Gender specific SNP markers in Coscinium fenestratum (Gaertn.) Colebr. for resource augmentation.

BACKGROUND: Unregulated extraction of highly traded medicinal plant species results in drastic decline of the natural resources and alters viable sex ratio of populations. Conservation and long-term survival of such species, require gender specific restoration programs to ensure reproductive success. However, it is often difficult to differentiate sex of individuals before reaching reproductive maturity. C. fenestratum is one of the medicinally important and overexploited dioecious woody liana, with a reproductive maturity of 15 years. Currently, no information is available to identify sex of C. fenestratum in seedling stage while augmenting the resources. Thus, the current study envisages to utilize transcriptomics approach for gender differentiation which is imperative for undertaking viable resource augmentation programmes. METHODS AND RESULTS: Gender specific SNPs with probable role in sexual reproduction/sex determination was located using comparative transcriptomics approach (sampling male and female individuals), alongside gene ontology and annotation. Nine sets of primers were synthesized from 7 transcripts (involved in sexual reproduction/other biological process) containing multiple SNP variants. Out of the nine primer pairs, only one SNP locus with no available information of its role in reproduction, showed consistent and accurate results (males-heterozygous and females-homozygous), in the analyzed 40 matured individuals of known sexes. Thus validated the efficiency of this SNP marker in differentiating male and female individuals. CONCLUSIONS: The study could identify SNPs linked to the loci with apparent role in gender differentiation. This SNP marker can be used for early sexing of seedlings for in-situ conservation and resource augmentation of C. fenestratum in Kerala, India.

Genetic variation supports a causal role for valproate in prevention of ischemic stroke.

BACKGROUND: Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. AIMS: We applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. METHODS: We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. As replication, we tested found associations in an independent cohort of valproate users of the Mass General Brigham Biobank. RESULTS: Among 2150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12 year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per 1 standard deviation (SD), 95% confidence interval (CI) (3.45, 8.11)). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (hazard ratio (HR) per 1 SD 0.73, 95% CI (0.58, 0.91)) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p trend = 0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per 1 SD 0.53, 95% CI (0.32, 0.86)) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs 13/71, 18.3%, p trend = 0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p = 0.61), suggesting minimal pleiotropy. In 1241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per 1 SD 0.77, 95% CI (0.61, 0.97)). CONCLUSION: These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention. DATA ACCESS STATEMENT: UK Biobank participant data are available after approval of a research proposal. The weights of the used genetic scores are available in the Supplemental Tables.

Fluorescence detection of apolipoprotein E gene polymorphisms based on oligonucleotide ligation and magnetic separation.

Alzheimer's disease is a progressive neurodegenerative condition that causes brain cell death and is the leading cause of dementia. Most patients with Alzheimer's disease are diagnosed with late-onset Alzheimer's disease (LOAD), with apolipoprotein E (APOE) genotypes being highly associated with the frequency of LOAD risk. A fluorescence detection system coupled with oligonucleotide ligation and magnetic separation was developed to identify two single-nucleotide polymorphisms (SNPs) for the APOE gene and recognize APOE alleles for LOAD. The system utilized a fluorescence probe with one base-discriminating nucleoside for SNP (F probe) and a perfectly complementary biotin-modified sequence against the target DNA (P probe). When the F and P probes matched the target DNA sequences, DNA ligation occurred, and ligation products were produced. Streptavidin magnetic beads were subsequently employed to remove the ligation products, and a decrease in fluorescence intensity was observed in the supernatant compared to when there was no target DNA. This system detected two SNPs of APOE alleles, namely rs429358 and rs7412. The results indicated that the R-values ((F0 - F1)/F0) for rs429358 were 0.92 ± 0.002 for the T/T target, 0.47 ± 0.004 for the T/C target and 0.11 ± 0.004 for the C/C target, respectively. The R-values for rs7412 were 0.73 ± 0.009 for the C/C target, 0.42 ± 0.001 for the C/T target and 0.16 ± 0.007 for the T/T target, respectively. F0 and F1 represent the fluorescence intensity of the F probe without and with target DNA, respectively. Based on fluorescence intensity, the fluorescence detection system was able to identify the genotypes of the APOE gene accurately to evaluate the risk of Alzheimer's disease.

Association between intake of the n-3 polyunsaturated fatty acid docosahexaenoic acid (n-3 PUFA DHA) and reduced risk of ovarian cancer: A systematic Mendelian Randomization study.

BACKGROUND & AIMS: Whether the intake of docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, is beneficial for ovarian cancer (OC) remains controversial and we hope to disentangle this puzzle using genetic data from large-scale populations in European and Asian. METHODS: We employed, for the first time, a systematic Mendelian randomization (MR) design to comprehensively evaluate the causal effect of plasma DHA levels, an objective biomarker of DHA intake, on OC risk in European and then verified the extrapolation of the results in the Asian. Data in the analysis included genetic association data obtained from large-scale genome-wide association studies with 13,499 individuals for plasma DHA measurements and 66,450 individuals for OC in the European population, and 1361 individuals for plasma DHA measurements and 61,457 individuals for OC in the Asian population. The causal relationship between DHA and OC was estimated using the inverse-variance weighted approach, together with extensive validation and sensitivity analyses to verify the main results. RESULTS: In the European population, MR evidence suggested a causal relationship between higher plasma DHA levels and lower OC risk (OR, 0.89 for OC per one-SD increment in DHA; 95% CI, 0.83 to 0.96; P = 0.003). Subgroup analysis by histological type of OC indicated that this observed association was stronger among endometrioid ovarian cancer (EOC) (OR, 0.82; 95% CI, 0.69 to 0.96; P = 0.014). A similar causal association of borderline significance was reached in the Asian replication set. The above results were consistently supported by a series of validation and sensitivity analyses. CONCLUSION: Our study provided robust genetic evidence for a protective association between plasma DHA levels and lower risk of OC, especially EOC, in the European population. These findings may inform prevention strategies and interventions directed towards DHA intake and OC.

Evaluating the distinct pleiotropic effects of omega-3 fatty acids on type 2 diabetes mellitus: a mendelian randomization study.

BACKGROUND: Observational studies and conventional Mendelian randomization (MR) studies showed inconclusive evidence to support the association between omega-3 fatty acids and type 2 diabetes. We aim to evaluate the causal effect of omega-3 fatty acids on type 2 diabetes mellitus (T2DM), and the distinct intermediate phenotypes linking the two. METHODS: Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty acids (N = 114,999) from UK Biobank and outcome data obtained from a large-scale T2DM GWAS (62,892 cases and 596,424 controls) in European ancestry. MR-Clust was applied to determine clustered genetic instruments of omega-3 fatty acids that influences T2DM. Two-step MR analysis was used to identify potential intermediate phenotypes (e.g. glycemic traits) that linking omega-3 fatty acids with T2DM. RESULTS: Univariate MR showed heterogenous effect of omega-3 fatty acids on T2DM. At least two pleiotropic effects between omega-3 fatty acids and T2DM were identified using MR-Clust. For cluster 1 with seven instruments, increasing omega-3 fatty acids reduced T2DM risk (OR: 0.52, 95%CI 0.45-0.59), and decreased HOMA-IR (ß = - 0.13, SE = 0.05, P = 0.02). On the contrary, MR analysis using 10 instruments in cluster 2 showed that increasing omega-3 fatty acids increased T2DM risk (OR:1.10; 95%CI 1.06-1.15), and decreased HOMA-B (ß = - 0.04, SE = 0.01, P = 4.52 × 10-5). Two-step MR indicated that increasing omega-3 fatty acid levels decreased T2DM risk via decreasing HOMA-IR in cluster 1, while increased T2DM risk via decreasing HOMA-B in cluster 2. CONCLUSIONS: This study provides evidence to support two distinct pleiotropic effects of omega-3 fatty acids on T2DM risk influenced by different gene clusters, which could be partially explained by distinct effects of omega-3 fatty acids on insulin resistance and beta cell dysfunction. The pleiotropic feature of omega-3 fatty acids variants and its complex relationships with T2DM need to be carefully considered in future genetic and clinical studies.

COMT Val158Met Affects the Analgesic Response to Acupuncture Among Cancer Survivors With Chronic Pain.

Catechol-O-methyltransferase (COMT) is the major enzyme involved in the catabolism of dopamine, a neurotransmitter in the brain's reward system. The common COMT polymorphism Val158Met (rs4680 G>A) modulates pain response to opioids through a reward-motivated mechanism; however, its role in nonpharmacological pain medicine has not been clinically characterized. We genotyped 325 participants from a randomized controlled trial of cancer survivors with chronic musculoskeletal pain. We found that carrying methionine at position 158 (158Met) of COMT, encoded by the A allele, significantly increased the analgesic response to electroacupuncture (74% vs 50%; odds ratio [OR]: 2.79; 95% confidence interval [CI]: 1.31, 6.05; P < .01), but not to auricular acupuncture (68% vs 60%; OR: 1.43; 95% CI: .65, 3.12; P = .37) or usual care (24% vs 18%; OR: 1.46; 95% CI: .38, 7.24; P = .61) compared to Val/Val. These findings raise the possibility that COMT Val158Met might be an important predictor of analgesic response to electroacupuncture, providing novel insights into precision nonpharmacologic pain management tailored to individual genetic backgrounds. PERSPECTIVE: This work suggests the modulating effects of the polymorphism in COMT Val158Met on the response to acupuncture. Further research needs to validate these findings, increase the mechanistic understanding of acupuncture, and guide further development of acupuncture as a precision pain management strategy.

Genome-wide association study of leaf-related traits in tea plant in Guizhou based on genotyping-by-sequencing.

BACKGROUND: Studying the genetic characteristics of tea plant (Camellia spp.) leaf traits is essential for improving yield and quality through breeding and selection. Guizhou Plateau, an important part of the original center of tea plants, has rich genetic resources. However, few studies have explored the associations between tea plant leaf traits and single nucleotide polymorphism (SNP) markers in Guizhou. RESULTS: In this study, we used the genotyping-by-sequencing (GBS) method to identify 100,829 SNP markers from 338 accessions of tea germplasm in Guizhou Plateau, a region with rich genetic resources. We assessed population structure based on high-quality SNPs, constructed phylogenetic relationships, and performed genome-wide association studies (GWASs). Four inferred pure groups (G-I, G-II, G-III, and G-IV) and one inferred admixture group (G-V), were identified by a population structure analysis, and verified by principal component analyses and phylogenetic analyses. Through GWAS, we identified six candidate genes associated with four leaf traits, including mature leaf size, texture, color and shape. Specifically, two candidate genes, located on chromosomes 1 and 9, were significantly associated with mature leaf size, while two genes, located on chromosomes 8 and 11, were significantly associated with mature leaf texture. Additionally, two candidate genes, located on chromosomes 1 and 2 were identified as being associated with mature leaf color and mature leaf shape, respectively. We verified the expression level of two candidate genes was verified using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and designed a derived cleaved amplified polymorphism (dCAPS) marker that co-segregated with mature leaf size, which could be used for marker-assisted selection (MAS) breeding in Camellia sinensis. CONCLUSIONS: In the present study, by using GWAS approaches with the 338 tea accessions population in Guizhou, we revealed a list of SNPs markers and candidate genes that were significantly associated with four leaf traits. This work provides theoretical and practical basis for the genetic breeding of related traits in tea plant leaves.

Association of regular glucosamine use with incident dementia: evidence from a longitudinal cohort and Mendelian randomization study.

BACKGROUND: Emerging data suggests the neuroprotective and anti-neuroinflammatory effects of glucosamine. We aimed to examine the association between regular glucosamine use and risk of incident dementia, including dementia subtypes. METHODS: We conducted large-scale observational and two-sample Mendelian randomization (MR) analyses. Participants in UK Biobank having accessible data for dementia incidence and who did not have dementia at baseline were included in the prospective cohort. Through the Cox proportional hazard model, we examined the risks of incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia among glucosamine users and non-users. To further test the causal association between glucosamine use and dementia, we conducted a 2-sample MR utilizing summary statistics from genome-wide association studies (GWAS). The GWAS data were obtained from observational cohort participants of mostly European ancestry. RESULTS: During a median follow-up of 8.9 years, there were 2458 cases of all-cause dementia, 924 cases of AD, and 491 cases of vascular dementia. In multivariable analysis, the hazard ratios (HR) of glucosamine users for all-cause dementia, AD, and vascular dementia were 0.84 (95% CI 0.75-0.93), 0.83 (95% CI 0.71-0.98), and 0.74 (95% CI 0.58-0.95), respectively. The inverse associations between glucosamine use and AD appeared to be stronger among participants aged below 60 years than those aged above 60 years (p = 0.04 for interaction). The APOE genotype did not modify this association (p > 0.05 for interaction). Single-variable MR suggested a causal relationship between glucosamine use and lower dementia risk. Multivariable MR showed that taking glucosamine continued to protect against dementia after controlling for vitamin, chondroitin supplement use and osteoarthritis (all-cause dementia HR 0.88, 95% CI 0.81-0.95; AD HR 0.78, 95% CI 0.72-0.85; vascular dementia HR 0.73, 95% CI 0.57-0.94). Single and multivariable inverse variance weighted (MV-IVW) and MR-Egger sensitivity analyses produced similar results for these estimations. CONCLUSIONS: The findings of this large-scale cohort and MR analysis provide evidence for potential causal associations between the glucosamine use and lower risk for dementia. These findings require further validation through randomized controlled trials.

GWAS-identified bipolar disorder risk allele in the FADS1/2 gene region links mood episodes and unsaturated fatty acid metabolism in mutant mice.

Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD.

Allele mining in gene encoding fc fragment of IgG receptor, transporter, alpha (FCGRT) and association of nucleotide variants with passive transfer of immunity in neonatal buffalo calves.

BACKGROUND: Neonatal Fc receptors (FcRn) mediate the transcytosis of IgG present in colostrum across absorptive gut epithelium of newborn calves. FcRn receptor is a heterodimer composed of two polypeptides encoded by FCGRT (Fc fragment of IgG Receptor Transporter neonatal) and B2M (Beta 2 microglobulin) genes. Polymorphism in FCGRT gene may have a bearing on absorption of colostral immunoglobulins by neonatal buffalo calves, thereby affecting their immune status and susceptibility to diseases. The primary aim of our study was to mine alleles and single nucleotide polymorphs in the FCGRT gene and determine their association with the levels of IgG in serum of neonatal buffalo calves. METHODS AND RESULTS: On the basis of serum IgG levels estimated by indirect ELISA in 80 newborn calves, 20 calves each with highest and lowest IgG concentration were selected to study polymorphism in the FCGRT gene. The exonic regions of this gene were amplified in nine fragments which were subjected to PCR-SSCP to detect variations followed by the sequencing of variants to locate the SNPs. A total of nine SNPs (7 in introns and 2 in exons) were detected in four polymorphic fragments. Association study based on Odds ratios (ORs) with 95% Confidence Interval (CIs) established that the SNP G40T in fragment 3 has a significant (P < 0.05) bearing on IgG level in serum of neonatal buffalo calves. CONCLUSION: Genetic variation in FCGRT gene in buffalo calves was found to be associated with their serum IgG levels in neonatal stage which may have implications in calf survival and growth vis-à-vis inadequate transfer of passive immunity.

In silico profiling of nonsynonymous SNPs of fat mass and obesity-associated gene: possible impacts on the treatment of non-alcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver, or NAFLD, is the most common chronic liver ailment. It is characterized by excessive fat deposition in hepatocytes of individuals who consume little or no alcohol and are unaffected by specific liver damaging factors. It is also associated with extrahepatic manifestations such as chronic kidney disease, cardiovascular disease, and sleep apnea. The global burden of NAFLD is increasing at an alarming rate. However, no pharmacologically approved drugs against NAFLD are available owing to their complex pathophysiology. Genome-wide association studies have uncovered SNPs in the fat mass and obesity-associated gene (FTO) that are robustly associated with obesity and higher BMI. The prevalence of NAFLD increases in parallel with the increasing prevalence of obesity. Since FTO might play a crucial role in NAFLD development, the current study identified five potentially deleterious mutations from 383 ns-SNPs in the human FTO gene using various in silico tools. METHODS: This study aims to identify potentially deleterious nonsynonymous SNPs (ns-SNPs) employing various in silico tools. Additionally, molecular modeling approaches further studied the structural changes caused by identified SNPs. Moreover, molecular dynamics studies finally investigated the binding potentials of the phytochemicals resveratrol, rosmarinic acid, and capsaicin with different mutant forms of FTO. RESULTS: The current investigation has five potentially deleterious mutations from 383 ns-SNPs in the human FTO gene using various in silico tools. The present study identified five nsSNPs of the human gene FTO, Gly103Asp, Arg96Pro, Tyr295Cys, and Arg322Gln, with an apparent connection to the disease condition. Modulation of demethylation activity by phytomolecule scanning explains the hepatoprotective action of molecules. The current investigation also suggested that predicted mutations did not affect the binding ability of three polyphenols: rosamarinic acid, resveratrol, and capsaicin. CONCLUSION: This study showed that the predicted mutations in FTO did not affect the binding of three polyphenols. Thus, these three molecules can significantly aid drug development against FTO and NAFLD.

Genetically predicted selenium concentrations and thyroid function: A two-sample Mendelian randomization study.

OBJECTIVE: The impact of selenium (Se) on human thyroid function remains unclear, with inconsistent results from recent epidemiological studies. Moreover, the observed associations are prone to bias due to potential confounding and reverse causation. Mendelian randomization (MR) analysis facilitates the large minimization of biases produced by environmental and lifestyle influences, providing unconfounded estimates of causal effects using instrumental variables. We aim to examine the association between Se concentrations and human thyroid function using a two-sample MR analysis. DESIGN AND METHODS: Genetic instruments for Se concentrations, including toenail and blood (TAB) and blood Se concentrations, were identified from a genome-wide association study (GWAS) of blood Se (n = 5477) and toenail Se levels (n = 4162). GWAS summary statistics on thyroid phenotypes were downloaded from the ThyroidOmics consortium, including thyroid-stimulating hormone (TSH) (n = 54,288), free thyroxin (FT4) (n = 49,269), hypo (n = 53,423), and hyperthyroidism (n = 51,823). The MR study was conducted using the inverse-variance weighted (IVW) method, supplemented with the weighted median and the mode-based method. RESULTS: Genetically determined TAB Se was negatively associated with FT4 (ß = -.067; 95% confidence interval [CI] = -0.106, -0.028; p = 0.001) using the IVW analyses, as well in the additional analyses using the weighted median and weighted-mode methods. No evidence in heterogeneity, pleiotropy or outlier single-nucleotide polymorphisms was detected (all p > 0.05). Suggestive casual association between increased genetically determined TAB Se concentrations and decreased hypothyroidism risk was found by the IVW method (odds ratio [OR] = 0.847; 95% CI = 0.728, 0.985; p = 0.031). The causal effect of TAB Se on FT4 was observed in women (ß = -.076; 95% CI = -0.129, -0.024; p = 0.004). However, the influence of genetically determined higher Se concentrations on TSH levels and hyperthyroidism revealed insignificance in the primary and sensitivity analyses. CONCLUSIONS: The present MR study indicated that high Se concentration enable the decreasing of FT4 levels, and the effects of Se concentrations on FT4 remain sex-specific.

Association between the CASC16 rs4784227 polymorphism and breast cancer risk and prognosis in a northeast Chinese Han population.

Background: Breast cancer (BC) poses a serious threat to women worldwide. This research was designed to explore the association between the rs4784227 polymorphism of cancer susceptibility candidate gene 16 (CASC16) and BC susceptibility and prognosis, aiming to provide further information for the early detection of BC and to accelerate comprehensive cancer management. Methods: A total of 1,733 subjects were recruited for this case-control study, of which 828 are BC patients and 905 are healthy individuals. The relevance between SNP rs4784227 and BC risk in diverse genetic models was analyzed by using the SNPStats analysis program and was assessed by odds ratios (ORs) and 95% confidence intervals (CIs) using the binary logistic regression model. Pearson's χ 2 test was used to determine the correlation between the polymorphism and clinical characteristics of BC patients. Additionally, univariate survival analysis was performed by the Kaplan-Meier method and log-rank test, and multivariate survival analysis was performed by Cox regression. Results: SNP rs4784227 was significantly associated with susceptibility to BC in the dominant model (CT/TT versus CC, OR = 1.237, 95% CI = 1.012-1.513, P = 0.038). The minor allele of SNP rs4784227 was significantly linked to an increased risk of BC (OR = 1.197, 95% CI = 1.022-1.401, P = 0.026). In addition, the rs4784227 polymorphism of CASC16 was associated with perineural invasion (P = 0.030), menstrual status (P = 0.016) and histological grade (P = 0.001, P = 0.003, P = 0.025; respectively) of BC patients. There was no significant association between the genotypes of rs4784227 and disease-free survival (DFS) or overall survival (OS) of breast cancer patients (P > 0.05). Conclusions: The rs4784227 polymorphism of CASC16 may affect susceptibility to breast cancer and is associated with perineural invasion, menstrual status and histological grade in BC patients. Additionally, our results could not confirm that this polymorphism was related to breast cancer prognosis.

Evidence that the pituitary gland connects type 2 diabetes mellitus and schizophrenia based on large-scale trans-ethnic genetic analyses.

BACKGROUND: Previous studies on European (EUR) samples have obtained inconsistent results regarding the genetic correlation between type 2 diabetes mellitus (T2DM) and Schizophrenia (SCZ). A large-scale trans-ethnic genetic analysis may provide additional evidence with enhanced power. OBJECTIVE: We aimed to explore the genetic basis for both T2DM and SCZ based on large-scale genetic analyses of genome-wide association study (GWAS) data from both East Asian (EAS) and EUR subjects. METHODS: A range of complementary approaches were employed to cross-validate the genetic correlation between T2DM and SCZ at the whole genome, autosomes (linkage disequilibrium score regression, LDSC), loci (Heritability Estimation from Summary Statistics, HESS), and causal variants (MiXeR and Mendelian randomization, MR) levels. Then, genome-wide and transcriptome-wide cross-trait/ethnic meta-analyses were performed separately to explore the effective shared organs, cells and molecular pathways. RESULTS: A weak genome-wide negative genetic correlation between SCZ and T2DM was found for the EUR (rg = - 0.098, P = 0.009) and EAS (rg =- 0.053 and P = 0.032) populations, which showed no significant difference between the EUR and EAS populations (P = 0.22). After Bonferroni correction, the rg remained significant only in the EUR population. Similar results were obtained from analyses at the levels of autosomes, loci and causal variants. 25 independent variants were firstly identified as being responsible for both SCZ and T2DM. The variants associated with the two disorders were significantly correlated to the gene expression profiles in the brain (P = 1.1E-9) and pituitary gland (P = 1.9E-6). Then, 61 protein-coding and non-coding genes were identified as effective genes in the pituitary gland (P < 9.23E-6) and were enriched in metabolic pathways related to glutathione mediated arsenate detoxification and to D-myo-inositol-trisphosphate. CONCLUSION: Here, we show that a negative genetic correlation exists between SCZ and T2DM at the whole genome, autosome, locus and causal variant levels. We identify pituitary gland as a common effective organ for both diseases, in which non-protein-coding effective genes, such as lncRNAs, may be responsible for the negative genetic correlation. This highlights the importance of molecular metabolism and neuroendocrine modulation in the pituitary gland, which may be responsible for the initiation of T2DM in SCZ patients.

Effects of SLCO1B1 on elimination and toxicities of high-dose methotrexate in pediatric acute lymphoblastic leukemia.

Aim: To evaluate the association between SLCO1B1 polymorphisms and elimination/toxicities of high-dose methotrexate (MTX). Methods: SLCO1B1 rs11045879 and rs4149056 polymorphisms were retrospectively genotyped in 301 children with newly diagnosed acute lymphoblastic leukemia. MTX concentration, doses of leucovorin rescue and toxicities were recorded. Results: SLCO1B1 rs11045879C carriers (CC + CT) had higher plasma MTX levels at 96 hr, and longer MTX elimination time. The number of leucovorin rescue doses in rs4149056C carriers (CC + CT) was more than those in TT ones. Moreover, SLCO1B1 polymorphisms were associated with HDMTX toxicities including thrombocytopenia, renal toxicity and anal mucositis, but not associated with MTX level at other time points or delayed elimination. Conclusions: Our data demonstrate that genotyping of SLCO1B1 might be useful to optimize MTX therapy.

Landscape genomics of the American lobster (Homarus americanus).

In marine species experiencing intense fishing pressures, knowledge of genetic structure and local adaptation represent a critical information to assist sustainable management. In this study, we performed a landscape genomics analysis in the American lobster to investigate the issues pertaining to the consequences of making use of putative adaptive loci to reliably infer population structure and thus more rigorously delineating biological management units in marine exploited species. Toward this end, we genotyped 14,893 single nucleotide polymorphism (SNPs) in 4190 lobsters sampled across 96 sampling sites distributed along 1000 km in the northwest Atlantic in both Canada and the USA. As typical for most marine species, we observed a weak, albeit highly significant genetic structure. We also found that adaptive genetic variation allows detecting fine-scale population structure not resolved by neutral genetic variation alone. Using the recent genome assembly of the American lobster, we were able to map and annotate several SNPs located in functional genes potentially implicated in adaptive processes such as thermal stress response, salinity tolerance and growth metabolism pathways. Taken together, our study indicates that weak population structure in high gene flow systems can be resolved at various spatial scales, and that putatively adaptive genetic variation can substantially enhance the delineation of biological management units of marine exploited species.

Diversity and population structure of Nordic potato cultivars and breeding clones.

BACKGROUND: The genetic diversity and population structure of breeding germplasm is central knowledge for crop improvement. To gain insight into the genetic potential of the germplasm used for potato breeding in a Nordic breeding program as well as all available accessions from the Nordic genebank (NordGen), 133 potato genotypes were genotyped using the Infinium Illumina 20 K SNP array. After SNP filtering, 11 610 polymorphic SNPs were included in the analysis. In addition, data from three important breeding traits - percent dry matter and uniformity of tuber shape and eye - were scored to measure the variation potato cultivars and breeding clones. RESULTS: The genetic diversity among the genotypes was estimated using principal coordinate analysis based on the genetic distance between individuals, as well as by using the software STRUCTURE. Both methods suggest that the collected breeding material and the germplasm from the gene-bank are closely related, with a low degree of population structure between the groups. The phenotypic distribution among the genotypes revealed significant differences, especially between farmer's cultivars and released cultivars and breeding clones. The percent heterozygosity was similar between the groups, with a mean average of 58-60%. Overall, the breeding germplasm and the accessions from the Nordic genebank seems to be closely related with similar genetic background. CONCLUSION: The genetic potential of available Nordic potato breeding germplasm is low, and for genetic hybridization purposes, genotypes from outside the Nordic region should be employed.

C1q Gene Polymorphism Is Associated with Asymptomatic Bacteriuria in Patients with Type 2 Diabetes Mellitus.

Background and Objectives: Asymptomatic bacteriuria (ASB) appears to have a higher prevalence in diabetics and has been associated with various genetic polymorphisms of the innate immune system. Single nucleotide polymorphisms (SNPs) of the C1q gene that encodes for the trigger molecule of the classical complement pathway increase the risk of bacterial infections as well as other diseases. In the present study, we sought to investigate the association of C1q rs292001 (G > A) SNP with ASB in patients with type 2 diabetes (T2D). Materials and Methods: In this case-control study, performed at the University and the Venizeleion General Hospital of Heraklion, Crete, Greece, 75 adult male and female Cretan patients with T2D and ASB and 75 adult male and female Cretan patients with T2D but without ASB were enrolled and genotyped for rs292001 SNP of C1q gene. Genetic analysis was based on the polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RLFPs) methods. Results: Τhe frequency of homozygotes for the G/G genotype of C1q rs292001 was significantly higher in patients with T2D and ASB than in the control group (p-value = 0.0480, OR = 2.952, 95% CI: 1.052−7.542). Conclusions: Τhe present study provides the first evidence of an association between the C1q rs292001 SNP and an increased susceptibility for ASB in an adult Cretan population with T2D, thus suggesting that this SNP can be encountered as a risk factor for the presence of ASB in patients with T2D.

Role of circulating polyunsaturated fatty acids on cardiovascular diseases risk: analysis using Mendelian randomization and fatty acid genetic association data from over 114,000 UK Biobank participants.

BACKGROUND: Despite early interest in the health effects of polyunsaturated fatty acids (PUFA), there is still substantial controversy and uncertainty on the evidence linking PUFA to cardiovascular diseases (CVDs). We investigated the effect of plasma concentration of omega-3 PUFA (i.e. docosahexaenoic acid (DHA) and total omega-3 PUFA) and omega-6 PUFA (i.e. linoleic acid and total omega-6 PUFA) on the risk of CVDs using Mendelian randomization. METHODS: We conducted the largest genome-wide association study (GWAS) of circulating PUFA to date including a sample of 114,999 individuals and incorporated these data in a two-sample Mendelian randomization framework to investigate the involvement of circulating PUFA on a wide range of CVDs in up to 1,153,768 individuals of European ancestry (i.e. coronary artery disease, ischemic stroke, haemorrhagic stroke, heart failure, atrial fibrillation, peripheral arterial disease, aortic aneurysm, venous thromboembolism and aortic valve stenosis). RESULTS: GWAS identified between 46 and 64 SNPs for the four PUFA traits, explaining 4.8-7.9% of circulating PUFA variance and with mean F statistics >100. Higher genetically predicted DHA (and total omega-3 fatty acids) concentration was related to higher risk of some cardiovascular endpoints; however, these findings did not pass our criteria for multiple testing correction and were attenuated when accounting for LDL-cholesterol through multivariable Mendelian randomization or excluding SNPs in the vicinity of the FADS locus. Estimates for the relation between higher genetically predicted linoleic acid (and total omega-6) concentration were inconsistent across different cardiovascular endpoints and Mendelian randomization methods. There was weak evidence of higher genetically predicted linoleic acid being related to lower risk of ischemic stroke and peripheral artery disease when accounting by LDL-cholesterol. CONCLUSIONS: We have conducted the largest GWAS of circulating PUFA to date and the most comprehensive Mendelian randomization analyses. Overall, our Mendelian randomization findings do not support a protective role of circulating PUFA concentration on the risk of CVDs. However, horizontal pleiotropy via lipoprotein-related traits could be a key source of bias in our analyses.

Mendelian Randomization Study of Causal Relationship between Omega-3 Fatty Acids and Risk of Lung Cancer.

Objective: Evidence suggests that omega-3 fatty acid intake exerts a protective effect on lung cancer, but its causal association with risk of lung cancer remains uncertain. This study attempts to clarify the causal effect of omega-3 fatty acids on lung cancer utilizing genome-wide association study (GWAS) data with Mendelian randomization (MR) approach. Methods: This study acquired omega-3 fatty acid data from the UK Biobank and data of lung cancer patients from the Consortium and International Lung Cancer Consortium (ILCCO). Single-nucleotide polymorphisms (SNPs) associated with omega-3 fatty acids were screened as instrumental variables (IVs) in line with the criteria of p < 5E - 8, linkage disequilibrium R 2 > 0.001 and distance < 10000 kb. Through inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode, causal association between omega-3 fatty acids and risk of lung cancer was evaluated. Cochran's Q test was applied for a heterogeneity test. The pleiotropy and horizontal pleiotropy among IVs were evaluated via MR-Egger regression intercept analysis. Results: Totally, 42 SNPs associated with omega-3 fatty acids were identified as IVs. According to the results of IVW (OR (95% CI): 0.899 (0.817, 0.990), p = 0.03), MR-Egger (OR (95% CI): 0.856 (0.750, 0.977), p = 0.026), weighted median (OR (95% CI): 0.899 (0.817, 0.990), p = 0.001), simple mode (OR (95% CI): 0.901 (-0.678, 1.199), p = 0.478), and weighted mode (OR (95% CI): 0.859 (0.782, 0.944), p = 0.003), omega-3 fatty acids showed a causal association with low risk of lung cancer. No genetic pleiotropy or horizontal pleiotropy was found according to MR-Egger regression intercept analysis. Conclusion: Our findings provide sufficient evidence that omega-3 fatty acids are causal protective factors of lung cancer. Despite this, further work is required for elucidating the potential mechanisms.