A new test for trait mean and variance detects unreported loci for blood-pressure variation.

Variability in quantitative traits has clinical, ecological, and evolutionary significance. Most genetic variants identified for complex quantitative traits have only a detectable effect on the mean of trait. We have developed the mean-variance test (MVtest) to simultaneously model the mean and log-variance of a quantitative trait as functions of genotypes and covariates by using estimating equations. The advantages of MVtest include the facts that it can detect effect modification, that multiple testing can follow conventional thresholds, that it is robust to non-normal outcomes, and that association statistics can be meta-analyzed. In simulations, we show control of type I error of MVtest over several alternatives. We identified 51 and 37 previously unreported associations for effects on blood-pressure variance and mean, respectively, in the UK Biobank. Transcriptome-wide association studies revealed 633 significant unique gene associations with blood-pressure mean variance. MVtest is broadly applicable to studies of complex quantitative traits and provides an important opportunity to detect novel loci.

Association of Win-Loss Record With Neuropsychiatric Symptoms and Brain Health Among Professional Fighters.

OBJECTIVE: Repetitive head impacts in professional fighting commonly lead to head injuries. Increased exposure to repetitive head trauma, measured by the number of professional fights and years of fighting, has been associated with slower processing speed and smaller brain volumes. The impact of win-loss outcomes has been investigated in other sports, with several studies suggesting that individuals on losing teams experience more head injuries. Here, the authors hypothesized that fighters with a worse fight record would exhibit poorer brain health outcomes. METHODS: The Professional Fighters Brain Health Study examined changes in neuropsychiatric symptoms, regional brain volume, and cognition among professional boxers and mixed martial arts fighters. These data were used to evaluate the relationship between win-loss ratios and brain health outcomes among professional fighters (N=212) by using validated neuropsychiatric symptom and cognitive measures and MRI data. RESULTS: Retired fighters with a better record demonstrated more impulsiveness (B=0.21, df=48) and slower processing speed (B=-0.42, df=31). More successful fighters did not perform better than fighters with worse records on any neuropsychiatric or cognitive test. Retired fighters with better fight records had smaller brain volumes in the subcortical gray matter, anterior corpus callosum, left and right hippocampi, left and right amygdala, and left thalamus. More successful active fighters had a smaller left amygdala volume. CONCLUSIONS: These findings suggest that among retired fighters, a better fight record was associated with greater impulsiveness, slower processing speed, and smaller brain volume in certain regions. This study shows that even successful fighters experience adverse effects on brain health.

Associations of Prior Head Injury With Mild Behavioral Impairment Domains.

OBJECTIVE: This study investigated associations of prior head injury and number of prior head injuries with mild behavioral impairment (MBI) domains. SETTING: The Atherosclerosis Risk in Communities (ARIC) Study. PARTICIPANTS: A total of 2534 community-dwelling older adults who took part in the ARIC Neurocognitive Study stage 2 examination were included. DESIGN: This was a prospective cohort study. Head injury was defined using self-reported and International Classification of Diseases, Ninth Revision ( ICD -9) code data. MBI domains were defined using the Neuropsychiatric Inventory Questionnaire (NPI-Q) via an established algorithm mapping noncognitive neuropsychiatric symptoms to the 6 domains of decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and abnormal perception/thought content. MAIN MEASURES: The primary outcome was the presence of impairment in MBI domains. RESULTS: Participants were a mean age of 76 years, with a median time from first head injury to NPI-Q administration of 32 years. The age-adjusted prevalence of symptoms in any 1+ MBI domains was significantly higher among individuals with versus without prior head injury (31.3% vs 26.0%, P = .027). In adjusted models, a history of 2+ head injuries, but not 1 prior head injury, was associated with increased odds of impairment in affective dysregulation and impulse dyscontrol domains, compared with no history of head injury (odds ratio [OR] = 1.83, 95% CI = 1.13-2.98, and OR = 1.74, 95% CI = 1.08-2.78, respectively). Prior head injury was not associated with symptoms in MBI domains of decreased motivation, social inappropriateness, and abnormal perception/thought content (all P > .05). CONCLUSION: Prior head injury in older adults was associated with greater MBI domain symptoms, specifically affective dysregulation and impulse dyscontrol. Our results suggest that the construct of MBI can be used to systematically examine the noncognitive neuropsychiatric sequelae of head injury; further studies are needed to examine whether the systematic identification and rapid treatment of neuropsychiatric symptoms after head injury is associated with improved outcomes.

Impact of motor dysfunction on neuropsychiatric symptom profile in patients with autopsy-confirmed Alzheimer's disease.

Motor dysfunction, which includes changes in gait, balance, and/or functional mobility, is a lesser-known feature of Alzheimer's Disease (AD), especially as it relates to the development of neuropsychiatric symptoms (NPS). This study (1) compared rates of NPS between autopsy-confirmed AD patients with and without early-onset motor dysfunction and (2) compared rates of non-AD dementia autopsy pathology (Lewy Body disease, Frontotemporal Lobar degeneration) between these groups. This retrospective longitudinal cohort study utilized National Alzheimer's Coordinating Center (NACC) data. Participants (N = 856) were required to have moderate-to-severe autopsy-confirmed AD, Clinical Dementia Rating-Global scores of ≤1 at their index visit, and NPS and clinician-rated motor data. Early motor dysfunction was associated with significantly higher NPI-Q total scores (T = 4.48, p < .001) and higher odds of delusions (OR [95%CI]: 1.73 [1.02-2.96]), hallucinations (2.45 [1.35-4.56]), depression (1.51 [1.11-2.06]), irritability (1.50 [1.09-2.08]), apathy (1.70 [1.24-2.36]), anxiety (1.38 [1.01-1.90]), nighttime behaviors (1.98 [1.40-2.81]), and appetite/eating problems (1.56 [1.09-2.25]). Early motor dysfunction was also associated with higher Lewy Body disease pathology (1.41 [1.03-1.93]), but not Frontotemporal Lobar degeneration (1.10 [0.71-1.69]), on autopsy. Our results suggest that motor symptoms in early AD are associated with a higher number and severity of NPS, which may be partially explained by comorbid non-AD neuropathology.

Sleepiness in retired male boxers: daytime sleepiness and its relationship with impulsiveness and depression symptomatology in retired professional male boxers.

BACKGROUND: Boxing exposes fighters to head impacts and potential traumatic brain injury (TBI). Though research has explored the neuropsychiatric consequences of contact sports, there is limited research into Excessive Daytime Sleepiness (EDS) and its relationship to other outcomes, such as impulsiveness and depression. Therefore, this study aimed to describe EDS in retired boxers using the Epworth Sleepiness Scale (ESS) and to examine how boxing and sleepiness relate to impulsiveness and depression symptomatology. METHODS: 86 male retired professional boxers from the Professional Fighters Brain Health Study (PFBHS) met the inclusion criteria. Adjusted multivariable models analyzed relationships between professional boxing bouts, EDS (ESS), impulsiveness (Barratt Impulsiveness Scale Version 11 (BIS-11)), and/or depression (Patient Health Questionnaire-9 (PHQ-9)). A causal mediation analysis was performed to assess whether boxing bouts and ESS scores predicted BIS-11 and PHQ-9 scores. RESULTS: Mean age was ∼51 years, fighters averaged ∼36 professional bouts, and ESS mean(SD) was 7.5(5.3). ESS scores were significantly associated with raw BIS-11 (Beta = 1.26, 95%CI = 0.77-1.75, p < 0.001) and ordinal PHQ-9 (OR = 1.20, 95%CI = 1.11-1.31, p < 0.001) scores in adjusted models, and the significant relationship between boxing bouts and BIS-11/PHQ-9 was mediated by ESS. CONCLUSIONS: EDS in retired male professional boxers may be strongly associated with other neuropsychiatric sequelae of TBI (impulsiveness and depression).Sleepiness; sleep; boxing; contact sports; impulsiveness; impulsivity; depression; Epworth sleepiness scale box.

Developing Workforce Skills and Capacity in Telehealth: What LEND Trainees Need to Know.

INTRODUCTION: The COVID-19 pandemic significantly impacted the way health-related services are delivered, rapidly shifting from in-person to telehealth visits. To ensure that future healthcare providers are fully prepared to deliver services to families of youth with neurodevelopmental disabilities (NDD), understanding telehealth's advantages and barriers is vital. To this end, data were gathered to inform the development of a nationally available telehealth curriculum aimed at training future healthcare professionals from the Leadership Education in Neurodevelopmental Disabilities (LEND) network. METHODS: Surveys were sent out nationally to current LEND trainees, practicing healthcare professionals, and family members of youth with NDD in November of 2020. Multiple choice and free response questions were completed and analyzed. A total of N = 208 surveys were completed (88 LEND trainees, 94 practicing professionals, 23 family members). RESULTS: Most survey respondents reported having positive experiences with telehealth. LEND trainees and current healthcare professionals cited increased access to care and engagement as the top benefit of telehealth. Most family members reported using telehealth services (78%) and felt it was superior to in-person visits in terms of location of visit, scheduling, and meeting transportation needs. Trainees and professionals agreed the top barriers to telehealth for families were lack of broadband access and complexity of implementation and use. LEND trainees agreed telehealth basics should be included in LEND curriculum. DISCUSSION: Trainees, professionals, and family members all agreed that knowing the basics of telehealth is essential for effective telehealth service delivery. Emerging healthcare professionals need to understand how those they will be serving engage with technology, their levels of experience in this area, and effective strategies for engaging children and youth with NDD through telehealth. This will bridge the engagement gap many families of children with disabilities face when not meeting in person. Findings from this study contributed to the design of learning materials that currently support LEND trainees across the country in developing these skills.

Using a LIFE Framework to Develop MCH Leaders.

INTRODUCTION: The Maternal Child Health (MCH) Bureau created MCH Leadership Competencies to support current and future leaders by defining the knowledge and skills necessary to lead in this field. The Michigan-LEND (MILEND) training program developed a 'LIFE. framework', an acronym that stands for Leadership, Interdisciplinary, Family-Professional Partnerships, and Equity, to codify the 12 MCH leadership competencies into an easy to remember and easy to apply structure. This manuscript addresses the question, Does the LIFE framework align with the 12 MCH Leadership Competencies? Our hypothesis is that MI-LEND trainees will demonstrate improvement in their self-assessment of the 12 MCH leadership competencies after completing the MI-LEND program which uses the LIFE framework. METHODS: Data were collected from 24 MI-LEND long-term trainees (> 300 hours) who completed a 100-itemleadership self-assessment questionnaire based on the MCH Navigator at the beginning and the end of the training year. Non-parametric sign tests were used to test the median difference, item by item for each of the questions under each competency. Parametric paired-sample t-tests were used to analyze mean difference, competency by competency when the assumption of normality was met. RESULTS: All basic and advanced-level competencies had a statistically significant improvement between the beginning and end of the training year. The greatest changes were seen in Family-Professional Partnerships, Policy, Interdisciplinary Team Building, MCH Knowledge Base and Critical Thinking - all areas emphasized in the L.I.F.E. DISCUSSION: While the LIFE framework may oversimplify MCH Leadership Competencies, it is an effective mnemonic tool to organize and articulate MCH leadership competencies and could foster consistency across MCH programs.

Evaluating the Benefits of a Family Support Program on the Health and Well-Being of Aging Family Caregivers of Adults with Intellectual and Developmental Disabilities.

Providing care to a family member with intellectual and developmental disabilities (I/DD) takes a toll on the health of the caregiver and the family, especially as they age. Research shows that peer mediated family support programs can improve caregiver health and well-being. To date, most family support programs have focused on family caregivers of children and youth with I/DD. The purpose of this study was to examine the benefits of participating in the Michigan Older Caregivers of Emerging Adults with Autism and Neurodevelopmental Disabilities (MI-OCEAN) family support program grounded in the Family Quality of Life (FQOL) framework. Specifically, we examined the effect of participation on health care utilization, caregiver well-being, and perceptions of global FQOL for older caregivers of adults with I/DD. Quantitative analysis of data gathered from 82 caregivers (age 50 and older) indicated that study participation was associated with increased use of Medicaid and improved caregiver well-being (reduced burden, stress, depression; increased health satisfaction and FQOL). Future research is needed to examine the long-term impact of the family support programs in improving the health and well-being of older caregivers of adults with I/DD.

The Promise of Polygenic Risk Prediction in Smoking Cessation: Evidence From Two Treatment Trials.

INTRODUCTION: Tobacco use disorder is a complex behavior with a strong genetic component. Genome-wide association studies (GWAS) on smoking behaviors allow for the creation of polygenic risk scores (PRSs) to approximate genetic vulnerability. However, the utility of smoking-related PRSs in predicting smoking cessation in clinical trials remains unknown. AIMS AND METHODS: We evaluated the association between polygenic risk scores and bioverified smoking abstinence in a meta-analysis of two randomized, placebo-controlled smoking cessation trials. PRSs of smoking behaviors were created using the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN) consortium summary statistics. We evaluated the utility of using individual PRS of specific smoking behavior versus a combined genetic risk that combines PRS of all four smoking behaviors. Study participants came from the Transdisciplinary Tobacco Use Research Centers (TTURCs) Study (1091 smokers of European descent), and the Genetically Informed Smoking Cessation Trial (GISC) Study (501 smokers of European descent). RESULTS: PRS of later age of smoking initiation (OR [95% CI]: 1.20, [1.04-1.37], p = .0097) was significantly associated with bioverified smoking abstinence at end of treatment. In addition, the combined PRS of smoking behaviors also significantly predicted bioverified smoking abstinence (OR [95% CI] 0.71 [0.51-0.99], p = .045). CONCLUSIONS: PRS of later age at smoking initiation may be useful in predicting smoking cessation at the end of treatment. A combined PRS may be a useful predictor for smoking abstinence by capturing the genetic propensity for multiple smoking behaviors. IMPLICATIONS: There is a potential for polygenic risk scores to inform future clinical medicine, and a great need for evidence on whether these scores predict clinically meaningful outcomes. Our meta-analysis provides early evidence for potential utility of using polygenic risk scores to predict smoking cessation amongst smokers undergoing quit attempts, informing further work to optimize the use of polygenic risk scores in clinical care.

Dissecting the genetic overlap of smoking behaviors, lung cancer, and chronic obstructive pulmonary disease: A focus on nicotinic receptors and nicotine metabolizing enzyme.

Smoking is a major contributor to lung cancer and chronic obstructive pulmonary disease (COPD). Two of the strongest genetic associations of smoking-related phenotypes are the chromosomal regions 15q25.1, encompassing the nicotinic acetylcholine receptor subunit genes CHRNA5-CHRNA3-CHRNB4, and 19q13.2, encompassing the nicotine metabolizing gene CYP2A6. In this study, we examined genetic relations between cigarettes smoked per day, smoking cessation, lung cancer, and COPD. Data consisted of genome-wide association study summary results. Genetic correlations were estimated using linkage disequilibrium score regression software. For each pair of outcomes, z-score-z-score (ZZ) plots were generated. Overall, heavier smoking and decreased smoking cessation showed positive genetic associations with increased lung cancer and COPD risk. The chromosomal region 19q13.2, however, showed a different correlational pattern. For example, the effect allele-C of the sentinel SNP (rs56113850) within CYP2A6 was associated with an increased risk of heavier smoking (z-score = 19.2; p = 1.10 × 10-81 ), lung cancer (z-score = 8.91; p = 5.02 × 10-19 ), and COPD (z-score = 4.04; p = 5.40 × 10-5 ). Surprisingly, this allele-C (rs56113850) was associated with increased smoking cessation (z-score = -8.17; p = 2.52 × 10-26 ). This inverse relationship highlights the need for additional investigation to determine how CYP2A6 variation could increase smoking cessation while also increasing the risk of lung cancer and COPD likely through increased cigarettes smoked per day.

Studying the Utility of Using Genetics to Predict Smoking-Related Outcomes in a Population-Based Study and a Selected Cohort.

INTRODUCTION: The purpose of this study is to examine the predictive utility of polygenic risk scores (PRSs) for smoking behaviors. AIMS AND METHODS: Using summary statistics from the Sequencing Consortium of Alcohol and Nicotine use consortium, we generated PRSs of ever smoking, age of smoking initiation, cigarettes smoked per day, and smoking cessation for participants in the population-based Atherosclerosis Risk in Communities (ARIC) study (N = 8638), and the Collaborative Genetic Study of Nicotine Dependence (COGEND) (N = 1935). The outcomes were ever smoking, age of smoking initiation, heaviness of smoking, and smoking cessation. RESULTS: In the European ancestry cohorts, each PRS was significantly associated with the corresponding smoking behavior outcome. In the ARIC cohort, the PRS z-score for ever smoking predicted smoking (odds ratio [OR]: 1.37; 95% confidence interval [CI]: 1.31, 1.43); the PRS z-score for age of smoking initiation was associated with age of smoking initiation (OR: 0.87; 95% CI: 0.82, 0.92); the PRS z-score for cigarettes per day was associated with heavier smoking (OR: 1.17; 95% CI: 1.11, 1.25); and the PRS z-score for smoking cessation predicted successful cessation (OR: 1.24; 95% CI: 1.17, 1.32). In the African ancestry cohort, the PRSs did not predict smoking behaviors. CONCLUSIONS: Smoking-related PRSs were associated with smoking-related behaviors in European ancestry populations. This improvement in prediction is greatest in the lowest and highest genetic risk categories. The lack of prediction in African ancestry populations highlights the urgent need to increase diversity in research so that scientific advances can be applied to populations other than those of European ancestry. IMPLICATIONS: This study shows that including both genetic ancestry and PRSs in a single model increases the ability to predict smoking behaviors compared with the model including only demographic characteristics. This finding is observed for every smoking-related outcome. Even though adding genetics is more predictive, the demographics alone confer substantial and meaningful predictive power. However, with increasing work in PRSs, the predictive ability will continue to improve.

Correction: Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

[This corrects the article DOI: 10.1371/journal.pgen.1006728.].

Traumatic brain injury alters neuropsychiatric symptomatology in all-cause dementia.

INTRODUCTION: Traumatic brain injury (TBI) may alter the course of neuropsychiatric symptom (NPS) onset during dementia development. The connection among TBI, NPS, and dementia progression is of increasing interest to researchers and clinicians. METHODS: Incidence of NPS was examined in participants with normal cognition who progressed to all-cause dementia based on whether TBI history was present (n = 130) or absent (n = 849). Survival analyses were used to examine NPS incidence across 7.6 ± 3.0 years of follow-up. RESULTS: Participants with TBI history had increased prevalence and incidence of apathy (44.7% vs 29.9%, P = .0062; HRadj. = 1.708, P = .0018) and motor disturbances (17.2% vs 9.5%, P = .0458; HRadj. = 2.023, P = .0168), controlling for demographics and type of dementia diagnosis. Earlier anxiety onset was associated with TBI (692 days prior to dementia diagnosis vs 161 days, P = .0265). DISCUSSION: History of TBI is associated with increased risk for and earlier onset of NPS in the trajectory of dementia development.

The effect of age of first exposure to competitive fighting on cognitive and other neuropsychiatric symptoms and brain volume.

It has long been established that fighting sports such as boxing and mixed martial arts can lead to head injury. Prior work from this group on the Professional Fighters Brain Health Study found that exposure to repetitive head impacts is associated with lower brain volumes and decreased processing speed in fighters. Current and previously licensed professional fighters were recruited, divided into active and retired cohorts, and matched with a control group that had no prior experience in sports with likely head trauma. This study examined the relationship between age of first exposure (AFE) to fighting sports and brain structure (MRI regional volume), cognitive performance (CNS Vital Signs, iComet C3), and clinical neuropsychiatric symptoms (PHQ-9, Barratt Impulsiveness Scale). Brain MRI data showed significant correlations between earlier AFE and smaller bilateral hippocampal and posterior corpus callosum volumes for both retired and active fighters. Earlier AFE in active fighters was correlated with decreased processing speed and decreased psychomotor speed. Retired fighters showed a correlation between earlier AFE and higher measures of depression and impulsivity. Overall, the results help to inform clinicians, governing bodies, parents, and athletes of the risks associated with beginning to compete in fighting sports at a young age.

History of traumatic brain injury interferes with accurate diagnosis of Alzheimer's dementia: a nation-wide case-control study.

Traumatic brain injury (TBI) and Alzheimer's disease (AD) bear a complex relationship, potentially increasing risk of one another reciprocally. However, recent evidence suggests post-TBI dementia exists as a distinct neurodegenerative syndrome, confounding AD diagnostic accuracy in clinical settings. This investigation sought to evaluate TBI's impact on the accuracy of clinician-diagnosed AD using gold standard neuropathological criteria. In this preliminary analysis, data were acquired from the National Alzheimer's Coordinating Centre (NACC), which aggregates clinical and neuropathologic information from Alzheimer's disease centres across the United States. Modified National Institute on Aging-Reagan criteria were applied to confirm AD by neuropathology. Among participants with clinician-diagnosed AD, TBI history was associated with misdiagnosis (false positives) (OR = 1.351 [95% CI: 1.091-1.674], p = 0.006). Among participants without clinician-diagnosed AD, TBI history was not associated with false negatives. TBI moderates AD diagnostic accuracy. Possible AD misdiagnosis can mislead patients, influence treatment decisions, and confound research study designs. Further work examining the influence of TBI on dementia diagnosis is warranted.

Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

Estimating Uterine Fibroid SNP-Based Heritability in European American Women with Imaging-Confirmed Fibroids.

BACKGROUND: Heritability estimates (including twin and single nucleotide polymorphism [SNP]-based heritability studies) for fibroids have been inconsistent across prior studies ranging between 9 and 69%. These inconsistencies are due to variations in study design and included populations. A major design issue has been lack of imaging confirmation to identify controls, where asymptomatic women without imaging confirmation may be misclassified as controls leading to an attenuation of heritability estimates. To reconcile the differences in prior heritability estimates and the impact of misclassification of controls on heritability, we determined SNP-based heritability and characterized the genetic architecture of pelvic image-confirmed fibroid cases and controls. METHODS: Analyses were performed among women of European American descent using genome-wide SNP data from BioVU, a clinical database composed of DNA linked to de-identified electronic health records. We estimated the genetic variance explained by all SNPs using Genome-Wide Complex Trait Analysis on imputed data. Fibroid cases and controls were identified using a previously reported phenotyping algorithm that required pelvic imaging confirmation. RESULTS: In total, we used 1,067 image-confirmed fibroid cases and 1,042 image-confirmed fibroid controls. The SNP-based heritability estimate for fibroid risk was h2 = 0.33 ± 0.18 (p = 0.040). We investigated the relationship between heritability per chromosome and chromosome length (r2 < 1%), with chromosome 8 explaining the highest proportion of variance for fibroid risk. There was no enrichment for intergenic or genic SNPs for the fibroid SNP-based heritability. Excluding loci previously associated with fibroid risk from genome-wide association study did not attenuate fibroid heritability suggesting that loci associating with fibroid risk are yet to be discovered. CONCLUSIONS: We observed that fibroid SNP-based heritability was higher than the previous estimate using genome-wide SNP data that relied on self-reported outcomes, but within the range of prior twin pair studies. Furthermore, these data support that imprecise phenotyping can significantly affect the ability to estimate heritability using genotype data.

Fine-scale geographic patterns of gene flow and reproductive character displacement in Drosophila subquinaria and Drosophila recens.

When two species are incompletely isolated, strengthening premating isolation barriers in response to the production of low fitness hybrids may complete the speciation process. Here, we use the sister species Drosophila subquinaria and Drosophila recens to study the conditions under which this reinforcement of species boundaries occurs in natural populations. We first extend the region of known sympatry between these species, and then we conduct a fine-scale geographic survey of mate discrimination coupled with estimates of gene flow within and admixture between species. Within D. subquinaria, reinforcement is extremely effective: we find variation in mate discrimination both against D. recens males and against conspecific allopatric males on the scale of a few kilometres and in the face of gene flow both from conspecific populations and introgression from D. recens. In D. recens, we do not find evidence for increased mate discrimination in sympatry, even where D. recens is rare, consistent with substantial gene flow throughout the species' range. Finally, we find that introgression between species is asymmetric, with more from D. recens into D. subquinaria than vice versa. Within each species, admixture is highest in the geographic region where it is rare relative to the other species, suggesting that when hybrids are produced they are of low fitness. In sum, reinforcement within D. subquinaria is effective at maintaining species boundaries, but even when reinforcing selection is strong it may not always result in a pattern of strong reproductive character displacement due to variation in the frequency of hybridization and gene flow from neighbouring populations.

An integrative genomics approach for identifying novel functional consequences of PBRM1 truncated mutations in clear cell renal cell carcinoma (ccRCC).

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Recent large-scale next-generation sequencing analyses reveal that PBRM1 is the second most frequently mutated gene harboring many truncated mutations and has a suspected tumor suppressor role in ccRCC. However, the biological consequences of PBRM1 somatic mutations (e.g., truncated mutations) that drive tumor progression in ccRCC remain unclear. METHODS: In this study, we proposed an integrative genomics approach to explore the functional consequences of PBRM1 truncated mutations in ccRCC by incorporating somatic mutations, mRNA expression, DNA methylation, and microRNA (miRNA) expression profiles from The Cancer Genome Atlas (TCGA). We performed a systematic analysis to detect the differential molecular features in a total of 11 ccRCC samples harboring PBRM1 truncated mutations from the 33 "pan-negative" ccRCC samples. We excluded the samples that had any of the five high-confidence driver genes (VHL, BAP1, SETD2, PTEN and KDM5C) reported in ccRCC to avoid their possible influence in our results. RESULTS: We identified 613 differentially expressed genes (128 up-regulated and 485 down-regulated genes using cutoff |log2FC| > 1 and p < 0.05) in PBRM1 mutated group versus "pan-negative" group. The gene function enrichment analysis revealed that down-regulated genes were significantly enriched in extracellular matrix organization (adjusted p = 2.05 × 10(-7)), cell adhesion (adjusted p = 2.85 × 10(-7)), and ion transport (adjusted p = 9.97 × 10(-6)). Surprisingly, 26 transcriptional factors (TFs) genes including HOXB9, PAX6 and FOXC1 were found to be significantly differentially expressed (23 over expressed TFs and three lower expressed TFs) in PBRM1 mutated group compared with "pan-negative" group. In addition, we identified 1405 differentially methylated CpG sites (targeting 1308 genes, ||log2FC| > 1, p < 0.01) and 185 significantly altered microRNAs (|log2FC| > 1, p < 0.05) associated with truncated PBRM1 mutations. Our integrative analysis suggested that methylation and miRNA alterations were likely the downstream events associated with PBRM1 truncation mutations. CONCLUSIONS: In summary, this study provided some important insights into the understanding of tumorigenesis driven by PBRM1 truncated mutations in ccRCC. The approach may be applied to many driver genes in various cancers.