Gene Association Studies Research Articles

25 Years of Molecular Psychology: The best is yet to come

This editorial defines the scope of the field of Molecular Psychology, which refers to the study of behavior and its underlying neural systems using the toolset of molecular biology, particularly molecular genetics and epigenetics. It is related to other well-established fields that use molecular tools in animal model organisms (Behavioral Neuroscience; Neuroethology) or that focus on molecular mechanisms of human mental health and disease (Molecular Psychiatry; Health Psychology), but extends beyond these fields by its inclusion of broad domains of human behavior; the precise molecular mechanisms by which environmental exposure and experiences modify gene expression; and the ethical, legal, and social implications (ELSI) of these discoveries. Considering the first 25 years of studies that included candidate gene and genome-wide association studies, I suggest a roadmap for the next decade of work. On the launch of F1000 Molecular Psychology: Brain, Behavior & Society, I hope this publication platform will become instrumental in growing this field by promoting a spirit of support and community among its practitioners, embracing transparency and rigor, and publishing novel ideas and studies ranging from pilot and proof-of-concept first steps to gold-standard definitive milestones.

Novel brown adipose tissue candidate genes predicted by the human gene connectome

Brown adipose tissue (BAT) is a promising therapeutic target against obesity. Therefore, research on the genetic architecture of BAT could be key for the development of successful therapies against this complex phenotype. Hypothesis-driven candidate gene association studies are useful for studying genetic determinants of complex traits, but they are dependent upon the previous knowledge to select candidate genes. Here, we predicted 107 novel-BAT candidate genes in silico using the uncoupling protein one (UCP1) as the hallmark of BAT activity. We first identified the top 1% of human genes predicted by the human gene connectome to be biologically closest to the UCP1, estimating 167 additional pathway genes (BAT connectome). We validated this prediction by showing that 60 genes already associated with BAT were included in the connectome and they were biologically closer to each other than expected by chance (p < 2.2 × 10−16). The rest of genes (107) are potential candidates for BAT, being also closer to known BAT genes and more expressed in BAT biopsies than expected by chance (p < 2.2 × 10−16; p = 4.39 × 10–02). The resulting new list of predicted human BAT genes should be useful for the discovery of novel BAT genes and metabolic pathways.

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program.

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

The impact of ADHD genetic risk on educational achievement: a comparative cross-national study

Abstract Human capital accumulation is a key driver of economic development across countries. Although previous studies have shown that country-specific circumstances (e.g., cultural, health-related, and educational factors) are strongly related with the accumulation of human capital in society, few studies have explored the importance of innate ability factors in general and ADHD-related behavioral symptoms in particular for cognitive skill outcomes. This paper hypothesizes and empirically establishes the educational burden of the ADHD-related behavioral symptoms on aggregate cognitive achievement outcomes. We use a novel compilation of the 2- and 7-repeat allele variants of the human DRD4 exon III gene that candidate gene association studies have identified as an important biomarker in the etiology of childhood ADHD. We find that our indicator for the prevalence of ADHD genetic risk in society has a negative and statistically significant impact on educational achievement. Additional sensitivity tests and estimation methods further corroborate our main hypothesis.

A systematic review and functional bioinformatics analysis of genes associated with Crohn\u2019s disease identify more than 120 related genes

BackgroundCrohn’s disease is one of the two categories of inflammatory bowel diseases that affect the gastrointestinal tract. The heritability estimate has been reported to be 0.75. Several genes linked to Crohn’s disease risk have been identified using a plethora of strategies such as linkage-based studies, candidate gene association studies, and lately through genome-wide association studies (GWAS). Nevertheless, to our knowledge, a compendium of all the genes that have been associated with CD is lacking.MethodsWe conducted functional analyses of a gene set generated from a systematic review where genes potentially related to CD found in the literature were analyzed and classified depending on the genetic evidence reported and putative biological function. For this, we retrieved and analyzed 2496 abstracts comprising 1067 human genes plus 22 publications regarding 133 genes from GWAS Catalog. Then, each gene was curated and categorized according to the type of evidence associated with Crohn’s disease.ResultsWe identified 126 genes associated with Crohn’s disease risk by specific experiments. Additionally, 71 genes were recognized associated through GWAS alone, 18 to treatment response, 41 to disease complications, and 81 to related diseases. Bioinformatic analysis of the 126 genes supports their importance in Crohn’s disease and highlights genes associated with specific aspects such as symptoms, drugs, and comorbidities. Importantly, most genes were not included in commercial genetic panels suggesting that Crohn’s disease is genetically underdiagnosed.ConclusionsWe identified a total of 126 genes from PubMed and 71 from GWAS that showed evidence of association to diagnosis, 18 to treatment response, and 41 to disease complications in Crohn’s disease. This prioritized gene catalog can be explored at http://victortrevino.bioinformatics.mx/CrohnDisease.

Genetic Variants of Glycogen Metabolism Genes Were Associated With Liver PDFF Without Increasing NAFLD Risk.

Background/Aims: The storage amount of liver glycogen could affect the liver fibrosis assessment made by MRI-based methods. However, it remained unclear whether glycogen amount could bias the estimation of liver fat content by proton density fat fraction. In this study, we aimed to investigate whether glycogen metabolism gene variants could contribute to the bias of PDFF by genetic association. Methods: We conducted an association study of the glycogen metabolism genes based on the PDFF data of 11,129 participants in the UK Biobank. The effect of the SNPs in these genes on non-alcoholic fatty liver disease was estimated by a meta-analysis of the available NAFLD case-control studies. Results: We identified significant associations of the SNPs near the genes encoding glycogen phosphorylase (PYGM and PYGL) and synthase (GYS2) with PDFF (FDR-corrected p value < 0.05). The genes encoding the regulatory proteins of glycogenolysis (PHKB, CALM2/3), glucose transporter (SLC2A1), and glucose kinase (GCK) were also associated with PDFF. The SNP rs5402 of SLC2A2 and rs547066 of PYGM were associated with NAFLD (p < 0.05) with others being insignificant. Except for the PYGM gene, the PDFF-associated SNPs showed no associations with NAFLD. In addition, the burden tests of rare variants in these genes were not significant after FDR correction. Conclusion: Liver glycogen metabolism genes associated with PDFF were not associated with NAFLD, which implicated a potential bias effect of glycogen storage on the quantification of liver fat content by PDFF.

Systematic review and meta-analysis of candidate gene association studies of benign prostate hyperplasia

BackgroundBenign prostate hyperplasia (BPH) is the most common urological problem in elderly males. Recent studies have reported polymorphism in various metabolic genes in BPH. However, their association with the susceptibility of BPH is still inconsistent. Here, we systematically reviewed and performed a meta-analysis of CYP17, VDR, and ACE genes to determine their precise association with the risk of BPH.MethodsA comprehensive literature search for published studies on candidate gene associations involving vitamin D receptor (VDR), angiotensin-converting enzyme (ACE), and CYP17 genes with the risk of BPH was done up to April 2020 in PubMed, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar databases. Fixed/random effects models were used to estimate the odd’s ratio (OR) and 95% confidence intervals (CIs). Begg’s funnel plot was used to assess the potential for publication bias.ResultsWe found a total of 23 studies containing 3461 cases and 3833 controls for these gene polymorphisms. A significant association of ACE gene polymorphism was observed under the recessive (II vs. ID + DD) model for BPH susceptibility compared to control subjects (overall OR = 1.67, 95% CI = 1.03–2.73). Similar trends were observed for ACE gene polymorphism in Caucasian (OR = 6.18, 95% CI = 1.38–27.68) and Asian (OR = 1.42, 95% CI = 0.99–2.03) populations under study. No significant association was observed in VDR and CYP17 gene polymorphisms in any dominant or recessive models.ConclusionSignificant OR demonstrated the implication of ACE gene polymorphism in the proliferation of prostate tissue, which in turn is associated with BPH susceptibility. However, prospective studies at large scale and sample size are needed to confirm the current findings.

Polymorphism of ghrelin genes among four Nigerian chicken populations as tool for improvement of chickens

Research on polymorphism of ghrelin (GHRL), an acylated peptide that stimulates the release of growth hormone from the pituitary, has shown that it is associated with some essential growth genes in chicken, hence veritable in genomic selection. There is porous information on the polymorphism of GHRL genes among Nigerian chickens. The objective of this study was to determine polymorphism of ghrelin gene among four Nigerian chicken populations. Blood sample (0.5 ml) was collected from the wing vein of 102 birds for DNA extraction. Tested PCR products were sequenced following Macrogen INC. The SNPs were determined using the sequence alignment program, CLUSTAL W, implemented in MEGA software. The sequence results showed 25 SNPs. The Nigerian chickens varied in polymorphic sites from Ogun chickens (348 and 535) to Nsukka chickens (558 and 696) at the GHRL 1 and GHRL2 loci respectively. Polymorphic sites and diversity were higher among the Nsukka chicken than other populations of the Nigerian chickens. SNPs common to one geographic varied in another. The result revealed that genomic selection based on ghrelin SNPs may yield higher predictive accuracy, while Nsukka chickens could be useful for the creation of more superior lines for the global poultry industry. Since past studies have revealed that ghrelin gene stimulates the pituitary and hypothalamus for releasing growth factor (GF) hormone and have strong effect on many organs, we suggest an association study of ghrelin gene and growth traits.

Genetic variants of PKLR are associated with acute pain in sickle cell disease

AbstractAcute pain, the most prominent complication of sickle cell disease (SCD), results from vaso-occlusion triggered by sickling of deoxygenated red blood cells (RBCs). Concentration of 2,3-diphosphoglycerate (2,3-DPG) in RBCs promotes deoxygenation by preferentially binding to the low-affinity T conformation of HbS. 2,3-DPG is an intermediate substrate in the glycolytic pathway in which pyruvate kinase (gene PKLR, protein PKR) is a rate-limiting enzyme; variants in PKLR may affect PKR activity, 2,3-DPG levels in RBCs, RBC sickling, and acute pain episodes (APEs). We performed a candidate gene association study using 2 cohorts: 242 adult SCD-HbSS patients and 977 children with SCD-HbSS or SCD-HbSβ0 thalassemia. Seven of 47 PKLR variants evaluated in the adult cohort were associated with hospitalization: intron 4, rs2071053; intron 2, rs8177970, rs116244351, rs114455416, rs12741350, rs3020781, and rs8177964. All 7 variants showed consistent effect directions in both cohorts and remained significant in weighted Fisher's meta-analyses of the adult and pediatric cohorts using P < .0071 as threshold to correct for multiple testing. Allele-specific expression analyses in an independent cohort of 52 SCD adults showed that the intronic variants are likely to influence APE by affecting expression of PKLR, although the causal variant and mechanism are not defined.

Genetics in the ADHD Clinic: How Can Genetic Testing Support the Current Clinical Practice?

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a childhood prevalence of 5%. In about two-thirds of the cases, ADHD symptoms persist into adulthood and often cause significant functional impairment. Based on the results of family and twin studies, the estimated heritability of ADHD approximates 80%, suggests a significant genetic component in the etiological background of the disorder; however, the potential genetic effects on disease risk, symptom severity, and persistence are unclear. This article provides a brief review of the genome-wide and candidate gene association studies with a focus on the clinical aspects, summarizing findings of ADHD disease risk, ADHD core symptoms as dimensional traits, and other traits frequently associated with ADHD, which may contribute to the susceptibility to other comorbid psychiatric disorders. Furthermore, neuropsychological impairment and measures from neuroimaging and electrophysiological paradigms, emerging as potential biomarkers, also provide a prominent target for molecular genetic studies, since they lie in the pathway from genes to behavior; therefore, they can contribute to the understanding of the underlying neurobiological mechanisms and the interindividual heterogeneity of clinical symptoms. Beyond the aforementioned aspects, throughout the review, we also give a brief summary of the genetic results, including polygenic risk scores that can potentially predict individual response to different treatment options and may offer a possibility for personalized treatment for the therapy of ADHD in the future.

A genome-wide association study of outcome from traumatic brain injury.

SummaryBackgroundFactors such as age, pre-injury health, and injury severity, account for less than 35% of outcome variability in traumatic brain injury (TBI). While some residual outcome variability may be attributable to genetic factors, published candidate gene association studies have often been underpowered and subject to publication bias.MethodsWe performed the first genome- and transcriptome-wide association studies (GWAS, TWAS) of genetic effects on outcome in TBI. The study population consisted of 5268 patients from prospective European and US studies, who attended hospital within 24 h of TBI, and satisfied local protocols for computed tomography.FindingsThe estimated heritability of TBI outcome was 0·26. GWAS revealed no genetic variants with genome-wide significance (p < 5 × 10−8), but identified 83 variants in 13 independent loci which met a lower pre-specified sub-genomic statistical threshold (p < 10−5). Similarly, none of the genes tested in TWAS met tissue-wide significance. An exploratory analysis of 75 published candidate variants associated with 28 genes revealed one replicable variant (rs1800450 in the MBL2 gene) which retained significance after correction for multiple comparison (p = 5·24 × 10−4).InterpretationWhile multiple novel loci reached less stringent thresholds, none achieved genome-wide significance. The overall heritability estimate, however, is consistent with the hypothesis that common genetic variation substantially contributes to inter-individual variability in TBI outcome. The meta-analytic approach to the GWAS and the availability of summary data allows for a continuous extension with additional cohorts as data becomes available.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Genetic and epigenetic studies in non-syndromic oral clefts.

The etiology of non-syndromic oral clefts (NSOFC) is complex with genetics, genomics, epigenetics, and stochastics factors playing a role. Several approaches have been applied to understand the etiology of non-syndromic oral clefts. These include linkage, candidate gene association studies, genome-wide association studies, whole-genome sequencing, copy number variations, and epigenetics. In this review, we shared these approaches, genes, and loci reported in some studies.

A Systematic Review of Candidate Genes for Major Depression.

Background and Objectives: The aim of this systematic review was to analyse which candidate genes were examined in genetic association studies and their association with major depressive disorder (MDD). Materials and Methods: We searched PUBMED for relevant studies published between 1 July 2012 and 31 March 2019, using combinations of keywords: “major depressive disorder” OR “major depression” AND “gene candidate”, “major depressive disorder” OR “major depression” AND “polymorphism”. Synthesis focused on assessing the likelihood of bias and investigating factors that may explain differences between the results of studies. For selected gene list after literature overview, functional enrichment analysis and gene ontology term enrichment analysis were conducted. Results: 141 studies were included in the qualitative review of gene association studies focusing on MDD. 86 studies declared significant results (p < 0.05) for 172 SNPs in 85 genes. The 13 SNPs associations were confirmed by at least two studies. The 18 genetic polymorphism associations were confirmed in both the previous and this systematic analysis by at least one study. The majority of the studies (68.79 %) did not use or describe power analysis, which may have had an impact over the significance of their results. Almost a third of studies (N = 54) were conducted in Chinese Han population. Conclusion: Unfortunately, there is still insufficient data on the links between genes and depression. Despite the reported genetic associations, most studies were lacking in statistical power analysis, research samples were small, and most gene polymorphisms have been confirmed in only one study. Further genetic research with larger research samples is needed to discern whether the relationship is random or causal. Summations: This systematic review had summarized all reported genetic associations and has highlighted the genetic associations that have been replicated. Limitations: Unfortunately, most gene polymorphisms have been confirmed only once, so further studies are warranted for replicating these genetic associations. In addition, most studies included a small number of MDD cases that could be indicative for false positive. Considering that polymorphism loci and associations with MDD is also vastly dependent on interpersonal variation, extensive studies of gene interaction pathways could provide more answers to the complexity of MDD.

Efficient privacy-preserving whole-genome variant queries.

MotivationDiagnosis and treatment decisions on genomic data have become widespread as the cost of genome sequencing decreases gradually. In this context, disease–gene association studies are of great importance. However, genomic data are very sensitive when compared to other data types and contains information about individuals and their relatives. Many studies have shown that this information can be obtained from the query-response pairs on genomic databases. In this work, we propose a method that uses secure multi-party computation to query genomic databases in a privacy-protected manner. The proposed solution privately outsources genomic data from arbitrarily many sources to the two non-colluding proxies and allows genomic databases to be safely stored in semi-honest cloud environments. It provides data privacy, query privacy and output privacy by using XOR-based sharing and unlike previous solutions, it allows queries to run efficiently on hundreds of thousands of genomic data.ResultsWe measure the performance of our solution with parameters similar to real-world applications. It is possible to query a genomic database with 3 000 000 variants with five genomic query predicates under 400 ms. Querying 1 048 576 genomes, each containing 1 000 000 variants, for the presence of five different query variants can be achieved approximately in 6 min with a small amount of dedicated hardware and connectivity. These execution times are in the right range to enable real-world applications in medical research and healthcare. Unlike previous studies, it is possible to query multiple databases with response times fast enough for practical application. To the best of our knowledge, this is the first solution that provides this performance for querying large-scale genomic data.Availability and implementation https://gitlab.com/DIFUTURE/privacy-preserving-variant-queries.Supplementary information Supplementary data are available at Bioinformatics online.

Polygenic risk impacts PDGFRA mutation penetrance in non-syndromic cleft lip and palate.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common, severe craniofacial malformation that imposes significant medical, psychosocial and financial burdens. NSCL/P is a multifactorial disorder with genetic and environmental factors playing etiologic roles. Currently, only 25% of the genetic variation underlying NSCL/P has been identified by linkage, candidate gene and genome-wide association studies. In this study, whole-genome sequencing and genome-wide genotyping followed by polygenic risk score (PRS) and linkage analyses were used to identify the genetic etiology of NSCL/P in a large three-generation family. We identified a rare missense variant in PDGFRA (c.C2740T; p.R914W) as potentially etiologic in a gene-based association test using pVAAST (P = 1.78×10-4) and showed decreased penetrance. PRS analysis suggested that variant penetrance was likely modified by common NSCL/P risk variants, with lower scores found among unaffected carriers. Linkage analysis provided additional support for PRS-modified penetrance, with a 7.4-fold increase in likelihood after conditioning on PRS. Functional characterization experiments showed that the putatively causal variant was null for signaling activity in vitro; further, perturbation of pdgfra in zebrafish embryos resulted in unilateral orofacial clefting. Our findings show that a rare PDGFRA variant, modified by additional common NSCL/P risk variants, have a profound effect on NSCL/P risk. These data provide compelling evidence for multifactorial inheritance long postulated to underlie NSCL/P and may explain some unusual familial patterns.

Genetic polymorphism of ADAM17 and decreased bilirubin levels are associated with allergic march in the Korean population

BackgroundThe “allergic march” refers to changes in the frequency and intensity of allergic diseases with age. Classically, the allergic march begins with atopic dermatitis in infancy and leads to asthma and rhinitis as it continues. There are many factors that induce the allergic march; however, TNF-α may play an important role in inducing inflammation. Therefore, the therapeutic potential of TNF alpha-targeting agents is being considered for allergic march treatment.MethodsWe performed a correlation study to determine whether genetic polymorphisms of ADAM17 and clinical serum values between allergic and normal groups affect disease development by using the cohort data of the Korean genome epidemiologic research project. Gene association study was performed using PLINK version 1.07 (http://pngu.mgh.harvard.edu/–purcell/plink) and other statistical analysis was performed using PASW Statistics (version 18.0, SPSS Inc. Chicago, IL, USA).ResultsADAM17 (also called TNF-α converting enzyme or TACE) showed a statistically significant association with the allergic march. The 13 and 8 SNPs in ADAM17 were significantly associated with asthma and allergies, respectively. Among them, on average, SNP of rs6432011 showed the greatest statistical correlation with asthma (P = 0.00041, OR = 1.95, 95% CI 1.35–2.82) and allergies (P = 0.02918, OR = 1.35, 95% CI 1.03–1.78). The effect of SNPs in ADAM17 on transcription factor binding was confirmed using RegulomeDB. The six SNPs are located in the genomic expression quantitative trait loci (eQTL) region and can affect transcription factor binding and gene expression. In clinical serum analysis, bilirubin levels were significantly decreased in the allergic group. The multivariate logistic regression analysis revealed that the low-bilirubin groups indicated a 3.22-fold increase in the prevalence of asthma compared with the high-bilirubin group.ConclusionsThe ADAM17 gene and low bilirubin levels are associated with the allergic march in the Korean population, which can provide new guidelines for managing this disease progression phenomena.

Neurobiological Correlates of Fatherhood During the Postpartum Period: A Scoping Review.

During the postpartum period, the paternal brain suffers extensive and complex neurobiological alterations, through the experience of father–infant interactions. Although the impact of such experience in the mother has been increasingly studied over the past years, less is known about the neurobiological correlates of fatherhood—that is, the alterations in the brain and other physiological systems associated with the experience of fatherhood. With the present study, we aimed to perform a scoping review of the available literature on the genetic, neuroendocrine, and brain correlates of fatherhood and identify the main gaps in the current knowledge. PubMed, Scopus, and Web of Science electronic databases were searched for eligible studies on paternal neuroplasticity during the postpartum period, over the past 15 years. Reference lists of relevant key studies and reviews were also hand-searched. The research team independently screened the identified studies based on the established inclusion criteria. Extracted data were analyzed using tables and descriptive synthesis. Among the 29 studies that met our inclusion criteria, the vast majority pertained to neuroendocrine correlates of fatherhood (n = 19), followed by brain activity or connectivity (n = 7), association studies of candidate genes (n = 2), and brain structure correlates (n = 1). Collectively, studies published during the past 15 years suggest the existence of significant endocrine (testosterone, oxytocin, prolactin, and cortisol levels) and neurofunctional alterations (changed activity in several brain networks related to empathy and approach motivation, emotional processing and mentalizing, emotion regulation, dorsal attention, and default mode networks) as a result of fatherhood, as well as preliminary evidence of genetic variability accounting for individual differences during the postpartum period in fathers. No studies were so far published evaluating epigenetic mechanisms associated with the paternal brain, something that was also the focus of the current review. We highlight the need for further research that examines neuroplasticity during the experience of fatherhood and that considers both the interplay between hormones and simultaneous assessment of the different biomarkers (e.g., associations between hormones and neural activity); data collection protocols and assessment times should also be refined.

Genome-wide association study of the candidate genes for grape berry shape-related traits

BackgroundIn the breeding of new horticultural crops, fruit shape is an important selection characteristic. A variety of fruit shapes appeared during the gradual process of selection and domestication. However, few studies have been conducted on grape berry shape, especially studies related to mining candidate genes. To discover candidate genes related to grape berry shape, the present study first took the berry shape parameters analyzed by Tomato Analyzer as the target traits and used a genome-wide association analysis to analyze candidate genes.ResultsIn total, 122 single-nucleotide polymorphism (SNP) loci had significant correlations with multiple berry shape traits in both years, and some candidate genes were further mined. These genes were mainly related to LRR receptor-like serine/threonine-protein kinase (At1g05700 and At1g07650), transcription factors (GATA transcription factor 23-like, transcription factor VIP1, transcription initiation factor TFIID, and MADS-box transcription factor 6), ubiquitin ligases (F-box protein SKIP19 and RING finger protein 44), and plant hormones (indole-3-acetic acid-amido synthetase GH3.6 and ethylene-responsive transcription factor ERF061). In addition, some important SNP loci were associated with multiple berry-shape traits. The study further revealed some genes that control multiple traits simultaneously, indicating that these berry shape traits are subject to the coordinated regulation of some genes in controlling berry shape.ConclusionsIn the present work, we identified interesting genetic determinants of grape berry shape-related traits. The identification of molecular markers that are closely related to these berry-shape traits is of great significance for breeding specific berry-shaped grape varieties.

Impact of Inherited Genetic Variants on Critically Ill Septic Children.

Sepsis remains an important source of morbidity and mortality in children, despite the development of standardized care. In the last decades, there has been an increased interest in genetic and genomic approaches to early recognition and development of treatments to manipulate the host inflammatory response. This review will present a summary of the normal host response to infection and progression to sepsis, followed by highlighting studies with a focus on gene association studies, epigenetics, and genome-wide expression profiling. The susceptibility (or outcome) of sepsis in children has been associated with several polymorphisms of genes broadly involved in inflammation, immunity, and coagulation. More recently, gene expression profiling has been focused on identifying novel biomarkers, pathways and therapeutic targets, and gene expression-based subclassification. Knowledge of a patient’s individual genotype may, in the not-too-remote future, be used to guide tailored treatment for sepsis. However, at present, the impact of genomics remains far from the bedside of critically ill children.

TaNRT2.1-6B is a dual-affinity nitrate transporter contributing to nitrogen uptake in bread wheat under both nitrogen deficiency and sufficiency

Multiple nitrate transporter (NRT) genes exist in the genome of bread wheat, and it is of great importance to identify the elite NRT genes for N-efficient wheat cultivar breeding. A candidate gene association study (CGAS) of six N use efficiency (NUE) related traits (grain N concentration (GNC), straw N concentration (SNC), grain yield (GY), grain N accumulation (GNA), shoot total N accumulation (STN) and N harvest index (NHI)) was performed based on SNPs in 46 NRT2 genes using a panel composed of 286 wheat cultivars. CGAS identified TaNRT2.1-6B as an elite NRT gene that is significantly associated with four (NHI, SNC, GNA and GY) of the six NUE-related traits simultaneously. TaNRT2.1-6B is located on the plasma membrane and acts as a dual-affinity NRT. The overexpression of TaNRT2.1-6B increased the N influx and root growth of wheat, whereas gene silence lines resulted in the opposite effects. The overexpression of TaNRT2.1-6B also improved GY and N accumulation of wheat under either limited or sufficient N conditions. The data provide the TaNRT2.1-6B gene and the two associated SNP markers as promising powerful tools for breeding wheat cultivars with high N uptake ability and NUE.