The hidden harm: alcohol’s impact on children and families

Examines the prevalence and effects of heavy drinking on families and children, and the extent to which they persisted or changed over time. Summary The 2015 study examined the prevalence and effects of heavy drinking on families and children, and the extent to which they persisted or changed over time. It paints a concerning picture of the prevalence of alcohol-related family and domestic violence in Australia, shedding new light on a hidden dimension of alcohol harms that occurs largely behind closed doors. Key findings The hidden harm draws on two national surveys of alcohol’s harm to others, service system data and qualitative interviews with families, providing for the first time a detailed and valuable insight into the magnitude of the problem and the large numbers of Australian children who are being put at risk. In 2011 there were 29,684 police-reported incidents of alcohol-related domestic violence in Australia, and that’s just in the four states and territories where this data is available. Children are being verbally abused, left in unsupervised or unsafe situations, physically hurt or exposed to domestic violence because of others’ drinking. Many were also witnessing verbal or physical conflict, drinking or inappropriate behaviour. Over a million children (22 per cent of all Australian children) are estimated to be affected in some way by the drinking of others (2008). 142,582 children were substantially affected (2008), and more than 10,000 Australian children are in the child protection system because of a carers drinking (2006-07)

Molecular characterisation of Haemoglobin Constant Spring and Haemoglobin Quong Sze with a combine-amplification refractory mutation system

Background: The interaction of the non-deletional α +- thalassaemia mutations Haemoglobin Constant Spring and Haemoglobin Quong Sze with the Southeast Asian double α-globin gene deletion results in non-deletional Haemoglobin H disease. Accurate detection of non-deletional Haemoglobin H disease, which is associated with severe phenotypes, is necessary as these mutations have been confirmed in the Malaysian population. Methods: DNA from two families with Haemoglobin H disease was extracted from EDTA-anticoagulated whole blood and subjected to molecular analysis for α-thalassaemia. A duplex polymerase chain reaction was used to detect the Southeast Asian α-globin gene deletion. Polymerase chain reaction-restriction fragment length polymorphism analysis was then carried out to determine the presence of Haemoglobin Constant Spring and Haemoglobin Quong Sze. A combine- amplification refractory mutation system protocol was optimised and implemented for the rapid and specific molecular characterisation of Haemoglobin Constant Spring and Haemoglobin Quong Sze in a single polymerase chain reaction. Results and Conclusions: The combine- amplification refractory mutation system for Haemoglobin Constant Spring and Haemoglobin Quong Sze, together with the duplex polymerase chain reaction, provides accurate pre- and postnatal diagnosis of non-deletional Haemoglobin H disease and allows detailed genotype analyses using minimal quantities of DNA

High throughput molecular confirmation of β-thalassemia mutations using novel TaqMan probes

β-Thalassemia is a public health problem where 4.5% of Malaysians are β-thalassemia carriers. The genetic disorder is caused by defects in the β-globin gene complex which lead to reduced or complete absence of β-globin chain synthesis. Five TaqMan genotyping assays were designed and developed to detect the common β-thalassemia mutations in Malaysian Malays. The assays were evaluated with 219 “blinded” DNA samples and the results showed 100% sensitivity and specificity. The in-house designed TaqMan genotyping assays were found to be cost- and time-effective for characterization of β-thalassemia mutations in the Malaysian population

High Prevalence of Alpha- and Beta-Thalassemia in the Kadazandusuns in East Malaysia: Challenges in Providing Effective Health Care for an Indigenous Group

Thalassemia can lead to severe transfusion-dependent anemia, and it is the most common genetic disorder in Malaysia. This paper aims to determine the prevalence of thalassemia in the Kadazandusuns, the largest indigenous group in Sabah, East Malaysia. α- and β-thalassemia were confirmed in 33.6% and 12.8%, of the individuals studied respectively. The high prevalence of α- and β-thalassemia in the Kadazandusuns indicates that thalassemia screening, genetic counseling, and prenatal diagnosis should be included as part of their healthcare system. This preliminary paper serves as a baseline for further investigations into the health and genetic defects of the major indigenous population in Sabah, East Malaysia

Molecular characterisation of β-globin gene mutations in Penang and Kedah, Malaysia

Introduction: Beta-thalassaemia is an autosomal recessive disorder and it is a public health problem in the Malaysian Malays and Chinese. This disorder mainly results from point mutations, small insertion or deletions in the β-globin gene complex. Beta-thalassaemia major patients require life-long monthly blood transfusions and iron-chelation therapies to sustain their lives. Mutation characterisation is necessary for affected couples at risk of having a β-thalassaemia major child. Objective: 1. To develop the TaqMan genotyping platform as a time- and cost-effective approach for characterisation of β-globin gene mutations. 2. To characterise the mutations using the developed assays in transfusion-dependent patients in Penang and Kedah. Methods: Ten sets of primers and TaqMan probes were designed to identify the common mutations in Malaysian Malays and Chinese: −28 (A→G), CD17 (A→T), CD19 (A→G), HbE (G→A), IVS1-1 (G→T), IVS1-5 (G→C), CD 41/42 (-CTTT), CD71/72 (+A), IVS2-654 (C→T) and Poly A (AATAAAHAATAGA). Another 7 sets of TaqMan genotyping assays were designed to identify the rare mutations in Malays and Chinese: −29 (A→G), Cap (+1) (A→C), CD8/9 (+G), CD16 (-C), CD27/28 (+C), IVS1-1 (G→A) and CD43 (G→T). The developed assays were used to screen 54 and 62 transfusion-dependent patients in Penang and Kedah respectively. Results & Discussion: The developed assays detected 92.9% of mutations in the β-thalassaemia major patients. The remaining mutations were detected by ARMS, gap-PCR and DNA sequencing. The most common mutation in β-thalassaemia major patients in Penang is CD41/42 with a frequency of 20.9%. The most common mutation in β-thalassaemia major patients in Kedah is HbE with a frequency of 30.8%. Conclusion: The simplicity and reproducibility of the TaqMan genotyping assays enable rapid and cost-effective analysis of the β-globin gene mutations in Malaysia

The time scale of recombination rate evolution in great apes

We present three linkage-disequilibrium (LD)-based recombination maps generated using whole-genome sequence data from 10 Nigerian chimpanzees, 13 bonobos, and 15 western gorillas, collected as part of the Great Ape Genome Project (Prado-Martinez J, et al. 2013. Great ape genetic diversity and population history. Nature 499:471-475). We also identified species-specific recombination hotspots in each group using a modified LDhot framework, which greatly improves statistical power to detect hotspots at varying strengths. We show that fewer hotspots are shared among chimpanzee subspecies than within human populations, further narrowing the time scale of complete hotspot turnover. Further, using species-specific PRDM9 sequences to predict potential binding sites (PBS), we show higher predicted PRDM9 binding in recombination hotspots as compared to matched cold spot regions in multiple great ape species, including at least one chimpanzee subspecies. We found that correlations between broad-scale recombination rates decline more rapidly than nucleotide divergence between species. We also compared the skew of recombination rates at centromeres and telomeres between species and show a skew from chromosome means extending as far as 10-15Mb from chromosome ends. Further, we examined broad-scale recombination rate changes near a translocation in gorillas and found minimal differences as compared to other great ape species perhaps because the coordinates relative to the chromosome ends were unaffected. Finally, on the basis of multiple linear regression analysis, we found that various correlates of recombination rate persist throughout the African great apes including repeats, diversity, and divergence. Our study is the first to analyze within- And between-species genome-wide recombination rate variation in several close relatives

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.Peer reviewedPublisher PD

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements