/kg had the best efficacy in increasing protein expression of NGF in sciatic nerves and serum NGF level. Our work demonstrated that curcumin has neuroprotective effects for the treatment of DPN.

Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection.

The development of cervical cancer is initiated by human papillomavirus (HPV) infection and involves both viral and host genetic factors. Genome-wide association studies (GWAS) of cervical cancer have identified associations in the HLA locus and two loci outside HLA, but the principal genes that control infection and pathogenesis have not been identified. In the present study, we performed GWAS of cervical cancer in East Asian populations, involving 2609 cases and 4712 controls in the discovery stage and 1461 cases and 3295 controls in the follow-up stage. We identified novel-significant associations at 5q14 with the lead single nucleotide polymorphism (SNP) rs59661306 (P = 2.4 × 10-11) and at 7p11 with the lead SNP rs7457728 (P = 1.2 × 10-8). In 5q14, the chromatin region of the GWAS-significant SNPs was found to be in contact with the promoter of the ARRDC3 (arrestin domain-containing 3) gene. In our functional studies, ARRDC3 knockdown in HeLa cells caused significant reductions in both cell growth and susceptibility to HPV16 pseudovirion infection, suggesting that ARRDC3 is involved in the infectious entry of HPV into the cell. Our study advances the understanding of host genes that are responsible for cervical cancer susceptibility and guides future research on HPV infection and cancer development.

An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs.

BACKGROUNDS & AIMS: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. METHODS: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. RESULTS: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. CONCLUSIONS: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. LAY SUMMARY: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.

Trans-ancestral dissection of urate- and gout-associated major loci SLC2A9 and ABCG2 reveals primate-specific regulatory effects.

Gout is a complex inflammatory arthritis affecting ~20% of people with an elevated serum urate level (hyperuricemia). Gout and hyperuricemia are essentially specific to humans and other higher primates, with varied prevalence across ancestral groups. SLC2A9 and ABCG2 are major loci associated with both urate and gout in multiple ancestral groups. However, fine mapping has been challenging due to extensive linkage disequilibrium underlying the associated regions. We used trans-ancestral fine mapping integrated with primate-specific genomic information to address this challenge. Trans-ancestral meta-analyses of GWAS cohorts of either European (EUR) or East Asian (EAS) ancestry resulted in single-variant resolution mappings for SLC2A9 (rs3775948 for urate and rs4697701 for gout) and ABCG2 (rs2622621 for gout). Tests of colocalization of variants in both urate and gout suggested existence of a shared candidate causal variant for SLC2A9 only in EUR and for ABCG2 only in EAS. The fine-mapped gout variant rs4697701 was within an ancient enhancer, whereas rs2622621 was within a primate-specific transposable element, both supported by functional evidence from the Roadmap Epigenomics project in human primary tissues relevant to urate and gout. Additional primate-specific elements were found near both loci and those adjacent to SLC2A9 overlapped with known statistical epistatic interactions associated with urate as well as multiple super-enhancers identified in urate-relevant tissues. We conclude that by leveraging ancestral differences trans-ancestral fine mapping has identified ancestral and functional variants for SLC2A9 or ABCG2 with primate-specific regulatory effects on urate and gout.

Cigarette smoking and schizophrenia: Mendelian randomisation study.

BACKGROUND: The link between schizophrenia and cigarette smoking has been well established through observational studies. However, the cause-effect relationship remains unclear. AIMS: We conducted Mendelian randomisation analyses to assess any causal relationship between genetic variants related to four smoking-related traits and the risk of schizophrenia. METHOD: We performed a two-sample Mendelian randomisation using summary statistics from genome-wide association studies (GWAS) of smoking-related traits and schizophrenia (7711 cases, 18 327 controls) in East Asian populations. Single nucleotide polymorphisms (SNPs) correlated with smoking behaviours (smoking initiation, smoking cessation, age at smoking initiation and quantity of smoking) were investigated in relation to schizophrenia using the inverse-variance weighted (IVW) method. Further sensitivity analyses, including Mendelian randomisation-Egger (MR-Egger), weighted median estimates and leave-one-out analysis, were used to test the consistency of the results. RESULTS: The associated SNPs for the four smoking behaviours were not significantly associated with schizophrenia status. Pleiotropy did not inappropriately affect the results. CONCLUSIONS: Cigarette smoking is a complex behaviour in people with schizophrenia. Understanding factors underlying the observed association remains important; however, our findings do not support a causal role of smoking in influencing risk of schizophrenia.

Identification of rare and common variants in BNIP3L: a schizophrenia susceptibility gene.

BACKGROUND: Schizophrenia is a chronic and severe mental disorder, and it has been predicted to be highly polygenic. Common SNPs located in or near BNIP3L were found to be genome-wide significantly associated with schizophrenia in recent genome-wide association studies. The purpose of our study is to investigate potential causal variants in BNIP3L gene. RESULTS: We performed targeted sequencing for all exons and un-translated regions of BNIP3L gene among 1806 patients with schizophrenia and 998 healthy controls of Han Chinese origin. Three rare nonsynonymous mutations, BNIP3L (NM_004331): c.52A>G, c.167G>A and c.313A>T, were identified in schizophrenia cases, and two of them were newly reported. The frequencies of these rare nonsynonymous mutations were significantly different between schizophrenia cases and healthy controls. For the common variants, rs147389989 achieved significance in both allelic and genotypic distributions with schizophrenia. Rs1042992 and rs17310286 were significantly associated with schizophrenia in meta-analyses using PGC, CLOZUK, and our new datasets in this study. CONCLUSIONS: Our findings provided further evidence that BNIP3L gene is a susceptibility gene of schizophrenia and revealed functional and potential causal mutations in BNIP3L. However, more functional validations are suggested to better understand the role of BNIP3L in the etiology of schizophrenia.

Performance comparison of four types of target enrichment baits for exome DNA sequencing.

BACKGROUND: Next-generation sequencing technology is developing rapidly and target capture sequencing has become an important technique. Several different platforms for library preparation and target capture with different bait types respectively are commercially available. Here we compare the performance of the four platforms with different bait types to find out their advantages and limitations. The purpose of this study is to help investigators and clinicians select the appropriate platform for their particular application and lay the foundation for the development of a better target capture platform for next-generation sequencing. RESULTS: We formulate capture efficiency as a novel parameter that can be used to better evaluations of specificity and coverage depth among the different capture platforms. Target coverage, capture efficiency, GC bias, AT Dropout, sensitivity in single nucleotide polymorphisms, small insertions and deletions detection, and the feature of each platform were compared for low input samples. In general, all platforms perform well and small differences among them are revealed. In our results, RNA baits have stronger binding power than DNA baits, and with ultra deep sequencing, double stranded RNA baits perform better than single stranded RNA baits in all aspects. DNA baits got better performance in the region with high GC content and RNA baits got lower AT dropout suggesting that the binding power is different between DNA and RNA baits to genome regions with different characteristics. CONCLUSIONS: The platforms with double stranded RNA baits have the most balanced capture performance. Our results show the key differences in performance among the four updated platforms with four different bait types. The better performance of double stranded RNA bait with ultra deep sequencing suggests that it may improve the sensitivity of ultra low frequent mutation detection. In addition, we further propose that the mixed baits of double stranded RNA and single stranded DNA may improve target capture performance.