Meta-Analysis of Genome-Wide Association Studies and Network Analysis-Based Integration with Gene Expression Data Identify New Suggestive Loci and Unravel a Wnt-Centric Network Associated with Dupuytren’s Disease

Dupuytren´s disease, a fibromatosis of the connective tissue in the palm, is a common complex disease with a strong genetic component. Up to date nine genetic loci have been found to be associated with the disease. Six of these loci contain genes that code for Wnt signalling proteins. In spite of this striking first insight into the genetic factors in Dupuytren´s disease, much of the inherited risk in Dupuytren´s disease still needs to be discovered. The already identified loci jointly explain ~1% of the heritability in this disease. To further elucidate the genetic basis of Dupuytren´s disease, we performed a genome-wide meta-analysis combining three genome-wide association study (GWAS) data sets, comprising 1,580 cases and 4,480 controls. We corroborated all nine previously identified loci, six of these with genome-wide significance (p-value < 5x10-8). In addition, we identified 14 new suggestive loci (p-value < 10−5). Intriguingly, several of these new loci contain genes associated with Wnt signalling and therefore represent excellent candidates for replication. Next, we compared whole-transcriptome data between patient- and control-derived tissue samples and found the Wnt/β-catenin pathway to be the top deregulated pathway in patient samples. We then conducted network and pathway analyses in order to identify protein networks that are enriched for genes highlighted in the GWAS meta-analysis and expression data sets. We found further evidence that the Wnt signalling pathways in conjunction with other pathways may play a critical role in Dupuytren´s disease

Musculoskeletal pain is associated with restless legs syndrome in young adults

Background - In recent years, there is considerable evidence of a relationship between the sensorimotor disorder restless legs syndrome (RLS) and pain disorders, including migraine and fibromyalgia. An association between multi-site pain and RLS has been reported in adult women. In the current study, we explored the association between musculoskeletal (MSK) pain and RLS in a large cohort of young adults. Methods - Twenty two year olds (n = 1072), followed since birth of part of the Western Australian Pregnancy Cohort (Raine) Study, provided data on MSK pain (duration, severity, frequency, number of pain sites). RLS was considered present when 4 diagnostic criteria recommended by the International Restless Legs Syndrome Study Group were met (urge to move, dysaesthesia, relief by movement, worsening symptoms during the evening/night) and participants had these symptoms at least 5 times per month. Associations between MSK pain and RLS were analyzed by multivariable logistic regression with bias-corrected bootstrapped confidence intervals, with final models adjusted for sex, psychological distress and sleep quality. Results - The prevalence of RLS was 3.0 % and MSK pain was reported by 37.4 % of the participants. In multivariable logistic regression models, strong associations were found between RLS-diagnosis and long duration (three months or more) of MSK pain (odds ratio 3.6, 95 % confidence interval 1.4–9.2) and reporting three or more pain sites (4.9, 1.6–14.6). Conclusions - Different dimensions of MSK pain were associated with RLS in young adults, suggestive of shared pathophysiological mechanisms. Overlap between these conditions requires more clinical and research attention

Mortality and Morbidity

Historically, morbidity and mortality rates related to surgery for locally recurrent rectal cancer (LRRC) have been >70% and 30%, respectively [1\u20133]. Because of the excessive operative risks, the benefit of such resections has been questioned and \u2014 although radical operation for LRRC was conceptualized and reported more than 60 years ago \u2014 for years it has not been accepted as being standard procedure. More appropriate selection of candidates for resection due to advances in imaging modalities, improvement in surgical techniques, establishment of specialized multidisciplinary surgical teams, and improvement in quality of perioperative management have resulted in better outcomes in recent years. Currently, mortality rates vary between 0\u20135% at 1 month and 8% at 3 months [4]. The causes of death are mainly disseminated coagulopathies related to prolonged sepsis and blood loss, multiorgan failure, cardiac events, and pulmonary embolism [5, 6]. Morbidity remains significant, ranging from 15 to 68%, and increases with the complexity of resection [7\u201310]. Bleeding is the main and most severe intraoperative complication, and occurs in 0.2\u20139% of cases, and related mortality is high (4%) [11\u201314]. The principal postoperative complications include pelvic abscess (7\u201350%), intestinal obstruction (5\u201310%), enterocutaneous or enteroperineal fistulas (1.2%), perineal wound dehiscence (4\u201324%), and cardiovascular, renal, and pulmonary complications (1\u201320%) [5, 7, 8]

Restless Legs Syndrome and Pain Disorders: What’s in common?

Between 10 % and 30 % of the population report chronic pain. More than half of these also have sleep complaints. From considering these data, it can be inferred there is a significant overlapping between these conditions. Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is characterized by complaints of an urge to move frequently associated with dysesthesias. From that perspective, these sensations can also have painful characteristics. By the same token, the presence of comorbid diseases as predicted by a higher prevalence RLS/WED, have many of them with pain as an important complaint. Pain is a multidimensional response involving several levels of expression ranging from somatosensory to emotional. the potential shared mechanisms between RLS/WED and pain may involve sleep deprivation/fragmentation effect, inducing an increase in markers of inflammation and reduction in pain thresholds. These are modulated by several different settings of neurotransmitters with a huge participation of monoaminergic dysfunctional circuits. A thorough comprehension of these mechanisms is of utmost importance for the correct approach and treatment choices.Hosp Israelita Albert Einstein, Dept Neurofisiol Clin, BR-05652900 São Paulo, BrazilUniv Brasilia, Fac Med, BR-70844110 Brasilia, DF, BrazilHosp Israelita Albert Einstein, BR-05652900 São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Fac Med ABC FMABC, BR-05652900 São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Fac Med ABC FMABC, BR-05652900 São Paulo, BrazilWeb of Scienc

A systems genetics resource and analysis of sleep regulation in the mouse

<div><p>Sleep is essential for optimal brain functioning and health, but the biological substrates through which sleep delivers these beneficial effects remain largely unknown. We used a systems genetics approach in the BXD genetic reference population (GRP) of mice and assembled a comprehensive experimental knowledge base comprising a deep “sleep-wake” phenome, central and peripheral transcriptomes, and plasma metabolome data, collected under undisturbed baseline conditions and after sleep deprivation (SD). We present analytical tools to interactively interrogate the database, visualize the molecular networks altered by sleep loss, and prioritize candidate genes. We found that a one-time, short disruption of sleep already extensively reshaped the systems genetics landscape by altering 60%–78% of the transcriptomes and the metabolome, with numerous genetic loci affecting the magnitude and direction of change. Systems genetics integrative analyses drawing on all levels of organization imply α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and fatty acid turnover as substrates of the negative effects of insufficient sleep. Our analyses demonstrate that genetic heterogeneity and the effects of insufficient sleep itself on the transcriptome and metabolome are far more widespread than previously reported.</p></div