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Background Previous studies have found that children born with a non-syndromic orofacial cleft have lower-than-average educational attainment. Differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as social stigmatization, impaired speech/language development) or confounding by the prenatal environment. A clearer understanding of this mechanism will inform interventions to improve educational attainment in individuals born with a cleft, which could substantially improve their quality of life. We assessed evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment. Methods We performed a genome-wide association study (GWAS) meta-analysis of nsCL/P with 1692 nsCL/P cases and 4259 parental and unrelated controls. Using GWAS summary statistics, we performed Linkage Disequilibrium (LD)-score regression to estimate the genetic correlation between nsCL/P, educational attainment (GWAS n = 766 345) and intelligence (GWAS n = 257 828). We used two-sample Mendelian randomization to evaluate the causal effects of genetic liability to nsCL/P on educational attainment and intelligence. Results There was limited evidence for shared genetic aetiology or causal relationships between nsCL/P and educational attainment [genetic correlation (rg) −0.05, 95% confidence interval (CI) −0.12 to 0.01, P 0.13; MR estimate (βMR) −0.002, 95% CI −0.009 to 0.006, P 0.679) or intelligence (rg −0.04, 95% CI −0.13 to 0.04, P 0.34; βMR −0.009, 95% CI −0.02 to 0.002, P 0.11). Conclusions Common variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This is an important first step towards understanding the aetiology of low educational attainment in this group.

A DNA bank has been created from the Millennium Cohort Study (MCS) saliva samples. A total of 23,336 samples are available, from 9,259 cohort members (4,630 males and 4,629 females), 8,898 mothers and 5,179 fathers. There are 4,533 mother, child, father ‘triads’. This paper describes the collection of the saliva samples from cohort members and their biological parents in the MCS. It analyses response rates and predictors of response, and details the DNA extraction, genotyping and imputation procedures performed on the data.Key messagesIt describes the collection of saliva samples in the Millennium Cohort Study, from cohort members and their resident biological parents.It analyses response rates and predictors of response.It details the DNA extraction, genotyping and imputation procedures performed on the data.

Background Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to ∼ 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival. Results Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold (PBonferroni < 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10−05). Conclusions Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.

Importance Previous studies have found that children born with a non-syndromic form of cleft lip and/or palate have lower-than-average educational attainment. These differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as school absence, social stigmatization and impaired speech and language development), or confounding by the prenatal environment. If the association is not explained by a genetic predisposition, interventions and policies to improve educational attainment in individuals born with a cleft could have wide-ranging knock-on effects on their quality of life. Objective To assess evidence for the hypothesis that genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment. Methods Using summary data from genome-wide association studies (GWAS), we performed Linkage Disequilibrium (LD)-score regression and two-sample Mendelian randomization to evaluate the relationship between genetic liability to nsCL/P (GWAS n=3,987) and educational attainment (GWAS n=766,345), and intelligence (GWAS n=257,828). Results There was little evidence for shared genetic aetiology between nsCL/P and educational attainment (rg −0.03, 95% CI −0.14 to 0.08, P 0.58; βMR 0.002, 95% CI −0.001 to 0.005, P 0.417) or intelligence (rg −0.01, 95% CI −0.12 to 0.10, P 0.85; βMR 0.002, 95% CI −0.010 to 0.014, P 0.669). Conclusions and relevance Individuals born with nsCL/P are unlikely to be genetically predisposed to low educational attainment or intelligence. Therefore, clinical-, school-, social- and family-level interventions to improve educational attainment could be effective. Research summary Evidence before this study Previous studies have found that children born with a cleft lip/palate tend to have lower-than-average educational attainment, even in the absence of other birth defects or known syndromes. These differences could be due to a genetic predisposition to low intelligence caused by undiagnosed congenital differences in brain structure or function. Alternatively, these differences might be explained by downstream factors related to having a cleft, such as higher school absences to attend healthcare appointments, social stigmatization, or impaired speech and language development. The differences might also be explained by confounding factors such as family socioeconomic position or parental health behaviours (for example smoking or drinking alcohol). None of these proposed explanations has been investigated in detail and it is currently unclear why individuals born with a cleft tend to do less well at school. Added value of this study Using a causal inference technique called Mendelian randomization, this study suggests that any association between non-syndromic cleft lip/palate and lower educational attainment is unlikely to be caused by a genetic predisposition to both cleft and low intelligence or academic achievement. Implications of all the available evidence This study provides reassurance that non-syndromic children born with cleft lip/palate are unlikely to be genetically predisposed to do poorly at school and have lower intelligence. Therefore, interventions and policies to improve educational attainment in children born with a cleft could be effective. The target of these interventions will depend on further research to understand the causes of lower educational attainment in this group. This highlights the need for a largescale longitudinal patient cohort study combining genetic data with detailed information on clinical, social, environmental and developmental factors. The Cleft Collective Cohort Study has been established to address this need.

Objectives Head and neck squamous cell carcinoma (HNSCC) is often associated with chronic systemic inflammation (SI). In the present study, we assessed if DNA methylation-derived SI (mdSI) indices: Neutrophil-to-Lymphocyte ratio (mdNLR) and Lymphocyte-to-Monocyte ratio (mdLMR) are associated with the presence of HNSCC and overall survival (OS). Materials and methods We used two peripheral blood DNA methylation datasets: an HNSCC case-control dataset (n = 183) and an HNSCC survival dataset (n = 407) to estimate mdSI indices. We then performed multivariate regressions to test the association between mdSI indices, HNSCC development and OS. Results Multivariate logistic regression revealed that elevated mdNLR was associated with increased odds of being an HNSCC case (OR = 3.25, 95% CI = 2.14–5.34, P = 4 × 10−7) while the converse was observed for mdLMR (OR = 0.88, 95% CI = 0.81–0.90, P = 2 × 10−3). In the HNSCC survival dataset, HPV16-E6 seropositive HNSCC cases had an elevated mdLMR (P = 9 × 10−5) and a lower mdNLR (P = 0.003) compared to seronegative patients. Multivariate Cox regression in the HNSCC survival dataset revealed that lower mdLMR (HR = 1.96, 95% CI = 1.30–2.95, P = 0.0013) but not lower mdNLR (HR = 0.68, 95% CI = 0.46–1.00, P = 0.0501) was associated with increased risk of death. Conclusion Our results indicate that mdSI estimated by DNA methylation data is associated with the presence of HNSCC and overall survival. The mdSI indices may be used as a valuable research tool to reliably estimate SI in the absence of cell-based estimates. Rigorous validation of our findings in large prospective studies is warranted in the future.

Background Genome-wide association studies have identified associations of genetic variants at 17q21 near ORMDL3 with childhood asthma. Objectives We sought to determine whether associations in this region are specific to particular asthma phenotypes and specific to ORMDL3 . Methods We examined associations between 244 independent single nucleotide polymorphisms (SNPs) plus 13 previously identified asthma-related SNPs in the region between 34 and 36 Mb on chromosome 17 and early wheezing phenotypes, doctor-diagnosed asthma and atopy at 7½ years, and bronchial hyperresponsiveness and lung function at 8½ years in 7045 children from the Avon Longitudinal Study of Parents and Children birth cohort study. With this, cis expression quantitative trait loci signals for the same SNPs were assessed in 875 samples across genes in the same region. Results The strongest evidence for phenotypic association was seen for persistent wheezing (rs8076131 near ORMDL3 : relative risk ratio [RRR], 1.60 [95% CI, 1.40-1.84], P = 1.4 × 10 −11 ; rs2305480 near GSDML : RRR, 1.60 [95% CI, 1.39-1.83], P = 1.5 × 10 −11 ; and rs9303277 near IKZF3 : RRR, 1.57 [95% CI, 1.37-1.79], P = 4.4 × 10 −11 ). Similar but less precisely estimated effects were seen for intermediate-onset wheeze, but there was little evidence of associations with other wheezing phenotypes. There was some evidence of associations with bronchial hyperresponsiveness. SNPs across the whole region show strong evidence of association with differential levels of expression at GSDML , IKZF3 , and MED24 , as well as ORMDL3. Conclusions Associations of SNPs in the 17q21 locus are specific to asthma and specific wheezing phenotypes and are not explained by associations with intermediate phenotypes, such as atopy or lung function.

Full text and MPG-specific services(opens in a new window)| Export | Download | Add to List | More... Cleft Palate-Craniofacial Journal Volume 53, Issue 3, May 2016, Pages 317-325 Opportunities and challenges in establishing a cohort study: An example from cleft lip/palate research in the United Kingdom (Article) Stock, N.M.a , Humphries, K.b, St. Pourcain, B.b, Bailey, M.b, Persson, M.a, Ho, K.M.b, Ring, S.b, Marsh, C.c, Albery, L.c, Rumsey, N.a, Sandy, J.b a Centre for Appearance Research, University of the West of England, Coldharbour Lane, Bristol, United Kingdom b Faculty of Medicine and Dentistry, University of Bristol, United Kingdom c South West Cleft Service, University Hospitals Bristol NHS Foundation Trust, United Kingdom Hide additional affiliations View references (32) Abstract Background: Cleft lip and/or palate (CL/P) is one of the most common birth conditions in the world, but little is known about its causes. Professional opinion remains divided as to which treatments may be the most beneficial for patients with CL/P, and the factors that contribute to psychological adjustment are poorly understood. The use of different methodological approaches and tools plays a key role in hampering efforts to address discrepancies within the evidence base. A new UK-wide program of research, The Cleft Collective, was established to combat many of these methodological challenges and to address some of the key research questions important to all CL/P stakeholders. Objective: To describe the establishment of CL/P cohort studies in the United Kingdom and to consider the many opportunities this resource will generate. Results: To date, protocols have been developed and implemented within most UK cleft teams. Biological samples, environmental information, and data pertaining to parental psychological well-being and child development are being collected successfully. Recruitment is currently on track to meet the ambitious target of approximately 9800 individuals from just more than 3000 families. Conclusions: The Cleft Collective cohort studies represent a significant step forward for research in the field of CL/P. The data collected will form a comprehensive resource of information about individuals with CL/P and their families. This resource will provide the basis for many future projects and collaborations, both in the United Kingdom and around the world.