A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect siz

Oral symptoms and functional outcome related to oral and oropharyngeal cancer

Purpose This study aimed to assess: (1) oral symptoms of patients treated for oral or oropharyngeal cancer; (2) how patients rank the burden of oral symptoms; (3) the impact of the tumor, the treatment, and oral symptoms on functional outcome. Methods Eighty-nine patients treated for oral or oropharyngeal cancer were asked about their oral symptoms related to mouth opening, dental status, oral sensory function, tongue mobility, salivary function, and pain. They were asked to rank these oral symptoms according to the degree of burden experienced. The Mandibular Function Impairment Questionnaire (MFIQ) was used to assess functional outcome. In a multivariate linear regression analyses, variables related to MFIQ scores (p a parts per thousand currency signaEuro parts per thousand 0.10) were entered as predictors with MFIQ score as the outcome. Results Lack of saliva (52%), restricted mouth opening (48%), and restricted tongue mobility (46%) were the most frequently reported oral symptoms. Lack of saliva was most frequently (32%) ranked as the most burdensome oral symptom. For radiated patients, an inability to wear a dental prosthesis, a T3 or T4 stage, and a higher age were predictive of MFIQ scores. For non-radiated patients, a restricted mouth opening, an inability to wear a dental prosthesis, restricted tongue mobility, and surgery of the mandible were predictive of MFIQ scores. Conclusions Lack of saliva was not only the most frequently reported oral symptom after treatment for oral or oropharyngeal cancer, but also the most burdensome. Functional outcome is strongly influenced by an inability to wear a dental prosthesis in both radiated and non-radiated patients

Effects of Therapy in Oropharyngeal Dysphagia by Speech and Language Therapists: A Systematic Review

Medical and paramedical treatments should be evaluated according to current standards of evidence-based medicine. Evaluation of therapy in oropharyngeal dysphagia fits into this growing interest. A systematic review is given of the literature on the effects of therapy in oropharyngeal dysphagia carried out by speech therapists. Thus, the review excludes reports of surgical or pharmacological treatments. The literature search was performed using the electronic databases PubMed and Embase. All available inclusion dates up to November 2008 were used. The search was limited to English, German, French, Spanish, and Dutch publications. MESH terms were supplemented by using free-text words (for the period after January 2005). Fifty-nine studies were included. In general, statistically significant positive therapy effects were found. However, the number of papers was rather small. Moreover, diverse methodological problems were found in many of these studies. For most studies, the conclusions could not be generalized; comparison was hindered by the range of diagnoses, types of therapies, and evaluation techniques. Many questions remain about the effects of therapy in oropharyngeal dysphagia as performed by speech and language therapists. Although some positive significant outcome studies have been published, further research based on randomized controlled trials is needed

De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures.

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Peer reviewe

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13×10– ¹⁵) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65×10– ²⁰) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69×10– ¹²; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR

Absence epilepsy and the CHD2 gene: an adolescent male with moderate intellectual disability, short-lasting psychoses, and an interstitial deletion in 15q26.1&ndash;q26.2

Willem MA Verhoeven,1,2 Jos IM Egger,1,3,4 Alida C Knegt,5 Jos&eacute; Zuydam,6 Tjitske Kleefstra7 1Centre of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, 2Department of Psychiatry, Erasmus University Medical Center, Rotterdam, 3Donders Institute for Brain, Cognition and Behaviour, 4Behavioural Science Institute, Radboud University, Nijmegen, 5Department of Clinical Genetics, University of Amsterdam Medical Center, Amsterdam, 6Reigersdaal Institute for Intellectual Disabilities, Heerhugowaard, 7Department of Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands Abstract: Deletions of the 15q26 region encompassing the chromodomain helicase DNA binding domain 2 (CHD2) gene have been associated with intellectual disability, behavioral problems, and several types of epilepsy. Including the cases mentioned in ECARUCA (European cytogeneticists association register of unbalanced chromosome aberrations) and DECIPHER (database of genomic variation and phenotype in humans using ensembl resources), so far, a total of 13 intellectually disabled patients with a genetically proven deletion of the CHD2 gene are described, of whom eleven had a history of severe forms of epilepsy starting from a young age. In this article, a moderately intellectually disabled 15-year-old male with a 15q26.1&ndash;q26.2 interstitial deletion is reported, who was referred for analysis of two recent short-lasting psychotic episodes that were nonresponsive to antipsychotic treatment and recurrent disinhibited behaviors since early infancy. Careful interdisciplinary assessment revealed that the psychotic phenomena originated from a previously unrecognized absence epilepsy. Treatment with valproic acid was started which resulted in full remission of psychotic symptoms, and consequently, substantial improvement of behavior. It was concluded that in case of (rare) developmental disorders with genetically proven etiology, a detailed inventory of anamnestic data and description of symptomatology over time may elucidate epilepsy-related psychopathology for which a specific treatment regimen is needed. Keywords: 15q26.1 interstitial deletion, CHD2 gene, intellectual disability, epilepsy, psychotic disorder, neuropsycholog