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The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.

BackgroundGestational diabetes and gestational hypertensive disorders are associated with offspring obesity, but the role of maternal adiposity in these associations remains unclear. We aimed to investigate whether these pregnancy complications affect the odds of offspring obesity independently of maternal obesity.MethodsWe did an individual participant data (IPD) meta-analysis of mother-offspring pairs from prospective birth cohort studies that had IPD on mothers with singleton liveborn children born from 1989 onwards and had information available about maternal gestational diabetes, gestational hypertension or pre-eclampsia, and childhood body-mass index (BMI). We applied multilevel mixed-effects models to assess associations of gestational diabetes, gestational hypertension, and pre-eclampsia with BMI SD scores and the odds of overweight and obesity throughout childhood, adjusting for lifestyle characteristics (offspring's sex, maternal age, educational level, ethnicity, parity, and smoking during pregnancy). We then explored the extent to which any association was explained by maternal pre-pregnancy or early-pregnancy BMI.Findings160 757 mother-offspring pairs from 34 European or North American cohorts were analysed. Compared with uncomplicated pregnancies, gestational diabetes was associated with increased odds of overweight or obesity throughout childhood (odds ratio [OR] 1·59 [95% CI 1·36 to 1·86] for early childhood [age 2·0-4·9 years], 1·41 [1·26 to 1·57] for mid childhood [5·0-9·9 years], and 1·32 [0·97 to 1·78] for late childhood [10·0-17·9 years]); however, these associations attenuated towards the null following adjustment for maternal BMI (OR 1·35 [95% CI 1·15 to 1·58] for early childhood, 1·12 [1·00 to 1·25] for mid childhood, and 0·96 [0·71 to 1·31] for late childhood). Likewise, gestational hypertension was associated with increased odds of overweight throughout childhood (OR 1·19 [95% CI 1·01 to 1·39] for early childhood, 1·23 [1·15 to 1·32] for mid childhood, and 1·49 [1·30 to 1·70] for late childhood), but additional adjustment for maternal BMI largely explained these associations (1·01 [95% CI 0·86 to 1·19] for early childhood, 1·02 [0·95 to 1·10] for mid childhood, and 1·18 [1·03 to 1·36] for late childhood). Pre-eclampsia was associated with decreased BMI in early childhood only (difference in BMI SD score -0·05 SD score [95% CI -0·09 to -0·01]), and this association strengthened following additional adjustment for maternal BMI.InterpretationAlthough lowering maternal risk of gestational diabetes, gestational hypertension, and pre-eclampsia is important in relation to maternal and fetal pregnancy outcomes, such interventions are unlikely to have a direct impact on childhood obesity. Preventive strategies for reducing childhood obesity should focus on maternal BMI rather than on pregnancy complications.FundingEU's Horizon 2020 research and innovation programme (LifeCycle Project).

The realisation of human potential for development requires age-specific investment throughout the 8000 days of childhood and adolescence. Focus on the first 1000 days is an essential but insufficient investment. Intervention is also required in three later phases: the middle childhood growth and consolidation phase (5-9 years), when infection and malnutrition constrain growth, and mortality is higher than previously recognised; the adolescent growth spurt (10-14 years), when substantial changes place commensurate demands on good diet and health; and the adolescent phase of growth and consolidation (15-19 years), when new responses are needed to support brain maturation, intense social engagement, and emotional control. Two cost-efficient packages, one delivered through schools and one focusing on later adolescence, would provide phase-specific support across the life cycle, securing the gains of investment in the first 1000 days, enabling substantial catch-up from early growth failure, and leveraging improved learning from concomitant education investments.

BackgroundMigraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine.MethodsWe performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS).ResultsWe identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene (P=2.97 × 10(-8), OR: 1.82, 95% CI: 1.47-2.25), although this was not replicated in a smaller sample of 289 migraine cases.LimitationsOur study is based on self-reported migraine.ConclusionsNBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium (n=118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder.

Chromatin-based functional genomic analyses and genomewide association studies (GWASs) together implicate enhancers as critical elements influencing gene expression and risk for common diseases. Here, we performed systematic chromatin and transcriptome profiling in human pancreatic islets. Integrated analysis of islet data with those from nine cell types identified specific and significant enrichment of type 2 diabetes and related quantitative trait GWAS variants in islet enhancers. Our integrated chromatin maps reveal that most enhancers are short (median = 0.8 kb). Each cell type also contains a substantial number of more extended (≥ 3 kb) enhancers. Interestingly, these stretch enhancers are often tissue-specific and overlap locus control regions, suggesting that they are important chromatin regulatory beacons. Indeed, we show that (i) tissue specificity of enhancers and nearby gene expression increase with enhancer length; (ii) neighborhoods containing stretch enhancers are enriched for important cell type-specific genes; and (iii) GWAS variants associated with traits relevant to a particular cell type are more enriched in stretch enhancers compared with short enhancers. Reporter constructs containing stretch enhancer sequences exhibited tissue-specific activity in cell culture experiments and in transgenic mice. These results suggest that stretch enhancers are critical chromatin elements for coordinating cell type-specific regulatory programs and that sequence variation in stretch enhancers affects risk of major common human diseases.

Gene transfer has therapeutic potential for treating HIV-1 infection by generating cells that are resistant to the virus. We have engineered a novel self-inactivating lentiviral vector, LVsh5/C46, using two viral-entry inhibitors to block early steps of HIV-1 cycle. The LVsh5/C46 vector encodes a short hairpin RNA (shRNA) for downregulation of CCR5, in combination with the HIV-1 fusion inhibitor, C46. We demonstrate here the effective delivery of LVsh5/C46 to human T cell lines, peripheral blood mononuclear cells, primary CD4(+) T lymphocytes, and CD34(+) hematopoietic stem/progenitor cells (HSPC). CCR5-targeted shRNA (sh5) and C46 peptide were stably expressed in the target cells and were able to effectively protect gene-modified cells against infection with CCR5- and CXCR4-tropic strains of HIV-1. LVsh5/C46 treatment was nontoxic as assessed by cell growth and viability, was noninflammatory, and had no adverse effect on HSPC differentiation. LVsh5/C46 could be produced at a scale sufficient for clinical development and resulted in active viral particles with very low mutagenic potential and the absence of replication-competent lentivirus. Based on these in vitro results, plus additional in vivo safety and efficacy data, LVsh5/C46 is now being tested in a phase 1/2 clinical trial for the treatment of HIV-1 disease.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in the DDC gene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno-associated virus serotype 2 vector encoding human AADC (AAV2-hAADC) in AADC-deficient children. Unfortunately, patients presented only modest amelioration of motor symptoms, which authors acknowledged could be due to insufficient transduction of putamen. We hypothesize that, with the development of a highly accurate MRI-guided cannula placement technology, a more effective approach might be to target the affected mid-brain neurons directly. Transduction of AADC-deficient dopaminergic neurons in the substantia nigra and ventral tegmental area with locally infused AAV2-hAADC would be expected to lead to restoration of normal dopamine levels in affected children. The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of non-human primates. Animals received either vehicle, low or high AAV2-hAADC vector dose and were euthanized 1, 3 or 9 months after surgery. Our data indicate that effective mid-brain transduction was achieved without untoward effects.