Newborn Dried Blood Spot Folate in Relation to Maternal Self-reported Folic Acid Intake, Autism Spectrum Disorder, and Developmental Delay.

BACKGROUND: Maternal folic acid intake has been associated with decreased risk for neurodevelopmental disorders including autism spectrum disorder (ASD). Genetic differences in folate metabolism could explain some inconsistencies. To our knowledge, newborn folate concentrations remain unexamined. METHODS: We measured folate in archived newborn dried blood spots of children from the CHARGE (Childhood Autism Risks from Genetics and the Environment) case-control study who were clinically confirmed at 24-60 months to have ASD (n = 380), developmental delay (n = 128), or typical development (n = 247). We quantified monthly folic acid intake from maternally-reported supplements and cereals consumed during pregnancy and 3 months prior. We assessed associations of newborn folate with maternal folic acid intake and with ASD or developmental delay using regression. We stratified estimates across maternal and child MTHFR genotypes. RESULTS: Among typically developing children, maternal folic acid intake in prepregnancy and each pregnancy month and prepregnancy prenatal vitamin intake were positively associated with newborn folate. Among children with ASD, prenatal vitamin intake in pregnancy months 2-9 was positively associated with newborn folate. Among children with developmental delay, maternal folic acid and prenatal vitamins during the first pregnancy month were positively associated with neonatal folate. Associations differed by MTHFR genotype. Overall, neonatal folate was not associated with ASD or developmental delay, though we observed associations with ASD in children with the MTHFR 677 TT genotype (odds ratio: 1.76, 95% CI = 1.19, 2.62; P for interaction = 0.08). CONCLUSION: Maternal prenatal folic acid intake was associated with neonatal folate at different times across neurodevelopmental groups. Neonatal folate was not associated with reduced ASD risk. MTHFR genotypes modulated these relationships.

Effect of statin treatment on metabolites, lipids and prostanoids in patients with Statin Associated Muscle Symptoms (SAMS).

BACKGROUND: Between 5-10% of patients discontinue statin therapy due to statin-associated adverse reactions, primarily statin associated muscle symptoms (SAMS). The absence of a clear clinical phenotype or of biomarkers poses a challenge for diagnosis and management of SAMS. Similarly, our incomplete understanding of the pathogenesis of SAMS hinders the identification of treatments for SAMS. Metabolomics, the profiling of metabolites in biofluids, cells and tissues is an important tool for biomarker discovery and provides important insight into the origins of symptomatology. In order to better understand the pathophysiology of this common disorder and to identify biomarkers, we undertook comprehensive metabolomic and lipidomic profiling of plasma samples from patients with SAMS who were undergoing statin rechallenge as part of their clinical care. METHODS AND FINDINGS: We report our findings in 67 patients, 28 with SAMS (cases) and 39 statin-tolerant controls. SAMS patients were studied during statin rechallenge and statin tolerant controls were studied while on statin. Plasma samples were analyzed using untargeted LC-MS metabolomics and lipidomics to detect differences between cases and controls. Differences in lipid species in plasma were observed between cases and controls. These included higher levels of linoleic acid containing phospholipids and lower ether lipids and sphingolipids. Reduced levels of acylcarnitines and altered amino acid profile (tryptophan, tyrosine, proline, arginine, and taurine) were observed in cases relative to controls. Pathway analysis identified significant increase of urea cycle metabolites and arginine and proline metabolites among cases along with downregulation of pathways mediating oxidation of branched chain fatty acids, carnitine synthesis, and transfer of acetyl groups into mitochondria. CONCLUSIONS: The plasma metabolome of patients with SAMS exhibited reduced content of long chain fatty acids and increased levels of linoleic acid (18:2) in phospholipids, altered energy production pathways (ß-oxidation, citric acid cycle and urea cycles) as well as reduced levels of carnitine, an essential mediator of mitochondrial energy production. Our findings support the hypothesis that alterations in pro-inflammatory lipids (arachidonic acid pathway) and impaired mitochondrial energy metabolism underlie the muscle symptoms of patients with statin associated muscle symptoms (SAMS).

Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.

Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.

Fetal High-Risk APOL1 Genotype Increases Risk for Small for Gestational Age in Term Infants Affected by Preeclampsia.

BACKGROUND: Hypertensive disorders of pregnancy cause fetal growth restriction and increased maternal morbidity and mortality, especially in women of African ancestry. Recently, preeclampsia risk was associated with polymorphisms in the apolipoprotein L1 (APOL1) gene in women of African ancestry. OBJECTIVES: We assessed APOL1 genotype effects on pregnancies with and without preeclampsia. METHOD: We conducted an unmatched case-control study of 1,358 mother-infant pairs from two independent cohorts of black women. RESULTS: Term preeclampsia cases with high-risk APOL1 genotypes were more likely to be small for gestational age compared to APOL1 low-risk term cases (odds ratio [OR] 2.8) and APOL1 high-risk controls (OR 5.5). Among preterm pregnancies, fetal APOL1 genotype was associated with preeclampsia. CONCLUSIONS: Fetal APOL1 genotype was associated with preeclampsia in preterm infants and with altered fetal growth in term infants. This may indicate APOL1 genotype impacts a spectrum of pregnancy complications mediated by a common pathophysiological event of placental insufficiency.

A novel de novo TP63 mutation in whole-exome sequencing of a Syrian family with Oral cleft and ectrodactyly.

BACKGROUND: Oral clefts and ectrodactyly are common, heterogeneous birth defects. We performed whole-exome sequencing (WES) analysis in a Syrian family. The proband presented with both orofacial clefting and ectrodactyly but not ectodermal dysplasia as typically seen in ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome-3. A paternal uncle with only an oral cleft was deceased and unavailable for analysis. METHODS: Variant annotation, Mendelian inconsistencies, and novel variants in known cleft genes were examined. Candidate variants were validated using Sanger sequencing, and pathogenicity assessed by knocking out the tp63 gene in zebrafish to evaluate its role during zebrafish development. RESULTS: Twenty-eight candidate de novo events were identified, one of which is in a known oral cleft and ectrodactyly gene, TP63 (c.956G > T, p.Arg319Leu), and confirmed by Sanger sequencing. CONCLUSION: TP63 mutations are associated with multiple autosomal dominant orofacial clefting and limb malformation disorders. The p.Arg319Leu mutation seen in this patient is de novo but also novel. Two known mutations in the same codon (c.956G > A, p.(Arg319His; rs121908839, c.955C > T), p.Arg319Cys) cause ectrodactyly, providing evidence that mutating this codon is deleterious. While this TP63 mutation is the best candidate for the patient's clinical presentation, whether it is responsible for the entire phenotype is unclear. Generation and characterization of tp63 knockout zebrafish showed necrosis and rupture of the head at 3 days post-fertilization (dpf). The embryonic phenotype could not be rescued by injection of zebrafish or human messenger RNA (mRNA). Further functional analysis is needed to determine what proportion of the phenotype is due to this mutation.

Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway.

Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, it's unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H 2 O 2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H 2 O 2 . Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H 2 O 2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.

Cdk5 mediates rotational force-induced brain injury.

Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury. All of these deleterious effects can contribute to secondary brain ischemia, cellular death, and neuroinflammation that progress for weeks, months, and lifetime after injury. While the linear effects of head trauma have been extensively modeled, less is known about how rotational injuries mediate neuronal damage following injury. Here, we developed a new model of repetitive rotational head trauma in rodents and demonstrated acute and prolonged pathological, behavioral, and electrophysiological effects of rotational TBI (rTBI). We identify aberrant Cyclin-dependent kinase 5 (Cdk5) activity as a principal mediator of rTBI. We utilized Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rTBI and show pharmacological inhibition of Cdk5 reduces the cognitive and pathological consequences of injury. These studies contribute meaningfully to our understanding of the mechanisms of rTBI and how they may be effectively treated.

Trans-ancestry, Bayesian meta-analysis discovers 20 novel risk loci for inflammatory bowel disease in an African American, East Asian and European cohort.

Inflammatory bowel disease (IBD) is an immune-mediated chronic intestinal disorder with major phenotypes: ulcerative colitis (UC) and Crohn's disease (CD). Multiple studies have identified over 240 IBD susceptibility loci. However, most studies have centered on European (EUR) and East Asian (EAS) populations. The prevalence of IBD in non-EUR, including African Americans (AAs), has risen in recent years. Here we present the first attempt to identify loci in AAs using a trans-ancestry Bayesian approach (MANTRA) accounting for heterogeneity between diverse ancestries while allowing for the similarity between closely related populations. We meta-analyzed genome-wide association studies (GWAS) and Immunochip data from a 2015 EUR meta-analysis of 38 155 IBD cases and 48 485 controls and EAS Immunochip study of 2824 IBD cases and 3719 controls, and our recent AA IBD GWAS of 2345 cases and 5002 controls. Across the major IBD phenotypes, we found significant evidence for 92% of 205 loci lead SNPs from the 2015 meta-analysis, but also for three IBD loci only established in latter studies. We detected 20 novel loci, all containing immunity-related genes or genes with other evidence for IBD or immune-mediated disease relevance: PLEKHG5;TNFSFR25 (encoding death receptor 3, receptor for TNFSF15 gene product TL1A), XKR6, ELMO1, BC021024;PI4KB;PSMD4 and APLP1 for IBD; AUTS2, XKR6, OSER1, TET2;AK094561, BCAP29 and APLP1 for CD; and GABBR1;MOG, DQ570892, SPDEF;ILRUN, SMARCE1;CCR7;KRT222;KRT24;KRT25, ANKS1A;TCP11, IL7, LRRC18;WDFY4, XKR6 and TNFSF4 for UC. Our study highlights the value of combining low-powered genomic studies from understudied populations of diverse ancestral backgrounds together with a high-powered study to enable novel locus discovery, including potentially important therapeutic IBD gene targets.

Gene-level association analysis of ordinal traits with functional ordinal logistic regressions.

In this paper, we develop functional ordinal logistic regression (FOLR) models to perform gene-based analysis of ordinal traits. In the proposed FOLR models, genetic variant data are viewed as stochastic functions of physical positions and the genetic effects are treated as a function of physical positions. The FOLR models are built upon functional data analysis which can be revised to analyze the ordinal traits and high dimension genetic data. The proposed methods are capable of dealing with dense genotype data which is usually encountered in analyzing the next-generation sequencing data. The methods are flexible and can analyze three types of genetic data: (1) rare variants only, (2) common variants only, and (3) a combination of rare and common variants. Simulation studies show that the likelihood ratio test statistics of the FOLR models control type I errors well and have good power performance. The proposed methods achieve the goals of analyzing ordinal traits directly, reducing high dimensionality of dense genetic variants, being computationally manageable, facilitating model convergence, properly controlling type I errors, and maintaining high power levels. The FOLR models are applied to analyze Age-Related Eye Disease Study data, in which two genes are found to strongly associate with four ordinal traits.

Associations between APOL1 genetic variants and blood pressure in African American mothers and children from a U.S. pregnancy cohort: Modification by air pollution exposures.

INTRODUCTION: Carriage of high-risk APOL1 genetic variants is associated with increased risks for kidney diseases in people of African descent. Less is known about the variants' associations with blood pressure or potential moderators. METHODS: We investigated these associations in a pregnancy cohort of 556 women and 493 children identified as African American. Participants with two APOL1 risk alleles were defined as having the high-risk genotype. Blood pressure in both populations was measured at the child's 4-6 years visit. We fit multivariate linear and Poisson regressions and further adjusted for population stratification to estimate the APOL1-blood pressure associations. We also examined the associations modified by air pollution exposures (particulate matter ≤2.5 µ m in aerodynamic diameter [PM2.5] and nitrogen dioxide) and explored other moderators such as health conditions and behaviors. RESULTS: Neither APOL1 risk alleles nor risk genotypes had a main effect on blood pressure in mothers or children. However, each 2-µg/m3 increase of four-year average PM2.5 was associated with a 16.3 (95%CI: 5.7, 26.9) mmHg higher diastolic blood pressure in mothers with the APOL1 high-risk genotype, while the estimated effect was much smaller in mothers with the low-risk genotype (i.e., 2.9 [95%CI: -3.1, 8.8] mmHg; Pinteraction = 0.01). Additionally, the associations of APOL1 risk alleles and the high-risk genotype with high blood pressure (i.e., SBP and/or DBP ≥ 90th percentile) were stronger in girls vs. boys (Pinteraction = 0.02 and 0.005, respectively). CONCLUSION: This study sheds light on the distribution of high blood pressure by APOL1 genetic variants and informs regulatory policy to protect vulnerable population subgroups.

Pharmacy Student Challenges and Strategies towards Initial COVID-19 Curriculum Changes.

Due to COVID-19, tertiary institutions were forced to deliver knowledge virtually, which proposed challenges for both institutions and students. In this study, we aimed to characterize pharmacy students' challenges and strategies during COVID-19 curriculum changes, therefore developing a comprehensive understanding of students' learning, wellbeing, and resilience in the ever-changing situation. Data were collected from student written reflections across four year levels at one school of pharmacy from March-May 2020. In addition, data were collected from written responses of second-year pharmacy students responding to prompted questions. The data were qualitatively analyzed inductively by five coders using NVivo 12. For each piece of data, two coders independently coded the data, calculated the inter-rater agreement, and resolved discrepancies. The most coded challenges were 'negative emotional response' and 'communication barrier during virtual learning'. The most coded strategies were 'using new technology' and 'time management'. This study allows researchers and education institutions to gain an overview of pharmacy students' experiences during COVID-19, therefore helping universities to provide students with necessary support and techniques on how to self-cope with COVID-19 as well as stressful events in the future.

Myopia in African Americans Is Significantly Linked to Chromosome 7p15.2-14.2.

Purpose: The purpose of this study was to perform genetic linkage analysis and association analysis on exome genotyping from highly aggregated African American families with nonpathogenic myopia. African Americans are a particularly understudied population with respect to myopia. Methods: One hundred six African American families from the Philadelphia area with a family history of myopia were genotyped using an Illumina ExomePlus array and merged with previous microsatellite data. Myopia was initially measured in mean spherical equivalent (MSE) and converted to a binary phenotype where individuals were identified as affected, unaffected, or unknown. Parametric linkage analysis was performed on both individual variants (single-nucleotide polymorphisms [SNPs] and microsatellites) as well as gene-based markers. Family-based association analysis and transmission disequilibrium test (TDT) analysis modified for rare variants was also performed. Results: Genetic linkage analysis identified 2 genomewide significant variants at 7p15.2 and 7p14.2 (in the intergenic region between MIR148A and NFE2L3 and in the noncoding RNA LOC401324) and 2 genomewide significant genes (CRHR2 and AVL9) both at 7p14.3. No genomewide results were found in the association analyses. Conclusions: This study identified a significant linkage peak in African American families for myopia at 7p15.2 to 7p14.2, the first potential risk locus for myopia in African Americans. Interesting candidate genes are located in the region, including PDE1C, which is highly expressed in the eyes, and known to be involved in retinal development. Further identification of the causal variants at this linkage peak will help elucidate the genetics of myopia in this understudied population.

Genetic Variation and Recurrent Haplotypes on Chromosome 6q23-25 Risk Locus in Familial Lung Cancer.

Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: ARID1B at 6q25.3, MAP3K4 at 6q26, and UTRN (6q24.1) and PHACTR2 (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work. SIGNIFICANCE: This study identifies four genes associated with lung cancer risk, which could help guide future lung cancer prevention and treatment approaches.

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Joint Associations of Maternal-Fetal APOL1 Genotypes and Maternal Country of Origin With Preeclampsia Risk.

RATIONALE & OBJECTIVES: Preeclampsia, which disproportionately affects Black women, is a leading cause of preterm delivery and risk for future hypertension and chronic kidney disease (CKD). Apolipoprotein L1 (APOL1) kidney risk alleles, common among Black individuals, contribute substantially to CKD disparities. Given the strong link between preeclampsia and CKD, we investigated whether maternal and fetal APOL1 risk alleles can jointly influence preeclampsia risk, and explored potential modifiers of the association between APOL1 and preeclampsia. STUDY DESIGN: Nested case-control study. SETTING & PARTICIPANTS: 426 Black mother-infant pairs (275 African Americans and 151 Haitians) from the Boston Birth Cohort. EXPOSURE: Maternal and fetal APOL1 risk alleles. OUTCOMES: Preeclampsia. ANALYTICAL APPROACH: Logistic regression models with adjustment for demographic characteristics were applied to analyze associations between fetal and maternal APOL1 risk alleles and risk of preeclampsia and to investigate the effects of modification by maternal country of origin. RESULTS: Fetal APOL1 risk alleles tended to be associated with an increased risk of preeclampsia, which was not statistically significant in the total genotyped population. However, this association was modified by maternal country of origin (P<0.05 for interaction tests): fetal APOL1 risk alleles were significantly associated with an increased risk of preeclampsia among African Americans under recessive (odds ratio [OR], 3.6 [95% CI, 1.3-9.7]; P=0.01) and additive (OR, 1.7 [95% CI, 1.1-2.6]; P=0.01) genetic models but not in Haitian Americans. Also, maternal-fetal genotype discordance at the APOL1 locus was associated with a 2.6-fold higher risk of preeclampsia (P<0.001) in African Americans. LIMITATIONS: Limited sample size in stratified analyses; self-reported maternal country of origin; pre-pregnancy estimated glomerular filtration rate (eGFR) and proteinuria data in mothers were not collected; unmeasured confounding social and/or environmental factors; no replication study. CONCLUSIONS: This study supports the hypothesis that fetal APOL1 kidney risk alleles are associated with increased risk for preeclampsia in a recessive mode of inheritance in African Americans and suggests that maternal-fetal genotype discordance is also associated with this risk. These conclusions underscore the need to better understand maternal-fetal interaction and their genetic and environmental factors as contributors to ethnic disparities in preeclampsia.

Applying graph database technology for analyzing perturbed co-expression networks in cancer.

Graph representations provide an elegant solution to capture and analyze complex molecular mechanisms in the cell. Co-expression networks are undirected graph representations of transcriptional co-behavior indicating (co-)regulations, functional modules or even physical interactions between the corresponding gene products. The growing avalanche of available RNA sequencing (RNAseq) data fuels the construction of such networks, which are usually stored in relational databases like most other biological data. Inferring linkage by recursive multiple-join statements, however, is computationally expensive and complex to design in relational databases. In contrast, graph databases store and represent complex interconnected data as nodes, edges and properties, making it fast and intuitive to query and analyze relationships. While graph-based database technologies are on their way from a fringe domain to going mainstream, there are only a few studies reporting their application to biological data. We used the graph database management system Neo4j to store and analyze co-expression networks derived from RNAseq data from The Cancer Genome Atlas. Comparing co-expression in tumors versus healthy tissues in six cancer types revealed significant perturbation tracing back to erroneous or rewired gene regulation. Applying centrality, community detection and pathfinding graph algorithms uncovered the destruction or creation of central nodes, modules and relationships in co-expression networks of tumors. Given the speed, accuracy and straightforwardness of managing these densely connected networks, we conclude that graph databases are ready for entering the arena of biological data.

Prevalence of the UGT1A1*28 promoter polymorphism and breast cancer risk among African American women in Memphis, TN.

Inherited variations in UDP-glucuronosyltransferase 1A1 (UGT1A1) are associated with an increased breast cancer risk in women of African ancestry. The UGT1A1*28 promoter polymorphism is characterized by the presence of 7 TA repeats in the TATA box sequence and results in reduced UGT1A1 gene expression and enzymatic activity. In this study, we investigated associations between the UGT1A1*28 polymorphism and breast cancer risk among African American (AA) women in Memphis, Tennessee, a city with increased breast cancer mortality rates among AA women. Saliva was collected from 352 AA women, including breast cancer cases (n=82) and controls (n=270) between June 2016 to June 2017. DNA was isolated and sequenced for the UGT1A1*28 polymorphism. The odds ratio for cases with the low UGT1A1 activity alleles (TA)7/8 repeat genotypes versus 5/5, 5/6, and 6/6 genotypes was 1.46 [95% CI, 0.65-3.31; P = 0.36] in premenopausal women and 1.10 (95% CI, 0.52-2.38; P = 0.79) in postmenopausal women. Further analysis of TCGA RNA-seq data showed that UGT1A1 mRNA was significantly lower among estrogen receptor (ER)-negative breast cancers from AA as compared to non-Hispanic white women with ER-negative breast cancer. Larger epidemiological studies are needed to determine the functional consequence of the UGT1A1*28 polymorphism on breast cancer risk in AA women.

Systematic analysis of the intersection of disease mutations with protein modifications.

BACKGROUND: Perturbed posttranslational modification (PTM) landscapes commonly cause pathological phenotypes. The Cancer Genome Atlas (TCGA) project profiles thousands of tumors allowing the identification of spontaneous cancer-driving mutations, while Uniprot and dbSNP manage genetic disease-associated variants in the human population. PhosphoSitePlus (PSP) is the most comprehensive resource for studying experimentally observed PTM sites and the only repository with daily updates on functional annotations for many of these sites. To elucidate altered PTM landscapes on a large scale, we integrated disease-associated mutations from TCGA, Uniprot, and dbSNP with PTM sites from PhosphoSitePlus. We characterized each dataset individually, compared somatic with germline mutations, and analyzed PTM sites intersecting directly with disease variants. To assess the impact of mutations in the flanking regions of phosphosites, we developed DeltaScansite, a pipeline that compares Scansite predictions on wild type versus mutated sequences. Disease mutations are also visualized in PhosphoSitePlus. RESULTS: Characterization of somatic variants revealed oncoprotein-like mutation profiles of U2AF1, PGM5, and several other proteins, showing alteration patterns similar to germline mutations. The union of all datasets uncovered previously unknown losses and gains of PTM events in diseases unevenly distributed across different PTM types. Focusing on phosphorylation, our DeltaScansite workflow predicted perturbed signaling networks consistent with calculations by the machine learning method MIMP. CONCLUSIONS: We discovered oncoprotein-like profiles in TCGA and mutations that presumably modify protein function by impacting PTM sites directly or by rewiring upstream regulation. The resulting datasets are enriched with functional annotations from PhosphoSitePlus and present a unique resource for potential biomarkers or disease drivers.

Small posterior fossa in Chiari I malformation affected families is significantly linked to 1q43-44 and 12q23-24.11 using whole exome sequencing.

The posterior fossa of the cranium contains the cerebellum and brainstem. Processes that reduce the volume of the posterior fossa squeeze the cerebellum and brainstem caudally, resulting in Chiari I malformation (CM1). CM1 causes neck pain, balance issues, decreased motor skills and headaches in those affected. We have posterior fossa measurements and whole exome sequence data on individuals from 7 extended families from Russia that have a family history of CM1. We performed parametric linkage analyses using an autosomal dominant inheritance model with a disease allele frequency of 0.01 and a penetrance of 0.8 for carriers and 0.0 for non-carriers. Variant-based two-point linkage analysis and gene-based linkage analysis was performed. Our results found a genome-wide significant signal on chromosome 1q43-44 (max HLOD = 3.3) in the variant-based analysis and 12q23 (max HLOD = 4.2) in the gene-based analysis. In both cases, the signal was driven by a single (different) family that contained a long, linked haplotype across the region in question. Using functional annotation, we were able to identify several rare nonsynonymous variants that were enriched in each family. The best candidate genes were rs765865412:G>A in MYBPC1 for the 12q haplotype and rs61749963:A>G in COX20 for the 1q haplotype. Good candidate variants in the 1q haplotype were also identified in CEP170 and AKT. Further laboratory work is planned to verify the causality of these genes.

Return to sport following surgical management of triangular fibrocartilage tears: a systematic review.

INTRODUCTION: This review aims to provide information on return rates and times to return to sport following surgical management of triangular fibrocartilage (TFC) tears. SOURCES OF DATA: A systematic search of CINAHAL, Cochrane, EMBASE, Google Scholar, Medline, PEDro, Scopus, SPORTDiscus and Web of Science was performed using the keywords 'triangular', 'fibro-cartilage', 'complex', 'tear', 'distal radio-ulnar joint', 'athletes', 'sports', 'non-operative', 'conservative', 'operative' and 'return to sport'. AREAS OF AGREEMENT: In all of the 10 studies included, conservative management for 6 weeks to 6 months was the first-line treatment. If symptoms persisted following this period, surgical management was advised. Arthroscopic debridement was recommended for central tears, and arthroscopic repair was recommended for peripheral tears. AREAS OF CONTROVERSY: The optimal treatment modalities for TFC tears remain to be defined. GROWING POINTS: Traumatic central tears can be treated with arthroscopic debridement alone. Arthroscopic repair with an all-inside repair can improve return rates to sport over an outside-in technique for ulna-sided tears. AREAS TIMELY FOR DEVELOPING RESEARCH: Future prospective studies should aim to establish the optimal treatment modalities for TFC tears.