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Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1-4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5-7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.

Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biological discovery and exploitation in animal breeding and human biomedicine. Here we show results from the pilot phase of PigGTEx by processing 5,457 RNA-sequencing and 1,602 whole-genome sequencing samples passing quality control from pigs. We build a pig genotype imputation panel and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We evaluate tissue specificity of regulatory effects and elucidate molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying 207 pig complex phenotypes and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, supporting the importance of pigs as a human biomedical model.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

BACKGROUND: Increased prevalence of mental illness has been reported in clinical studies of sex chromosome aneuploidies, but accurate population-based estimates of the prevalence and clinical detection rate of sex chromosome aneuploidies and the associated risks of psychiatric disorders are needed. In this study, we provide such estimates, valid for children and young adults of the contemporary Danish population. METHODS: We used the iPSYCH2015 case-cohort dataset, which is based on a source population of single-born individuals born in Denmark between May 1, 1981, and Dec 31, 2008. The case sample comprises all individuals from the source population with a diagnosis of any index psychiatric disorder (schizophrenia spectrum disorder, bipolar disorder, major depressive disorder, autism spectrum disorder, or ADHD) by the end of follow-up (Dec 31, 2015), registered in the hospital-based Danish Psychiatric Central Research Register. The cohort consists of individuals randomly selected from the source population, and overlaps with the case sample. Biobanked blood samples for individuals in the case and cohort samples underwent genotyping and quality-control filtering, after which we analysed microarray data to detect sex chromosome aneuploidy karyotypes (45,X, 47,XXX, 47,XXY, and 47,XYY). We estimated the population-valid prevalence of these karyotypes from the cohort sample. Weighted Cox proportional hazards models were used to estimate the risks of each index psychiatric disorder associated with each sex chromosome aneuploidy karyotype, by use of date of first hospitalisation with the index disorder in the respective case group and the cohort as outcome. The clinical detection rate was determined by comparing records of clinical diagnoses of genetic conditions from the Danish National Patient Register with sex chromosome aneuploidy karyotype determined by our study. FINDINGS: The assessed sample comprised 119 481 individuals (78 726 in the case sample and 43 326 in the cohort) who had genotyped and quality-control-filtered blood samples, including 64 533 (54%) people of gonadal male sex and 54 948 (46%) of gonadal female sex. Age during follow-up ranged from 0 to 34·7 years (mean 10·9 years [SD 3·5 years]). Information on ethnicity was not available. We identified 387 (0·3%) individuals as carriers of sex chromosome aneuploidies. The overall prevalence of sex chromosome aneuploidies was 1·5 per 1000 individuals. Each sex chromosome aneuploidy karyotype was associated with an increased risk of at least one index psychiatric disorder, with hazard ratios (HRs) of 2·20 (95% CI 1·42-3·39) for 47,XXY; 2·73 (1·25-6·00) for 47,XXX; 3·56 (1·01-12·53) for 45,X; and 4·30 (2·48-7·55) for 47,XYY. All karyotypes were associated with an increased risk of ADHD (HRs ranging from 1·99 [1·24-3·19] to 6·15 [1·63-23·19]), autism spectrum disorder (2·72 [1·72-4·32] to 8·45 [2·49-28·61]), and schizophrenia spectrum disorder (1·80 [1·15-2·80] to 4·60 [1·57-13·51]). Increased risk of major depressive disorder was found for individuals with 47,XXY (1·88 [1·07-3·33]) and 47,XYY (2·65 [1·12-5·90]), and of bipolar disorder for those with 47,XXX (4·32 [1·12-16·62]). The proportion of sex chromosome aneuploidy carriers who had been clinically diagnosed was 93% for 45,X, but lower for 47,XXY (22%), 47,XXX (15%), and 47,XYY (15%). Among carriers, the risk of diagnosis of at least one index psychiatric disorder did not significantly differ between those who had and had not been clinically diagnosed with sex chromosome aneuploidies (p=0·65). INTERPRETATION: Increased risks of psychiatric disorders associated with sex chromosome aneuploidies, combined with low rates of clinical diagnosis of sex chromosome aneuploidies, compromise the adequate provision of necessary health care and counselling to affected individuals and their families, which might be helped by increased application of genetic testing in clinical settings. FUNDING: Lundbeck Foundation and National Institutes of Health.

RationaleElectronic (e)-cigarettes are popular among youth and cigarette smokers attempting to quit. Studies to date have focused on the utility of e-cigarettes as a smoking cessation tool, but the biological effects are largely unknown.ObjectivesTo identify transcriptomic differences in the blood and sputum of e-cigarette users compared to conventional cigarettes smokers and healthy controls and describe biological pathways affected by these tobacco products.MethodsCross-sectional analysis of whole blood and sputum RNA-sequencing data from 8 smokers, 9 e-cigarette users (e-cigs) and 4 controls. Weighted gene co-network analysis (WGCNA) identified gene module associations. Ingenuity Pathway Analysis (IPA) identified canonical pathways associated with tobacco products.Main resultsIn blood, a three-group comparison showed 16 differentially expressed genes (DEGs); pair-wise comparison showed 7 DEGs between e-cigs and controls, 35 DEGs between smokers and controls, and 13 DEGs between smokers and e-cigs. In sputum, 438 DEGs were in the three-group comparison. In pair-wise comparisons, there were 2 DEGs between e-cigs and controls, 270 DEGs between smokers and controls, and 468 DEGs between smokers and e-cigs. Only 2 genes in the smokers vs. control comparison overlapped between blood and sputum. Most gene modules identified through WGCNA associated with tobacco product exposures also were associated with cotinine and exhaled CO levels. IPA showed more canonical pathways altered by conventional cigarette smoking than by e-cigarette use.ConclusionCigarette smoking and e-cigarette use led to transcriptomic changes in both blood and sputum. However, conventional cigarettes induced much stronger transcriptomic responses in both compartments.

PURPOSE: Previous research suggests that job loss in a household during pregnancy may perturb fetal growth. However, this work often cannot rule out unmeasured confounding due to selection into job loss. Recent work using data on exogenous job loss (due to a plant closure) finds that a fathers unexpected job loss during his spouses pregnancy increases the risk of a low weight birth. Using a unique set of linked registries in Denmark, we build on this work and examine whether associations between a fathers unexpected job loss and low birthweight differ by trimester of in utero exposure. We additionally examine trimester-specific associations of job loss with small-for-gestational-age, a proxy for restricted fetal growth, which may cause low birthweight. METHODS: We apply a sibling control design to over 1.4 million live births in Denmark, 1980 to 2017, to examine whether this plausibly exogenous form of job loss corresponds with increased risk of low weight or small-for-gestational-age births, depending on the timing of displacement in the first, second, or third trimester. RESULTS: Results indicate an elevated risk of low birthweight (OR = 1.80, 95% CI: 1.24, 2.62) and small-for-gestational-age (OR = 1.40, 95% CI: 1.02, 1.93) among gestations exposed to job loss in the second trimester of pregnancy. Sensitivity analyses using continuous outcome measures (e.g., birthweight in grams, birthweight for gestational age percentile) and maternal fixed effects analyses produce substantively similar inference. CONCLUSIONS: Findings support the notion that unexpected job loss may affect fetal growth and that the second trimester in particular appears sensitive to this external stressor.

BACKGROUND: Coronary artery calcium (CAC) is commonly quantified as the product of 2 generally correlated measures: plaque area and calcium density. OBJECTIVES: The authors sought to determine whether discordance between calcium area and density has long-term prognostic importance in atherosclerotic cardiovascular disease (ASCVD) risk. METHODS: The authors studied 10,373 primary prevention participants from the CAC Consortium with CAC >0. Based on their median values, calcium area and mean calcium density were divided into 4 mutually exclusive concordant/discordant groups. Cox proportional hazards regression assessed the association of calcium area/density groups with ASCVD mortality over a median of 11.7 years, adjusting for traditional risk factors and the Agatston CAC score. RESULTS: The mean age was 56.7 years, and 24% were female. The prevalence of plaque discordance was 19% (9% low calcium area/high calcium density, 10% high calcium area/low calcium density). Female sex (odds ratio [OR]: 1.48 [95% CI: 1.27-1.74]) and body mass index (OR: 0.81 [95% CI: 0.76-0.87], per 5 kg/m2 higher) were significantly associated with high calcium density discordance, whereas diabetes (OR: 2.23 [95% CI: 1.85-3.19]) was most strongly associated with discordantly low calcium density. Compared to those with low calcium area/low calcium density, individuals with low calcium area/high calcium density had a 71% lower risk of ASCVD death (HR: 0.29 [95% CI: 0.09-0.95]). CONCLUSIONS: For a given CAC score, high calcium density relative to plaque area confers lower long-term ASCVD risk, likely serving as an imaging marker of biological resilience for lesion vulnerability. Additional research is needed to define a robust definition of calcium area/density discordance for routine clinical risk prediction.

BackgroundOver the last two decades, a number of studies have highlighted the potential of psychedelic therapy. However, questions remain to what extend these results translate to naturalistic samples, and how contextual factors and the acute psychedelic experience relate to improvements in affective symptoms following psychedelic experiences outside labs/clinics. The present study sought to address this knowledge gap.AimHere, we aimed to investigate changes in anxiety and depression scores before versus after psychedelic experiences in naturalistic contexts, and how various pharmacological, extrapharmacological and experience factors related to outcomes.MethodIndividuals who planned to undergo a psychedelic experience were enrolled in this online survey study. Depressive symptoms were assessed at baseline and 2 and 4 weeks post-psychedelic experience, with self-rated Quick Inventory of Depressive Symptomatology (QIDS-SR-16) as the primary outcome. To facilitate clinical translation, only participants with depressive symptoms at baseline were included. Sample sizes for the four time points were N = 302, N = 182, N = 155 and N = 109, respectively.ResultsRelative to baseline, reductions in depressive symptoms were observed at 2 and 4 weeks. A medicinal motive, previous psychedelic use, drug dose and the type of acute psychedelic experience (i.e. specifically, having an emotional breakthrough) were all significantly associated with changes in self-rated QIDS-SR-16.ConclusionThese results lend support to therapeutic potential of psychedelics and highlight the influence of pharmacological and non-pharmacological factors in determining response. Mindful of a potential sample and attrition bias, further controlled and observational longitudinal studies are needed to test the replicability of these findings.

BackgroundCoronary artery calcium (CAC) is a marker of plaque burden. Whether CAC improves risk stratification for incident sudden cardiac death (SCD) beyond atherosclerotic cardiovascular disease (ASCVD) risk factors is unknown.ObjectivesSCD is a common initial manifestation of coronary heart disease (CHD); however, SCD risk prediction remains elusive.MethodsThe authors studied 66,636 primary prevention patients from the CAC Consortium. Multivariable competing risks regression and C-statistics were used to assess the association between CAC and SCD, adjusting for demographics and traditional risk factors.ResultsThe mean age was 54.4 years, 33% were women, 11% were of non-White ethnicity, and 55% had CAC >0. A total of 211 SCD events (0.3%) were observed during a median follow-up of 10.6 years, 91% occurring among those with baseline CAC >0. Compared with CAC = 0, there was a stepwise higher risk (P trend 1,000 (SHR: 4.9; 95% CI: 2.6-9.9). CAC provided incremental improvements in the C-statistic for the prediction of SCD among individuals with a 10-year risk 20% (ΔC-statistic = +0.01; P = 0.54).ConclusionsHigher CAC burden strongly associates with incident SCD beyond traditional risk factors, particularly among primary prevention patients with low-intermediate risk. SCD risk stratification can be useful in the early stages of CHD through the measurement of CAC, identifying patients most likely to benefit from further downstream testing.

BackgroundResearch documents social and economic antecedents of adverse birth outcomes, which may include involuntary job loss. Previous work on job loss and adverse birth outcomes, however, lacks high-quality individual data on, and variation in, plausibly exogenous job loss during pregnancy and therefore cannot rule out strong confounding.MethodsWe analysed unique linked registries in Denmark, from 1980 to 2017, to examine whether a father's involuntary job loss during his spouse's pregnancy increases the risk of a low-weight (i.e.

AimsThis study explored the association of coronary artery calcium (CAC) with incident cancer subtypes in the Multi-Ethnic Study of Atherosclerosis (MESA). CAC is an established predictor of cardiovascular disease (CVD), with emerging data also supporting independent predictive value for cancer. The association of CAC with risk for individual cancer subtypes is unknown.Methods and resultsWe included 6271 MESA participants, aged 45-84 and without known CVD or self-reported history of cancer. There were 777 incident cancer cases during mean follow-up of 12.9 ± 3.1 years. Lung and colorectal cancer (186 cases) were grouped based on their strong overlap with CVD risk profile; prostate (men) and ovarian, uterine, and breast cancer (women) were considered as sex-specific cancers (in total 250 cases). Incidence rates and Fine and Gray competing risks models were used to assess relative risk of cancer-specific outcomes stratified by CAC groups or Log(CAC+1). The mean age was 61.7 ± 10.2 years, 52.7% were women, and 36.5% were White. Overall, all-cause cancer incidence increased with CAC scores, with rates per 1000 person-years of 13.1 [95% confidence interval (CI): 11.7-14.7] for CAC = 0 and 35.8 (95% CI: 30.2-42.4) for CAC ≥400. Compared with CAC = 0, hazards for those with CAC ≥400 were increased for lung and colorectal cancer in men [subdistribution hazard ratio (SHR): 2.2 (95% CI: 1.1-4.7)] and women [SHR: 2.2 (95% CI: 1.0-4.6)], but not significantly for sex-specific cancers across sexes.ConclusionCAC scores were associated with cancer risk in both sexes; however, this was stronger for lung and colorectal when compared with sex-specific cancers. Our data support potential synergistic use of CAC scores in the identification of both CVD and lung and colorectal cancer risk.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P

ObjectivesThis study sought to assess the relationship between mean vs peak calcified plaque density and their impact on calculating coronary artery calcium (CAC) scores and to compare the corresponding differential prediction of atherosclerotic cardiovascular disease (ASCVD) and coronary heart disease (CHD) mortality.BackgroundThe Agatston CAC score is quantified per lesion as the product of plaque area and a 4-level categorical peak calcium density factor. However, mean calcium density may more accurately measure the heterogenous mixture of lipid-rich, fibrous, and calcified plaque reflective of ASCVD risk.MethodsWe included 10,373 individuals from the CAC Consortium who had CAC >0 and per-vessel measurements of peak calcium density factor and mean calcium density. Area under the curve and continuous net reclassification improvement analyses were performed for CHD and ASCVD mortality to compare the predictive abilities of mean calcium density vs peak calcium density factor when calculating the Agatston CAC score.ResultsParticipants were on average 53.4 years of age, 24.4% were women, and the median CAC score was 68 Agatston units. The average values for mean calcium density and peak calcium density factor were 210 ± 50 HU and 3.1 ± 0.5, respectively. Individuals younger than 50 years of age and/or those with a total plaque area 100.ConclusionMean and peak calcium density may differentially describe plaque composition early in the atherosclerotic process. Mean calcium density performs better than peak calcium density factor when combined with plaque area for ASCVD mortality prediction among persons with Agatston CAC 1-99.

This cross-sectional study examines changes in levels of health care coverage and cost-related delays in care for Latino individuals after elimination of the individual coverage mandate from the Affordable Care Act (ACA).

Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disorders which include deficits in behavior, social interaction and communication. ASD has a complex genetic architecture, and it is also influenced by certain environmental exposures. Both types of predisposing factors may be related to immunological mechanisms, involving, for example, immune system genes and infections. Past studies have shown an association between infections occurring during the pregnancy in the mother and increased risk of ASD in the child, an observation which has received recent support from experimental animal studies of ASD-like behavior. The aim of this study was to study the genetic contribution to this effect. We employed genetic correlation analyses across potential ASD subtypes stratified on the basis of maternal pregnancy-related infections within the iPSYCH ASD case-cohort sample, as well as a case-case GWAS. We validated the trends of the genetic correlation analyses observed in our sample using GWAS summary statistics from the PGC ASD study (excluding iPSYCH). The genetic correlation between ASD with a history of maternal pregnancy-related infections and ASD without a history of maternal infections in iPSYCH was rg = 0.3811. We obtained a similar estimate between the former and the PGC ASD phenotype (rg = 0.3997). Both estimates are lower compared to the genetic correlation between ASD without a history of maternal infections and the PGC ASD phenotype (rg = 0.6735), and between ASD with a history of maternal infections occurring only more than 2 months following childbirth and the PGC ASD phenotype (rg = 0.6293). Additionally, we observed genetic variance between the two main ASD phenotypes using summary statistics from the case-case GWAS in iPSYCH (h2cc = 0.1059), indicating genome-wide differences between the phenotypes. Our results suggest potentially different etiologies of ASD based on a history of maternal pregnancy-related infections, which may, in part, be genetic. This highlights the relevance of maternal pregnancy-related infections to genetic studies of ASD and provides new insights into the molecular underpinnings of ASD.

Background and aimsCoronary artery calcium (CAC) scores have been shown to be associated with CVD and cancer mortality. The use of CAC scores for overall and lung cancer mortality risk prediction for patients in the Coronary Artery Calcium Consortium was analyzed.MethodsWe included 55,943 patients aged 44-84 years without known heart disease from the CAC Consortium. There were 1,088 cancer deaths, among which 231 were lung cancer, identified by death certificates with a mean follow-up of 12.2 ± 3.9 years. Fine-and-Gray competing-risk regression was used for overall and lung cancer-specific mortality, accounting for the competing risk of CVD death and after adjustment for CVD risk factors. Subdistribution hazard ratios (SHR) were reported.ResultsThe mean age of all patients was 57.1 ± 8.6 years, 34.9% were women, and 89.6% were white. Overall, CAC was strongly associated with cancer mortality. Lung cancer mortality increased with increasing CAC scores, with rates per 1000-person years of 0.2 (95% CI: 0.1-0.3) for CAC = 0 and 0.8 (95% CI: 0.6-1.0) for CAC ≥400. Compared with CAC = 0, hazards were increased for those with CAC ≥400 for lung cancer mortality [SHR: 1.7 (95% CI: 1.2-2.6)], which was driven by women [SHR: 2.3 (95% CI: 1.1-4.8)], but not significantly increased for men. Risks were higher in those with positive smoking history [SHR: 2.2 (95% CI: 1.2-4.2)], with associations driven by women [SHR: 4.0 (95% CI: 1.4-11.5)].ConclusionsCAC scores were associated with increased risks for lung cancer mortality, with strongest associations for current and former smokers, especially in women. Used in conjunction with other clinical variables, our data pinpoint a potential synergistic use of CAC scanning beyond CVD risk assessment for identification of high-risk lung cancer screening candidates.

BackgroundThere are currently no recommendations guiding when best to perform coronary artery calcium (CAC) scanning among young adults to identify those susceptible for developing premature atherosclerosis.ObjectivesThe purpose of this study was to determine the ideal age at which a first CAC scan has the highest utility according to atherosclerotic cardiovascular disease (ASCVD) risk factor profile.MethodsWe included 22,346 CAC Consortium participants aged 30-50 years who underwent noncontrast computed tomography. Sex-specific equations were derived from multivariable logistic modeling to estimate the expected probability of CAC >0 according to age and the presence of ASCVD risk factors.ResultsParticipants were on average 43.5 years of age, 25% were women, and 34% had CAC >0, in whom the median CAC score was 20. Compared with individuals without risk factors, those with diabetes developed CAC 6.4 years earlier on average, whereas smoking, hypertension, dyslipidemia, and a family history of coronary heart disease were individually associated with developing CAC 3.3-4.3 years earlier. Using a testing yield of 25% for detecting CAC >0, the optimal age for a potential first scan would be at 36.8 years (95% CI: 35.5-38.4 years) in men and 50.3 years (95% CI: 48.7-52.1 years) in women with diabetes, and 42.3 years (95% CI: 41.0-43.9 years) in men and 57.6 years (95% CI: 56.0-59.5 years) in women without risk factors.ConclusionsOur derived risk equations among health-seeking young adults enriched in ASCVD risk factors inform the expected prevalence of CAC >0 and can be used to determine an appropriate age to initiate clinical CAC testing to identify individuals most susceptible for early/premature atherosclerosis.

BackgroundThere are limited data on the unique cardiovascular disease (CVD), non-CVD, and mortality risks of primary prevention individuals with very high coronary artery calcium (CAC; ≥1000), especially compared with rates observed in secondary prevention populations.MethodsOur study population consisted of 6814 ethnically diverse individuals 45 to 84 years of age who were free of known CVD from MESA (Multi-Ethnic Study of Atherosclerosis), a prospective, observational, community-based cohort. Mean follow-up time was 13.6±4.4 years. Hazard ratios of CAC ≥1000 were compared with both CAC 0 and CAC 400 to 999 for CVD, non-CVD, and mortality outcomes with the use of Cox proportional hazards regression adjusted for age, sex, and traditional risk factors. Using a sex-adjusted logarithmic model, we calculated event rates in MESA as a function of CAC and compared them with those observed in the placebo group of stable secondary prevention patients in the FOURIER clinical trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk).ResultsCompared with CAC 400 to 999, those with CAC ≥1000 (n=257) had a greater mean number of coronary vessels with CAC (3.4±0.5), greater total area of CAC (586.5±275.2 mm2), similar CAC density, and more extensive extracoronary calcification. After full adjustment, CAC ≥1000 demonstrated a 4.71- (3.63-6.11), 7.57- (5.50-10.42), 4.86-(3.32-7.11), and 1.94-fold (1.57-2.41) increased risk for all CVD events, all coronary heart disease events, hard coronary heart disease events, and all-cause mortality, respectively, compared with CAC 0 and a 1.65- (1.25-2.16), 1.66- (1.22-2.25), 1.51- (1.03-2.23), and 1.34-fold (1.05-1.71) increased risk compared with CAC 400 to 999. With increasing CAC, hazard ratios increased for all event types, with no apparent upper CAC threshold. CAC ≥1000 was associated with a 1.95- (1.57-2.41) and 1.43-fold (1.12-1.83) increased risk for a first non-CVD event compared with CAC 0 and CAC 400 to 999, respectively. CAC 1000 corresponded to an annualized 3-point major adverse cardiovascular event rate of 3.4 per 100 person-years, similar to that of the total FOURIER population (3.3) and higher than those of the lower-risk FOURIER subgroups.ConclusionsIndividuals with very high CAC (≥1000) are a unique population at substantially higher risk for CVD events, non-CVD outcomes, and mortality than those with lower CAC, with 3-point major adverse cardiovascular event rates similar to those of a stable treated secondary prevention population. Future guidelines should consider a less distinct stratification algorithm between primary and secondary prevention patients in guiding aggressive preventive pharmacotherapy.

Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531-538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known "polygenic resilience score" that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10-10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.

Schizophrenia is a heterogeneous disorder, exhibiting variability in presentation and outcomes that complicate treatment and recovery. To explore this heterogeneity, we leverage the comprehensive Danish health registries to conduct a prospective, longitudinal study from birth of 5432 individuals who would ultimately be diagnosed with schizophrenia, building individual trajectories that represent sequences of comorbid diagnoses, and describing patterns in the individual-level variability. We show that psychiatric comorbidity is prevalent among individuals with schizophrenia (82%) and multi-morbidity occur more frequently in specific, time-ordered pairs. Three latent factors capture 79% of variation in longitudinal comorbidity and broadly relate to the number of co-occurring diagnoses, the presence of child versus adult comorbidities and substance abuse. Clustering of the factor scores revealed five stable clusters of individuals, associated with specific risk factors and outcomes. The presentation and course of schizophrenia may be associated with heterogeneity in etiological factors including family history of mental disorders.

The functional annotation of livestock genomes is crucial for understanding the molecular mechanisms that underpin complex traits of economic importance, adaptive evolution and comparative genomics. Here, we provide the most comprehensive catalogue to date of regulatory elements in the pig (Sus scrofa) by integrating 223 epigenomic and transcriptomic data sets, representing 14 biologically important tissues. We systematically describe the dynamic epigenetic landscape across tissues by functionally annotating 15 different chromatin states and defining their tissue-specific regulatory activities. We demonstrate that genomic variants associated with complex traits and adaptive evolution in pig are significantly enriched in active promoters and enhancers. Furthermore, we reveal distinct tissue-specific regulatory selection between Asian and European pig domestication processes. Compared with human and mouse epigenomes, we show that porcine regulatory elements are more conserved in DNA sequence, under both rapid and slow evolution, than those under neutral evolution across pig, mouse, and human. Finally, we provide biological insights on tissue-specific regulatory conservation, and by integrating 47 human genome-wide association studies, we demonstrate that, depending on the traits, mouse or pig might be more appropriate biomedical models for different complex traits and diseases.

BackgroundVariation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.MethodsTo conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.FindingsWe identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.InterpretationThese findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.FundingNational Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.

BackgroundCoronary artery calcium (CAC) is a guideline recommended cardiovascular disease (CVD) risk stratification tool that increases with age and is associated with non-cardiovascular disease outcomes including cancer. We sought to define the age-specific change in the association between CAC and cause-specific mortality.MethodsThe Coronary Artery Calcium Consortium includes 59,502 asymptomatic patients age 40-75 without known CVD. Age-stratified mortality rates and parametric survival regression modeling was performed to estimate the age-specific CAC score at which CVD and cancer mortality risk were equal.ResultsThe mean age was 54±8 years (67% men) and there were 2,423 deaths over a mean 12±3 years follow-up. Among individuals with CAC = 0, cancer was the leading cause of death, with low CVD mortality rates for both younger (40-54 years) 0.2/1,000 person-years and older participants (65-75 years) 1.3/1,000 person-years. When CAC ≥400, CVD was consistently the leading cause of death among younger (71% of deaths) and older participants (56% of deaths). The CAC score at which CVD overtook cancer as the leading cause of death increased exponentially with age and was approximately 115 at age 50 and 380 at age 65.ConclusionsRegardless of age, when CAC = 0 cancer was the leading cause of death and the cardiovascular disease mortality rate was low. Our age-specific estimate for the CAC score at which CVD overtakes cancer mortality allows for a more precise approach to synergistic prediction and prevention strategies for CVD and cancer.

Paclitaxel-induced peripheral neuropathy (PIPN) is a common and dose-limiting adverse event. The role of P-glycoprotein (P-gp) in the neuronal efflux of paclitaxel was assessed using a translational approach. SH-SY5Y cells were differentiated to neurons and paclitaxel toxicity in the absence and presence of a P-gp inhibitor was determined. Paclitaxel caused marked dose-dependent toxicity in SH-SY5Y-derived neurons. Paclitaxel neurotoxicity was exacerbated with concomitant P-gp inhibition by valspodar and verapamil, consistent with increased intracellular accumulation of paclitaxel. Patients with cancer treated with paclitaxel and P-gp inhibitors had a 2.4-fold (95% confidence interval (CI) 1.3-4.3) increased risk of peripheral neuropathy-induced dose modification while a 4.7-fold (95% CI 1.9-11.9) increased risk for patients treated with strong P-gp inhibitors was observed, and a 7.0-fold (95% CI 2.3-21.5) increased risk in patients treated with atorvastatin. Atorvastatin also increased neurotoxicity by paclitaxel in SH-SY5Y-derived neurons. Clinicians should be aware that comedication with P-gp inhibitors may lead to increased risk of PIPN.

BackgroundRecent American College of Cardiology/American Heart Association Primary Prevention Guidelines recommended considering low-dose aspirin therapy only among adults 40 to 70 years of age who are at higher atherosclerotic cardiovascular disease (ASCVD) risk but not at high risk of bleeding. However, it remains unclear how these patients are best identified. The present study aimed to assess the value of coronary artery calcium (CAC) for guiding aspirin allocation for primary prevention by using 2019 aspirin meta-analysis data on cardiovascular disease relative risk reduction and bleeding risk.MethodsThe study included 6470 participants from the MESA Study (Multi-Ethnic Study of Atherosclerosis). ASCVD risk was estimated using the pooled cohort equations, and 3 strata were defined: 20%. All participants underwent CAC scoring at baseline, and CAC scores were stratified as =0, 1 to 99, ≥100, and ≥400. A 12% relative risk reduction in cardiovascular disease events was used for the 5-year number needed to treat (NNT5) calculations, and a 42% relative risk increase in major bleeding events was used for the 5-year number needed to harm (NNH5) estimations.ResultsOnly 5% of MESA participants would qualify for aspirin consideration for primary prevention according to the American College of Cardiology/American Heart Association guidelines and using >20% estimated ASCVD risk to define higher risk. Benefit/harm calculations were restricted to aspirin-naive participants

Gastrointestinal infections can be life threatening, but not much is known about the host's genetic contribution to susceptibility to gastrointestinal infections or the latter's association with psychiatric disorders. We utilized iPSYCH, a genotyped population-based sample of individuals born between 1981 and 2005 comprising 65,534 unrelated Danish individuals (45,889 diagnosed with mental disorders and 19,645 controls from a random population sample) in which all individuals were linked utilizing nationwide population-based registers to estimate the genetic contribution to susceptibility to gastrointestinal infections, identify genetic variants associated with gastrointestinal infections, and examine the link between gastrointestinal infections and psychiatric and neurodevelopmental disorders. The SNP heritability of susceptibility to gastrointestinal infections ranged from 3.7% to 6.4% on the liability scale. Significant correlations were found between gastrointestinal infections and the combined group of mental disorders (OR = 2.09; 95% CI: 1.82-2.4, P = 1.87 × 10-25). Correlations with autism spectrum disorder, attention deficit hyperactivity disorder, and depression were also significant. We identified a genome-wide significant locus associated with susceptibility to gastrointestinal infections (OR = 1.13; 95% CI: 1.08-1.18, P = 2.9 × 10-8), where the top SNP was an eQTL for the ABO gene. The risk allele was associated with reduced ABO expression, providing, for the first time, genetic evidence to support previous studies linking the O blood group to gastrointestinal infections. This study also highlights the importance of integrative work in genetics, psychiatry, infection, and epidemiology on the road to translational medicine.

Background Coronary artery calcium (CAC) is a predictor for the development of cardiovascular disease (CVD) and to a lesser extent cancer. The age- and sex-specific relationship of CAC with CVD and cancer mortality is unknown. Methods and Results Asymptomatic patients aged 40 to 75 years old without known CVD were included from the CAC Consortium. We calculated sex-specific mortality rates per 1000 person-years' follow-up. Using parametric survival regression modeling, we determined the age- and sex-specific CAC score at which the risk of death from CVD and cancer were equal. Among the 59 502 patients included in this analysis, the mean age was 54.9 (±8.5) years, 34% were women, and 89% were white. There were 671 deaths attributable to CVD and 954 deaths attributable to cancer over a mean follow-up of 12±3 years. Among patients with CAC=0, cancer was the leading cause of death, the total mortality rate was low (women, 1.8; men, 1.5), and the CVD mortality rate was exceedingly low for women (0.3) and men (0.3). The age-specific CAC score at which the risk of CVD and cancer mortality were equal had a U-shaped relationship for women, while the relationship was exponential for men. Conclusions The age- and sex-specific relationship of CAC with CVD and cancer mortality differed significantly for women and men. Our age- and sex-specific CAC score provides a more precise estimate and further facilitates the use of CAC as a synergistic tool in strategies for the prediction and prevention of CVD and cancer mortality.

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10-8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10-8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10-9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10-8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10-9), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Infections and mental disorders are two of the major global disease burdens. While correlations between mental disorders and infections have been reported, the possible genetic links between them have not been assessed in large-scale studies. Moreover, the genetic basis of susceptibility to infection is largely unknown, as large-scale genome-wide association studies of susceptibility to infection have been lacking. We utilized a large Danish population-based sample (N = 65,534) linked to nationwide population-based registers to investigate the genetic architecture of susceptibility to infection (heritability estimation, polygenic risk analysis, and a genome-wide association study (GWAS)) and examined its association with mental disorders (comorbidity analysis and genetic correlation). We found strong links between having at least one psychiatric diagnosis and the occurrence of infection (P = 2.16 × 10-208, OR = 1.72). The SNP heritability of susceptibility to infection ranged from ~2 to ~7% in samples of differing psychiatric diagnosis statuses (suggesting the environment as a major contributor to susceptibility), and polygenic risk scores moderately but significantly explained infection status in an independent sample. We observed a genetic correlation of 0.496 (P = 2.17 × 10-17) between a diagnosis of infection and a psychiatric diagnosis. While our GWAS did not identify genome-wide significant associations, we found 90 suggestive (P ≤ 10-5) associations for susceptibility to infection. Our findings suggest a genetic component in susceptibility to infection and indicate that the occurrence of infections in individuals with mental illness may be in part genetically driven.

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

Human leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants' HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.

ObjectiveMore than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.MethodsThe samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.ResultsThree genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).ConclusionsThis study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Spatial mapping is a promising strategy to investigate the mechanisms underlying the incidence of psychosis. We analyzed a case-cohort study (n = 24,028), drawn from the 1.47 million Danish persons born between 1981 and 2005, using a novel framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing and polygenic scores. Upbringing in a high environmental risk locale increases the risk for schizophrenia by 122%. Individuals living in a high gene-by-environmental risk locale have a 78% increased risk compared to those who have the same genetic liability but live in a low-risk locale. Effects of specific locales vary substantially within the most densely populated city of Denmark, with hazard ratios ranging from 0.26 to 9.26 for environment and from 0.20 to 5.95 for gene-by-environment. These findings indicate the critical synergism of gene and environment on the etiology of schizophrenia and demonstrate the potential of incorporating geolocation in genetic studies.

BackgroundAlthough the pathogenic nature of copy number variants (CNVs) on chromosome 22q11.2 has been recognised for decades, unbiased estimates of their population prevalence, mortality, disease risks, and diagnostic trajectories are absent. We aimed to provide the true population prevalence of 22q11.2 CNVs and associated trajectory of disease risk and mortality by use of the unbiased, representative Danish iPSYCH population case cohort.MethodsThis case-cohort study was done on a population of 86 189 individuals selected from the iPSYCH case cohort of 1 472 762 singletons born in Denmark between May 1, 1981, and Dec 31, 2005, who have a known mother from the Danish Civil Registration System, were residents in Denmark at 1 year of age, and enrolled in the iPSYCH Initiative. We used epidemiological methods in conjunction with nationwide hospital registers to analyse the iPSYCH case cohort of individuals with attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, autism, or bipolar disorder and a random population-based sample. The main outcomes assessed were the population prevalence of 22q11.2 rearrangements, and associated unbiased, population-adjusted estimates and 31-year disease risk trajectories for major neuropsychiatric disorders.FindingsPopulation prevalence in the Danish population was one in 3672 (seven of 25 704 [0·027%; 95% CI 0·012-0·057]) for deletions and one in 1606 (17 of 25 704 [0·066%; 0·040-0·107]) for duplications. Mortality after the age of 1 year among carriers was zero, and hazard ratios for neuropsychiatric disorders ranged from 2·60 to 82·44 for both rearrangements. By the age of 32 years, about 10% of individuals with deletions or duplications had developed ADHD, autism, or intellectual disability, and deletion carriers had higher probability than duplication carriers of co-occurring intellectual disability or epilepsy.InterpretationThe significantly different prevalence of 22q11.2 duplications and deletions indicates distinct selective pressures on these rearrangements. Although risk of congenital abnormalities, developmental delay, and intellectual disability is elevated in deletion carriers, the overall prevalence of neuropsychiatric disorders is higher in duplication carriers, which implies that identification and clinical monitoring should extend beyond congenital traits and into child and adolescent psychiatry.FundingCapital Region's Research Foundation for Mental Health Research, The Lundbeck Foundation, and US National Institutes of Health.

Because the human brain consumes a disproportionate fraction of the resting body's energy, positron emission tomography (PET) measurements of absolute glucose metabolism (CMRglc) can serve as disease biomarkers. Global mean normalization (GMN) of PET data reveals disease-based differences from healthy individuals as fractional changes across regions relative to a global mean. To assess the impact of GMN applied to metabolic data, we compared CMRglc with and without GMN in healthy awake volunteers with eyes closed (i.e., control) against specific physiological/clinical states, including healthy/awake with eyes open, healthy/awake but congenitally blind, healthy/sedated with anesthetics, and patients with disorders of consciousness. Without GMN, global CMRglc alterations compared to control were detected in all conditions except in congenitally blind where regional CMRglc variations were detected in the visual cortex. However, GMN introduced regional and bidirectional CMRglc changes at smaller fractions of the quantitative delocalized changes. While global information was lost with GMN, the quantitative approach (i.e., a validated method for quantitative baseline metabolic activity without GMN) not only preserved global CMRglc alterations induced by opening eyes, sedation, and varying consciousness but also detected regional CMRglc variations in the congenitally blind. These results caution the use of GMN upon PET-measured CMRglc data in health and disease.

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.

ObjectivesThis study sought to determine whether coronary artery calcium (CAC) could be used to optimize statin allocation among individuals for whom trial-based evidence supports efficacy of statin therapy.BackgroundRecently, allocation of statins was proposed for primary prevention of atherosclerotic cardiovascular disease (ASCVD) based on proven efficacy from randomized controlled trials (RCTs) of statin therapy, a so-called trial-based approach.MethodsThe study used data from MESA (Multi-Ethnic Study of Atherosclerosis) with 5,600 men and women, 45 to 84 years of age, and free of clinical ASCVD, lipid-lowering therapy, or missing information for risk factors at baseline examination.ResultsDuring 10 years' follow-up, 354 ASCVD and 219 hard coronary heart disease (CHD) events occurred. Based on enrollment criteria for 7 RCTs of statin therapy in primary prevention, 73% of MESA participants (91% of those >55 years of age) were eligible for statin therapy according to a trial-based approach. Among those individuals, CAC = 0 was common (44%) and was associated with low rates of ASCVD and CHD (3.9 and 1.7, respectively, per 1,000 person-years). There was a graded increase in event rates with increasing CAC score, and in individuals with CAC >100 (27% of participants) the rates of ASCVD and CHD were 18.9 and 12.7, respectively. Consequently, the estimated number needed to treat (NNT) in 10 years to prevent 1 event varied greatly according to CAC score. For ASCVD events, the NNT was 87 for CAC = 0 and 19 for CAC >100. For CHD events, the NNT was 197 for CAC = 0 and 28 for CAC >100.ConclusionsMost MESA participants qualified for trial-based primary prevention with statins. Among the individuals for whom trial-based evidence supports efficacy of statin therapy, CAC = 0 and CAC >100 were common and associated with low and high cardiovascular risks, respectively. This information may guide shared decision making aimed at targeting evidence-based statins to those who are likely to benefit the most.

BackgroundElective abortions show a secular decline in high income countries. That general pattern, however, may mask meaningful differences-and a potentially rising trend-among age, income, and other racial/ethnic groups. We explore these differences in Denmark, a high-income, low-fertility country with excellent data on terminations and births.MethodsWe examined monthly elective abortions (n = 225,287) from 1995 to 2009, by maternal age, parity, income level and mother's country of origin. We applied time-series methods to live births as well as spontaneous and elective abortions to approximate the denominator of pregnancies at risk of elective abortion. We used linear regression methods to identify trend and seasonal patterns.ResultsDespite an overall declining trend, teenage women show a rising proportion of pregnancies that end in an elective termination (56% to 67%, 1995 to 2009). Non-Western immigrant women also show a slight increase in incidence. Heightened economic disadvantage among non-Western immigrant women does not account for this rise. Elective abortions also show a sustained "summer peak" in June, July and August. Low-income women show the most pronounced summer peak.ConclusionsIdentification of the causes of the increase over time in elective abortion among young women, and separately among non-Western immigrant women, represents key areas of further inquiry. The unexpected increase over time in elective abortions among teens and non-Western immigrants in Denmark may signal important social and cultural impediments to contraception. The summer peak in abortions among low-income women, moreover, conflicts with the conventional assumption that the social and demographic composition of mothers who electively end their pregnancy remains stable within a calendar year.

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.

BackgroundReadmissions after hospitalization for pneumonia are common, but the few risk-prediction models have poor to modest predictive ability. Data routinely collected in the electronic health record (EHR) may improve prediction.ObjectiveTo develop pneumonia-specific readmission risk-prediction models using EHR data from the first day and from the entire hospital stay ("full stay").DesignObservational cohort study using stepwise-backward selection and cross-validation.SubjectsConsecutive pneumonia hospitalizations from 6 diverse hospitals in north Texas from 2009-2010.MeasuresAll-cause nonelective 30-day readmissions, ascertained from 75 regional hospitals.ResultsOf 1463 patients, 13.6% were readmitted. The first-day pneumonia-specific model included sociodemographic factors, prior hospitalizations, thrombocytosis, and a modified pneumonia severity index; the full-stay model included disposition status, vital sign instabilities on discharge, and an updated pneumonia severity index calculated using values from the day of discharge as additional predictors. The full-stay pneumonia-specific model outperformed the first-day model (C statistic 0.731 vs 0.695; P = 0.02; net reclassification index = 0.08). Compared to a validated multi-condition readmission model, the Centers for Medicare and Medicaid Services pneumonia model, and 2 commonly used pneumonia severity of illness scores, the full-stay pneumonia-specific model had better discrimination (C statistic range 0.604-0.681; P < 0.01 for all comparisons), predicted a broader range of risk, and better reclassified individuals by their true risk (net reclassification index range, 0.09-0.18).ConclusionsEHR data collected from the entire hospitalization can accurately predict readmission risk among patients hospitalized for pneumonia. This approach outperforms a first-day pneumonia-specific model, the Centers for Medicare and Medicaid Services pneumonia model, and 2 commonly used pneumonia severity of illness scores. Journal of Hospital Medicine 2017;12:209-216.