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We empirically investigated genomic clusters associated with both height and postmenopausal breast cancer (BC) or colorectal cancer (CRC) (or both) in the Netherlands Cohort Study to unravel shared underlying mechanisms between height and these cancers. The Netherlands Cohort Study (1986–2006) includes 120,852 participants (case-cohort study: nsubcohort = 5,000; 20.3 years of follow-up). Variants in clusters on chromosomes 2, 4, 5, 6 (2 clusters), 10, and 20 were genotyped using toenail DNA. Cluster-specific genetic risk scores were modeled in relation to height and postmenopausal BC and CRC risk using age-adjusted linear regression and multivariable-adjusted Cox regression, respectively. Only the chromosome 10 cluster risk score was associated with all 3 phenotypes in the same sex (women); that is, it was associated with increased height (βcontinuous = 0.34, P = 0.014), increased risk of hormone-receptor–positive BC (for estrogen-receptor–positive BC, hazard ratio (HRcontinuous score) = 1.10 (95% confidence interval (CI): 1.02, 1.20); for progesterone-receptor–positive BC, HRcontinuous score = 1.15 (95% CI: 1.04, 1.26)), and increased risk of distal colon (HRcontinuous score = 1.13, 95% CI: 1.01, 1.27) and rectal (HRcontinuous score = 1.14, 95% CI: 0.99, 1.30) cancer. The chromosome 10 cluster variants were all annotated to the zinc finger MIZ-type containing 1 gene (ZMIZ1), which is involved in androgen receptor activity. This suggests that hormone-related growth mechanisms could influence both height and postmenopausal BC and CRC.

Sirtuin 1 (SIRT1), a histone deacetylase, is involved in maintenance of genetic stability, inflammation, immune response, metabolism (energy-sensing molecule) and colorectal tumorigenesis. We investigated SIRT1’s specific role in colorectal tumorigenesis by studying SIRT1 polymorphisms in relation to colorectal cancer (CRC) risk by microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) status. The Netherlands Cohort study (NLCS) was initiated in 1986 and includes 120,852 participants in a case-cohort design. CRC tumour samples were available for incident cases between 1989 and 1993. Toenail deoxyribonucleic acid (DNA) was used for genotyping of two SIRT1 tagging variants (rs10997870 and rs12778366). Excluding the first 2.3 years of follow-up, subcohort members and CRC cases with no toenail DNA available and those with low sample call rates, and CRC cases with no tumour DNA available left 3478 subcohort members and 533 CRC cases. Cox regression was utilised to estimate hazard ratios (HRs) for MSI and CIMP positive and negative tumours by SIRT1 genotypes. The results were that the rs12778366 TC/CC versus TT genotype was inversely associated with MSI CRC (HR = 0.41, 95% confidence interval: 0.20, 0.88), while no association was found with the risk of an MSS tumour (TC/CC versus TT carriers: HR = 1.13, 95% CI: 0.89, 1.44). No significant associations were found between other SIRT1 genotypes and CRC subtypes. In conclusion, the results suggest a role for SIRT1 polymorphisms in colorectal tumorigenesis, particularly MSI CRC.

Background Autosomal recessive congenital ichthyosis (ARCI) is a rare genetically heterogeneous cutaneous disease predominantly characterized by erythroderma, generalized abnormal scaling of the whole body and a collodion membrane at birth. Numerous causative genes have been demonstrated to be responsible for ARCI including PNPLA1 which can cause ARCI type 10. The objectives of this study are to describe clinical features of three ARCI patients from two Chinese unrelated families and to identify the underlying causative mutations. Methods Genomic DNA was extracted from peripheral venous blood obtained from the two Chinese ARCI families in Shandong province. Subsequently, targeted regions sequencing (TRS) followed by Sanger sequencing was conducted to identify and validate the likely pathogenic mutations of the ARCI families. Results Genetic analyses revealed four novel PNPLA1 variants that are predicted to be probably to lead to ARCI in three patients of two families. Patient 1 in one family was in compound heterozygous status for c.604delC/p.Arg202Glyfs*27 and c.820dupC/p.Arg274Profs*15, whereas c.738_742delinsCCCACAGATCCTGC/ p.Gly247_Tyr248delinsProGlnIleLeuHis, and c.816dupC/p.Arg274Profs*15 were found in patient 2 and 3 of the other family. In addition, these variants cosegregate in the two pedigrees and are all within highly conserved regions of the PNPLA1 protein, which indicate that the four mutations are likely pathogenic. Conclusion Our findings not only broaden the mutational spectrum of PNPLA1, but also contribute to establishing genotype–phenotype correlations for different forms of ARCI., Genetic analyses in the present study revealed four novel PNPLA1 variants that are predicted to be probably to lead to ARCI in three patients of two families. In addition, these variants co segregate in the two pedigrees and are all within highly conserved regions of the PNPLA1 protein, which indicate that the four mutations are likely pathogenic.

We analyzed the highly pathogenic avian influenza (HPAI) H5 epizootic of 2016-17 in Europe by epidemiologic and genetic characteristics and compared it with 2 previous epizootics caused by the same H5 Guangdong lineage. The 2016-17 epizootic was the largest in Europe by number of countries and farms affected and greatest diversity of wild birds infected. We observed significant differences among the 3 epizootics regarding region affected, epidemic curve, seasonality, and outbreak duration, making it difficult to predict future HPAI epizootics. However, we know that in 2005-06 and 2016-17 the initial peak of wild bird detections preceded the peak of poultry outbreaks within Europe. Phylogenetic analysis of 2016-17 viruses indicates 2 main pathways into Europe. Our findings highlight the need for global surveillance of viral changes to inform disease preparedness, detection, and control.

Alcohol consumption has consistently been shown to increase breast cancer (BC) risk. This association may be modified by single nucleotide polymorphisms (SNPs) in alcohol dehydrogenase (ADH) isoenzymes ADH1B and ADH1C. The Netherlands Cohort Study comprises 62 573 women, aged 55-69 years at baseline (1986). Follow-up for postmenopausal BC for 20.3 years was available. Genotyping of six tag SNPs in ADH1B and ADH1C was performed on DNA from toenails. A case-cohort approach was used for analysis (complete data available for n(subcohort) = 1301; n(cases) = 1630). Cox regression models for postmenopausal BC were applied to determine marginal effects of alcohol intake and SNPs using a dominant genetic model, as well as multiplicative interaction of the two. Results were also obtained for subtypes by estrogen receptor (ER) and progesterone receptor (PR) status. Multiple testing was adjusted for by applying the false discovery rate (FDR). Alcohol intake (categorical) increased the risk of postmenopausal BC (P-trend = 0.031). Trends for ER and PR subgroups followed a similar pattern. Continuous modeling of alcohol resulted in a hazard rate ratio (HR) for overall postmenopausal BC of 1.09 (95% confidence interval: 1.01-1.19) per 10 g/day of alcohol. SNPs were not associated with BC risk. No effect modification of the alcohol-BC association by SNP genotype was seen after FDR correction in overall BC and ER/PR subgroups. In conclusion, alcohol consumption was shown to increase the risk of postmenopausal BC. This association was not significantly modified by common SNPs in ADH1B and ADH1C, neither in overall BC nor in hormone receptor-defined subtypes.

Coronaviruses are the well-known cause of severe respiratory, enteric and systemic infections in a wide range of hosts including man, mammals, fish, and avian. The scientific interest on coronaviruses increased after the emergence of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) outbreaks in 2002-2003 followed by Middle East Respiratory Syndrome CoV (MERS-CoV). This decade’s first CoV, named 2019-nCoV, emerged from Wuhan, China, and declared as ‘Public Health Emergency of International Concern’ on January 30th, 2020 by the World Health Organization (WHO). As on February 4, 2020, 425 deaths reported in China only and one death outside China (Philippines). In a short span of time, the virus spread has been noted in 24 countries. The zoonotic transmission (animal-to-human) is suspected as the route of disease origin. The genetic analyses predict bats as the most probable source of 2019-nCoV though further investigations needed to confirm the origin of the novel virus. The ongoing nCoV outbreak highlights the hidden wild animal reservoir of the deadly viruses and possible threat of spillover zoonoses as well. The successful virus isolation attempts have made doors open for developing better diagnostics and effective vaccines helping in combating the spread of the virus to newer areas.

We genetically characterized 22 Swiss patients who had been diagnosed with Stargardt disease after clinical examination. We identified in 11 patients (50%) pathogenic bi-allelic ABCA4 variants, c.1760+2T&gt, C and c.4496T&gt, C being novel. The dominantly inherited pathogenic ELOVL4 c.810C&gt, G p.(Tyr270*) and PRPH2-c.422A&gt, G p.(Tyr141Cys) variants were identified in eight (36%) and three patients (14%), respectively. All patients harboring the ELOVL4 c.810C&gt, G p.(Tyr270*) variant originated from the same small Swiss area, identifying a founder mutation. In the ABCA4 and ELOVL4 cohorts, the clinical phenotypes of “flecks”, “atrophy”, and “bull”s eye like” were observed by fundus examination. In the small number of patients harboring the pathogenic PRPH2 variant, we could observe both “flecks” and “atrophy” clinical phenotypes. The onset of disease, progression of visual acuity and clinical symptoms, inheritance patterns, fundus autofluorescence, and optical coherence tomography did not allow discrimination between the genetically heterogeneous Stargardt patients. The genetic heterogeneity observed in the relatively small Swiss population should prompt systematic genetic testing of clinically diagnosed Stargardt patients. The resulting molecular diagnostic is required to prevent potentially harmful vitamin A supplementation, to provide genetic counseling with respect to inheritance, and to schedule appropriate follow-up visits in the presence of increased risk of choroidal neovascularization.

Context: Heterozygous pathogenic germline variants in CDC73 predispose to the development of primary hyperparathyroidism (pHPT) and, less frequently, ossifying fibroma of the jaw and renal and uterine tumors. Clinical information on CDC73-related disorders has so far been limited to small case series.Objective: To assess the clinical manifestations and penetrance in CDC73-related disorders and to improve case detection in pHPT.Design: Nationwide retrospective Dutch cohort study.Setting: Tertiary referral center.Patients: We studied 89 patients with pHPT referred for germline CDC73 analysis and 43 subsequently tested relatives who proved to be mutation carriers.Investigation: Germline CDC73 mutation analysis.Mean Outcome: CDC73 mutation detection yield, referral rate, and CDC73-related disease penetrance.Results: Pathogenic germline CDC73 variants were identified in 11 of the 89 referred pHPT patients (12.4%), with (suspected) hyperparathyroidism-jaw tumor (HPT-JT) syndrome (n = 3), familial isolated pHPT (n = 5), apparently sporadic parathyroid carcinoma (n = 2), and apparently sporadic parathyroid adenoma (n = 1). The estimated penetrance of CDC73-related disorders was 65% at age 50 years (95% confidence interval, 48% to 82%) in 43 nonindex mutation carriers.Conclusions: Germline CDC73 analysis is recommended in individuals with (suspected) HPT-JT syndrome, familial isolated pHPT, atypical or malignant parathyroid histology, and young individuals with pHPT. These criteria would increase germline CDC73 mutation detection, enabling optimal clinical management of pHPT as well as genetic counseling and surveillance for family members at risk for developing CDC73-related disorders.

Background Pulmonary arterial hypertension (PAH) is a progressive and fatal disorder associated with high pulmonary artery pressure. Genetic testing enables early diagnosis and offers an opportunity for family screening. To identify genetic mutations and help make a precise diagnosis, we performed genetic testing in 191 probands with PAH and tried to analyze the genotype-phenotype correlation. Methods Initially, PAH samples (n = 119) were submitted to BMPR2 screening using Sanger sequencing. Later, we developed a PAH panel test to identify causal mutations in 13 genes related to PAH and tried to call BMPR2 copy number variations (CNVs) with the panel data. Multiplex ligation-dependent probe amplification (MLPA) was used to search for CNVs in BMPR2, ACVRL1 and ENG. Notably, EIF2AK4 gene was also involved in the panel, which allowed to distinguish pulmonary veno-occlusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH) patients from idiopathic PAH (IPAH). Characteristics of patients were compared using t test for continuous variables. Results Pathogenic BMPR2 mutations were detected most frequently in 32 (17.9%) IPAH and 5 (41.7%) heritable PAH (HPAH) patients by sequencing, and 12 BMPR2 CNVs called from the panel data were all successfully confirmed by MLPA analysis. In addition, homozygous or compound heterozygous EIF2AK4 mutations were identified in 6 patients, who should be corrected to a diagnosis of PVOD/PCH. Genotype-phenotype correlation analysis revealed that PAH patients with BMPR2 mutations were younger at diagnosis (27.2y vs. 31.6y, p = 0.0003) and exhibited more severe pulmonary hemodynamic impairment and a worse cardiac index compared with those without BMPR2 mutations. Conclusions The panel assay represented a highly valuable tool in PAH genetic testing, not only for the detection of small sequence alterations, but also for an indication of BMPR2 CNVs, which had implications for the specific samples to perform further MLPA assay. Analyses of PAH causal genes have a great help to clinical diagnosis and deep implications in disease treatment. Electronic supplementary material The online version of this article (10.1186/s12931-018-0789-9) contains supplementary material, which is available to authorized users.

The alcohol-colorectal cancer (CRC) association may differ by sex and ADH1B and ADH1C genotypes. ADH enzymes oxidize ethanol to acetaldehyde, both of which are human carcinogens. The Netherlands Cohort Study includes 120 852 participants, aged 55-69 years at baseline (1986), and has 20.3 years follow-up (case-cohort: n(subcohort) = 4774; n(cases) = 4597). The baseline questionnaire included questions on alcohol intake at baseline and 5 years before. Using toenail DNA, available for similar to 75% of the cohort, we successfully genotyped six ADH1B and six ADH1C SNPs (n(subcohort) = 3897; n(cases) = 3558). Sex-and subsite-specific Cox hazard ratios and 95% confidence intervals for CRC were estimated comparing alcohol categories, genotypes within drinkers and alcohol categories within genotype strata. We used a dominant genetic model and adjusted for multiple testing. Alcohol intake increased CRC risk in both sexes, though in women only in the (proximal) colon when in excess of 30 g/day. In male drinkers, ADH1B rs4147536 increased (distal) colon cancer risk. In female drinkers, ADH1C rs283415 increased proximal colon cancer risk. ADH1B rs3811802 and ADH1C rs4147542 decreased CRC risk in heavy (> 30 g/day) and stable drinkers (compared to 5 years before baseline), respectively. Rs3811802 and rs4147542 significantly modified the alcohol-colon cancer association in women (P-for interaction = 0.004 and 0.02, respectively). A difference in associations between genotype strata was generally clearer in men than women. In conclusion, men showed increased CRC risks across subsites and alcohol intake levels, while only colon cancer risk was increased in women at heavy intake levels. ADH1B rs3811802 and ADH1C rs4147542 significantly modified the alcohol-colon cancer association in women.

ResumenEl cáncer es una patología con prevalencia en alza y cuyo origen se encuentra en el DNA, más específicamente en las alteraciones que lo afectan, y que finalmente se traducen en la desregulación del ciclo celular y de los mecanismos celulares reparadores del DNA. La desregulación del ciclo celular se traduce finalmente en la formación de tumores, que pueden invadir tejidos u órganos distantes, provocando la muerte del paciente. Conocer y entender las alteraciones y/o daños que puede sufrir el DNA permite comprender el proceso de carcinogénesis a escala molecular, pero también a escala humana. Esta revisión pretende actualizar y/o clarificar algunos conceptos moleculares básicos del cáncer, cómo éstos pueden estudiarse en un laboratorio de biología molecular y cómo pueden ayudar a mejorar la práctica clínica con un paciente oncológico.SummaryCancer prevalence is rising worldwide. The main pathogenic events of this devastating disease are alterations in the DNA, which eventually result in the dysregulation of both the cell cycle and DNA repair mechanisms. This dysregulation of the cell cycle results in the formation of a tumor, from which cancer cells disseminate to distant organs, finally bringing about patient death. Knowledge and understanding of the nature of the DNA alterations is essential to the comprehension of the carcinogenic process at both a molecular and human scale. This review aims to update and clarify some basic molecular concepts in cancer, focusing principally on how alterations can be studied within the molecular biology lab, and how this discipline can improve clinical cancer practice.

Jurisprudence will profit considerably from methods and applications of the neurosciences. In fact, it is proposed that the neurosciences will provide unique possibilities and advantages in understanding motivations and causes for staying lawful or for becoming unlawful. Neuroscientific models on brain-behavior interactions have profited considerably from the advent of neuroimaging techniques and genetic analyses. Furthermore, advances in interdisciplinary investigations, which combine conventional psychological and sociological explorations with biological examinations, provide refined insights into the question 'What makes us tick?' (Weiskrantz, 1973, British Journal of Psychology, 64, 511-520). The search for such interactions from the time of the nineteenth century to the present is briefly surveyed and it is concluded that the interdisciplinary approaches within and across neuroscientific fields will lead and have already led to a considerable expansion of our knowledge. The articles in this issue devoted to highlighting the latest neuroscience research related to criminal behavior underline the power of this new approach.

Retroviruses favor target-DNA (tDNA) distortion and particular bases at sites of integration, but the mechanism underlying HIV-1 selectivity is unknown. Crystal structures revealed a network of prototype foamy virus (PFV) integrase residues that distort tDNA: Ala188 and Arg329 interact with tDNA bases, while Arg362 contacts the phosphodiester backbone. HIV-1 integrase residues Ser119, Arg231, and Lys258 were identified here as analogs of PFV integrase residues Ala188, Arg329 and Arg362, respectively. Thirteen integrase mutations were analyzed for effects on integrase activity in vitro and during virus infection, yielding a total of 1610 unique HIV-1 integration sites. Purine (R)/pyrimidine (Y) dinucleotide sequence analysis revealed HIV-1 prefers the tDNA signature (0)RYXRY(4), which accordingly favors overlapping flexible dinucleotides at the center of the integration site. Consistent with roles for Arg231 and Lys258 in sequence specific and non-specific binding, respectively, the R231E mutation altered integration site nucleotide preferences while K258E had no effect. S119A and S119T integrase mutations significantly altered base preferences at positions -3 and 7 from the site of viral DNA joining. The S119A preference moreover mimicked wild-type PFV selectivity at these positions. We conclude that HIV-1 IN residue Ser119 and PFV IN residue Ala188 contact analogous tDNA bases to effect virus integration.

Cerebral cavernous malformations (CCMs) are a diffuse cerebrovascular disease affecting approximately 0.5% of the population. A CCM is characterized by abnormally enlarged and leaky capillaries arranged in mulberry-like structures with no clear flow pattern. The lesion might predispose to seizures, focal neurological deficits or fatal intracerebral hemorrhage. However, a CCM can also remain neurologically silent. It might either occur sporadically or as an inherited disorder with incomplete penetrance and variable expressivity. Due to advances in imaging techniques, the incidence of CCM diagnoses are increasing, and the patient must be managed on a multidisciplinary basis: genetic counselling, treatment if needed, and follow-up. Advances have been made using radiological and pathological correlates of CCM lesions adding to the accumulated knowledge of this disease, although management of these patients is very variable among centers. This review is aimed at providing an update in genetic and molecular insights of this condition. Included are implications for genetic counselling, and possible approaches to prevention and treatment that derive from the understanding of pathogenetic mechanisms.

Archived otolith collections represent an invaluable source of information to study demographic and genetic changes in commercially important fish populations. Studies combining both approaches are however rare and reliable extraction of molecular and population demographic data from the same collection of otoliths has never been assessed in the endangered European eel ( Anguilla anguilla L.). Here we evaluate various DNA extraction protocols to compare DNA yield, microsatellite amplification success, genotype integrity and precision of age determination for eel otoliths that have been archived for 4 weeks, and for 28 and 48 years. Our results show a high amplification success and an equal genotype integrity for DNA fragments extracted from both recently sampled otoliths and high quality reference DNA tissue. Although historical samples yielded low amounts of DNA, PCR amplification was successful and genotyping reliable for short fragments, but decreased significantly with PCR fragment size. None of the extraction protocols caused physical damage to the otoliths and precision of age determination was high for both treated and untreated otoliths. Hence, the methodology can be applied as a standard for the further joint analysis of past demographic and genetic changes during the last century in the highly exploited European eel and in other fish requiring urgent conservation measures.

Background Coronary artery disease (CAD) is a major cause of death and disability worldwide. Depression has complex bidirectional adverse associations with CAD, although the mechanisms mediating these relationships remain unclear. Compared to European Americans, African Americans (AAs) have higher rates of morbidity and mortality from CAD. Although depression is common in AAs, its role in the development and features of CAD in this group has not been well examined. This project hypothesizes that the relationships between depression and CAD can be explained by common physiological pathways and gene-environment interactions. Thus, the primary aims of this ongoing project are to: a) determine the prevalence of CAD and depression phenotypes in a population-based sample of community-dwelling older AAs; b) examine the relationships between CAD and depression phenotypes in this population; and c) evaluate genetic variants from serotoninP and inflammatory pathways to discover potential gene-depression interactions that contribute significantly to the presence of CAD in AAs. Methods/design The St. Louis African American Health (AAH) cohort is a population-based panel study of community-dwelling AAs born in 1936–1950 (inclusive) who have been followed from 2000/2001 through 2010. The AAH-Heart study group is a subset of AAH participants recruited in 2009–11 to examine the inter-relationships between depression and CAD in this population. State-of-the-art CAD phenotyping is based on cardiovascular characterizations (coronary artery calcium, carotid intima-media thickness, cardiac structure and function, and autonomic function). Depression phenotyping is based on standardized questionnaires and detailed interviews. Single nucleotide polymorphisms of selected genes in inflammatory and serotonin-signaling pathways are being examined to provide information for investigating potential gene-depression interactions as modifiers of CAD traits. Information from the parent AAH study is being used to provide population-based prevalence estimates. Inflammatory and other biomarkers provide information about potential pathways. Discussion This population-based investigation will provide valuable information on the prevalence of both depression and CAD phenotypes in this population. The study will examine interactions between depression and genetic variants as modulators of CAD, with the intent of detecting mechanistic pathways linking these diseases to identify potential therapeutic targets. Analytic results will be reported as they become available.