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Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.A genetic study of problematic alcohol use in 435,563 individuals, including data from the Million Veteran Program, Psychiatric Genomics Consortium and UK Biobank, found many novel risk loci and provided new insights into trait biology.

Fluxes of calcium (Ca ) across cell membranes enable fast cellular responses. Calmodulin (CaM) senses local changes in Ca concentration and relays the information to numerous interaction partners. The critical role of accurate Ca signaling on cellular function is underscored by the fact that there are three independent CaM genes ( ) in the human genome. All three genes are functional and encode the exact same CaM protein. Moreover, CaM has a completely conserved amino acid sequence across all vertebrates. Given this degree of conservation, it was long thought that mutations in CaM were incompatible with life. It was therefore a big surprise when the first CaM mutations in humans were identified six years ago. Today, more than a dozen human CaM missense mutations have been described, all found in patients with severe cardiac arrhythmias. Biochemical studies have demonstrated differential effects on Ca binding affinities for these CaM variants. Moreover, CaM regulation of central cardiac ion channels is impaired, including the voltage-gated Ca channel, Ca 1.2, and the sarcoplasmic reticulum Ca release channel, ryanodine receptor isoform 2, RyR2. Currently, no non-cardiac phenotypes have been described for CaM variant carriers. However, sequencing of large human cohorts reveals a cumulative frequency of additional rare CaM mutations that raise the possibility of CaM variants not exclusively causing severe cardiac arrhythmias. Here, we provide an overview of the identified CaM variants and their known consequences for target regulation and cardiac disease phenotype. We discuss experimental data, patient genotypes and phenotypes as well as which questions remain open to understand this complexity.

Background Massively parallel cDNA sequencing (RNA-seq) experiments are gradually superseding microarrays in quantitative gene expression profiling. However, many biologists are uncertain about the choice of differentially expressed gene (DEG) analysis methods and the validity of cost-saving sample pooling strategies for their RNA-seq experiments. Hence, we performed experimental validation of DEGs identified by Cuffdiff2, edgeR, DESeq2 and Two-stage Poisson Model (TSPM) in a RNA-seq experiment involving mice amygdalae micro-punches, using high-throughput qPCR on independent biological replicate samples. Moreover, we sequenced RNA-pools and compared their results with sequencing corresponding individual RNA samples. Results False-positivity rate of Cuffdiff2 and false-negativity rates of DESeq2 and TSPM were high. Among the four investigated DEG analysis methods, sensitivity and specificity of edgeR was relatively high. We documented the pooling bias and that the DEGs identified in pooled samples suffered low positive predictive values. Conclusions Our results highlighted the need for combined use of more sensitive DEG analysis methods and high-throughput validation of identified DEGs in future RNA-seq experiments. They indicated limited utility of sample pooling strategies for RNA-seq in similar setups and supported increasing the number of biological replicate samples.

Missense variants in CALM genes encoding the Ca 2+ -binding protein calmodulin (CaM) cause severe cardiac arrhythmias. The disease mechanisms have been attributed to dysregulation of RyR2, for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and/or Ca V 1.2, for Long-QT Syndrome (LQTS). Recently, a novel CALM2 variant, G114R, was identified in a mother and two of her four children, all of whom died suddenly while asleep at a young age. The G114R variant impairs closure of Ca V 1.2 and RyR2, consistent with a CPVT and/or mild LQTS phenotype. However, the children carrying the CALM2 G114R variant displayed a phenotype commonly observed with variants in Na V 1.5 , i.e., Brugada Syndrome (BrS) or LQT3, where death while asleep is a common feature. We therefore hypothesized that the G114R variant specifically would interfere with Na V 1.5 binding. Here, we demonstrate that CaM binding to the Na V 1.5 IQ-domain is severely impaired for two CaM variants G114R and G114W. The impact was most severe at low and intermediate Ca 2+ concentrations (up to 4 µM) resulting in more than a 50-fold reduction in Na V 1.5 binding affinity, and a smaller 1.5 to 11-fold reduction at high Ca 2+ concentrations (25–400 µM). In contrast, the arrhythmogenic CaM-N98S variant only induced a 1.5-fold reduction in Na V 1.5 binding and only at 4 µM Ca 2+ . A non-arrhythmogenic I10T variant in CaM did not impair Na V 1.5 IQ binding. These data suggest that the interaction between Na V 1.5 and CaM is decreased with certain CaM variants, which may alter the cardiac sodium current, I Na . Overall, these results suggest that the phenotypic spectrum of calmodulinopathies may likely expand to include BrS- and/or LQT3-like traits.

Introduction Due to diagnostic challenges, normalization of symptoms and an overall lack of awareness among both patients and physicians, endometriosis is an underdiagnosed disease. This can result in delayed treatment and potentially worsening of the disease. Despite initiatives, such as patients' support organizations and specialized endometriosis referral centers, differences in awareness, socioeconomic factors and lifestyle, combined with varying distances to specialized referral centers, could result in regional differences in the degree of underdiagnosing. This study aims to explore temporal and regional variations in the incidence of endometriosis based on the Danish hospital discharge register, and shed light on the degree of underdiagnosing of endometriosis in Denmark. Material and methods This registry‐based cohort study included all women aged 15–55 living in Denmark from 1990–2017. Participants were identified through the Danish Civil Registration system and endometriosis diagnoses received at a hospital were obtained from the Danish National Patient Registry. Incidence rates of diagnosed endometriosis were calculated for each year of the study period and for each municipality in Denmark. A Cox regression analysis, stratified by calendar time and adjusted for ethnic origin, household composition, highest educational level and family socioeconomic status, was performed to estimate the association between residence and likelihood of receiving a hospital‐based diagnosis of endometriosis. Results The nationwide incidence rate of hospital‐diagnosed endometriosis was 7.89 (95% confidence interval [CI] 7.80–7.99) per 10 000 person‐years and the prevalence in 2017 was 1.63%. The results showed an overall increase in the incidence of diagnosed endometriosis of 46.8% (95% CI 32.9–62.2) during the study period and also displayed significant regional differences. After adjustments, women living in northern Jutland had the highest probability of receiving a hospital‐based diagnosis of endometriosis (hazard ratio 1.13, 95% CI 1.09–1.18), whereas women living in northern Zealand had the lowest probability (hazard ratio 0.63, 95% CI 0.60–0.67) compared with eastern Jutland. These regional differences have become more evident over time. Conclusions Our results reveal significant regional differences in the incidence of hospital‐diagnosed endometriosis, suggesting that a significant number of women may be left behind without a diagnosis. Further studies are needed to assess the underlying reasons for the significant regional differences.

Hydatidiform moles (HMs) are abnormal human pregnancies with vesicular chorionic villi, imposing two clinical challenges; miscarriage and a risk of gestational trophoblastic neoplasia (GTN). The parental type of most HMs are either diandric diploid (PP) or diandric triploid (PPM). We consecutively collected 154 triploid or near-triploid samples from conceptuses with vesicular chorionic villi. We used analysis of DNA markers and/or methylation sensitive-MLPA and collected data from registries and patients records. We performed whole genome SNP analysis of one case of twinning (PP+PM).In all 154 triploids or near-triploids we found two different paternal contributions to the genome (P1P2M). The ratios between the sex chromosomal constitutions XXX, XXY, and XYY were 5.7: 6.9: 1.0. No cases of GTN were observed. Our results corroborate that all triploid human conceptuses with vesicular chorionic villi have the parental type P1P2M. The sex chromosomal ratios suggest approximately equal frequencies of meiosis I and meiosis II errors with selection against the XYY conceptuses or a combination of dispermy, non-disjunction in meiosis I and meiosis II and selection against XYY conceptuses. Although single cases of GTN after a triploid HM have been reported, the results of this study combined with data from previous prospective studies estimate the risk of GTN after a triploid mole to 0% (95% CI: 0-1,4%).

PurposeTo establish a cohort that enables identification of genomic factors that influence human health and empower increased blood donor health and safe blood transfusions. Human health is complex and involves several factors, a major one being the genomic aspect. The genomic era has resulted in many consortia encompassing large samples sizes, which has proven successful for identifying genetic factors associated with specific traits. However, it remains a big challenge to establish large cohorts that facilitate studies of the interaction between genetic factors, environmental and life-style factors as these change over the course of life. A major obstacle to such endeavours is that it is difficult to revisit participants to retrieve additional information and obtain longitudinal, consecutive measurements.ParticipantsBlood donors (n=110 000) have given consent to participate in the Danish Blood Donor Study. The study uses the infrastructure of the Danish blood banks.Findings to dateThe cohort comprises extensive phenotype data and whole genome genotyping data. Further, it is possible to retrieve additional phenotype data from national registries as well as from the donors at future visits, including consecutive measurements.Future plansTo provide new knowledge on factors influencing our health and thus provide a platform for studying the influence of genomic factors on human health, in particular the interaction between environmental and genetic factors.

Observational epidemiological studies indicate that endometriosis and migraine co-occur within individuals more than expected by chance. However, the aetiology and biological mechanisms underlying their comorbidity remain unknown. Here we examined the relationship between endometriosis and migraine using genome-wide association study (GWAS) data. Single nucleotide polymorphism (SNP) effect concordance analysis found a significant concordance of SNP risk effects across endometriosis and migraine GWAS. Linkage disequilibrium score regression analysis found a positive and highly significant genetic correlation (rG = 0.38, P = 2.30 × 10−25) between endometriosis and migraine. A meta-analysis of endometriosis and migraine GWAS data did not reveal novel genome-wide significant SNPs, and Mendelian randomisation analysis found no evidence for a causal relationship between the two traits. However, gene-based analyses identified two novel loci for migraine. Also, we found significant enrichment of genes nominally associated (Pgene < 0.05) with both traits (Pbinomial-test = 9.83 × 10−6). Combining gene-based p-values across endometriosis and migraine, three genes, two (TRIM32 and SLC35G6) of which are at novel loci, were genome-wide significant. Genes having Pgene < 0.1 for both endometriosis and migraine (Pbinomial-test = 1.85 ×10−°3) were significantly enriched for biological pathways, including interleukin-1 receptor binding, focal adhesion-PI3K-Akt-mTOR-signaling, MAPK and TNF-α signalling. Our findings further confirm the comorbidity of endometriosis and migraine and indicate a non-causal relationship between the two traits, with shared genetically-controlled biological mechanisms underlying the co-occurrence of the two disorders.

Genetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD-associated SNPs and five CAD-related inflammatory biomarkers. We genotyped 45 CAD-associated SNPs in 701 stable CAD patients in whom levels of high-sensitivity C-reactive protein (hsRCP), interleukin-6, calprotectin, fibrinogen and complement component 3 levels had previously been measured. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. A multiple linear regression model was used to assess associations between the genetic risk score, single SNPs, and the five inflammatory biomarkers. The minor allele (G) (CAD risk allele) of rs2075650 (TOMM40/APOE) was associated with lower levels of high-sensitivity C-reactive protein (effect per risk allele: -0.37 mg/l [95%CI -0.56 to -0.18 mg/l]). The inflammatory markers tested showed no association with the remaining 44 SNPs or with the genetic risk score. In stable CAD patients, the risk allele of a common CAD-associated marker at the TOMM40/APOE locus was associated with lower hsCRP levels. No other genetic variants or the combined effect of all variants were associated with the five inflammatory biomarkers.

As the world's population ages, the age-related cognitive decline presents a great challenge to world's healthcare systems. One of the molecular mechanisms implicated in cognitive ageing is DNA methylation, an epigenetic modification known to be a key player in memory formation, maintenance, and synaptic plasticity. Using the twin design we performed an epigenome-wide association study (EWAS) in a population of 486 middle-aged monozygotic twins (mean age at follow-up 65.9, = 6.1) and correlated their blood DNA methylation to their level (cross-sectional analysis) and change in cognitive abilities over 10 years (longitudinal analysis). We identified several CpG sites where cross-sectional cognitive functioning was associated with DNA methylation levels. The top identified loci were located in ( = 5.84 × 10 ), and ( = 4.91 × 10 ). KEGG's enrichment analyses of the most associated findings identified \"Neuroactive ligand-receptor interaction\" as the most enriched pathway ( = 0.0098). Change in cognitive functioning over 10 years was associated with DNA methylation levels in ( = 9.01 × 10 ) and ( = 5.28 × 10 ), with the first gene playing an important role in neuronal survival and the latter gene implicated before in Alzheimer's disease and ischemic stroke. Our findings point to an association between changes in DNA methylation of genes related to neuronal survival and change of cognitive functioning in aging individuals.