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Background The pattern of cancer in long-term survivors from childhood cancer has not been investigated comprehensively. Methods We obtained a cohort of 47697 children and adolescents aged 0-19 years with cancer as defined by the country-wide cancer registries of Denmark, Finland, Iceland, Norway, and Sweden during 1943-2005. Cohort members were followed through age 79 years for subsequent primary cancers notified to the registries, and the age-specific risk pattern of the survivors was compared with that of the national populations using country and sex standardized incidence ratios (SIRs). We used a multiplicative Poisson regression model to estimate relative risk of cancer for attained age, with adjustment for calendar period and age at diagnosis of primary cancer. We also calculated excess absolute risk (EAR) attributable to status as childhood cancer survivor and determined the cumulative incidence of second primary cancer as a function of attained age for three subcohorts defined by period of treatment for childhood cancer. Results A total of 1180 asynchronous second primary cancers were observed in 1088 persons, yielding an overall SIR of 3.3 (95% confidence interval = 3.1 to 3.5). The relative risk was statistically significantly increased in all age groups, even for cohort members approaching 70 years of age. The EAR for second primary cancer among survivors increased gradually from one additional case per 1000 person-years of observation in early life to six additional cases per 1000 person-years in the age group 60-69 years. For children treated in the prechemotherapy era (1943-1959), the cumulative risk for a second primary cancer reached 18%, 34%, and 48% at ages 60, 70, and 80 years, respectively. The age-specific incidence rates were highest for cohort members treated in the era of intensive, multiple-agent chemotherapy (1975-2005). Conclusion Survivors of childhood cancer have a persistent excess risk for a second primary cancer throughout their lives, accompanied by continuous changes in the risk of cancers at specific sites.

Background Results from randomized trials indicate that treatment with tamoxifen or chemotherapy for primary breast cancer reduces the risk for contralateral breast cancer. However, less is known about how long the risk is reduced and the impact of factors such as age and menopausal status. Methods The study included 634 women with contralateral breast cancer (case patients) and 1158 women with unilateral breast cancer (control subjects) from the Women's Environment, Cancer and Radiation Epidemiology Study. The women were younger than age 55 when they were first diagnosed with breast cancer during 1985-1999. Rate ratios (RRs) and 95% confidence intervals (CIs) for contralateral breast cancer after treatment with chemotherapy or tamoxifen were assessed by multivariable adjusted conditional logistic regression analyses. Results Chemotherapy was associated with a lower risk for contralateral breast cancer (RR = 0.57, 95% CI = 0.42 to 0.75) than no chemotherapy. A statistically significant association between chemotherapy and reduced risk for contralateral breast cancer persisted up to 10 years after the first breast cancer diagnosis and was stronger among women who became postmenopausal within 1 year of the first breast cancer diagnosis (RR = 0.28, 95% CI = 0.11 to 0.76). Tamoxifen use was also associated with reduced risk for contralateral breast cancer (RR = 0.66, 95% CI = 0.50 to 0.88) compared with no use, and the association was statistically significant for 5 years after the first diagnosis. Conclusion The associations between chemotherapy and tamoxifen treatment and reduced risk for contralateral breast cancer appear to continue for 10 and 5 years, respectively, after the initial breast cancer is diagnosed. Ovarian suppression may have a role in the association between chemotherapy and reduced risk for contralateral breast cancer.

Nocturnal enuresis (bedwetting) is a common disorder affecting 10–16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology.

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P= 9.31 × 10−12) that replicates in an independent population (Preplication= 3.27 × 10−3, Pmeta-analysis= 9.09 × 10−12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD. The study reports a genome-wide significant locus for cannabis use disorder, replicating in an independent cohort, and implicates CHRNA2, which encodes an acetylcholine receptor subunit, in the disorder by analyses of genetically regulated gene expression.

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.

Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure.

Common genetic variants increase the risk of schizophrenia, but the downstream biological mechanisms are largely unknown. A new study demonstrates that schizophrenia risk genes cause neuronal dysfunction and have synergistic effects on gene expression.

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype. A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent risk loci. Comparisons with other psychiatric disorders and candidate gene analyses provide new insights into major depressive disorder.

Background: Variants in SLC34A2encoding the sodium-dependent phosphate transport protein 2b (NaPi-IIb) cause the rare lung disease pulmonary alveolar microlithiasis (PAM). PAM is characterised by the deposition of calcium-phosphate concretions in the alveoli usually progressing over time. No effective treatment is available. So far, 30 allelic variants in patients have been reported but only a few have been functionally characterised. This study aimed to determine the impact of selected SLC34A2variants on transporter expression and phosphate uptake in cellular studies. Methods: Two nonsense variants (c.910A > T and c.1456C > T), one frameshift (c.1328delT), and one in-frame deletion (c.1402_1404delACC) previously reported in patients with PAM were selected for investigation. Wild-type and mutant c-Myc-tagged human NaPi-IIb constructs were expressed in Xenopus laevisoocytes. The transport function was investigated with a 32Pi uptake assay. NaPi-IIb protein expression and localisation were determined with immunoblotting and immunohistochemistry, respectively. Results: Oocytes injected with the wild-type human NaPi-IIb construct had significant 32Pi transport compared to water-injected oocytes. In addition, the protein had a molecular weight as expected for the glycosylated form, and it was readily detectable in the oocyte membrane. Although the protein from the Thr468del construct was synthesised and expressed in the oocyte membrane, phosphate transport was similar to non-injected control oocytes. All other mutants were non-functional and not expressed in the membrane, consistent with the expected impact of the truncations caused by premature stop codons. Conclusions: Of four analysed SLC34A2variants, only the Thr468del showed similar protein expression as the wild-type cotransporter in the oocyte membrane. All mutant transporters were non-functional, supporting that dysfunction of NaPi-IIb underlies the pathology of PAM.

Context:Cardiovascular disease is the major cause of death in the Western world, but the association between 25-hydroxyvitamin D [25(OH)D] levels and the risk of cardiovascular disease mortality remains unclear.Objective:The objective of the study was to determine the association between cardiovascular, stroke, and acute myocardial infarct mortality and serum levels of 25(OH)D.Design:This was an observational cohort study, the Copenhagen vitamin D study, data from a single laboratory center in Copenhagen, Denmark. Follow-up was from 2004 to 2011.Setting:Serum 25(OH)D was analyzed from 247 574 subjects from the Copenhagen general practice sector.Participants:Examination of the association 25(OH)D levels and mortality from cardiovascular disease, stroke, and acute myocardial infarct was performed among 161 428 women and 86 146 men.Main Outcome Measures:A multivariate Cox regression analysis was used to compute hazard ratios for cardiovascular, stroke, and acute myocardial infarct mortality.Results:Of 247 574 subjects, a total of 16 645 subjects died in the ensuing 0–7 years. A total of 5454 died from cardiovascular disease including 1574 from stroke and 702 from acute myocardial infarct. The 25(OH)D level of 70 nmol/L was associated with the lowest cardiovascular disease mortality risk. Compared with that level, the hazard ratio for cardiovascular disease mortality was 2.0 [95% confidence interval (CI) 1.8–2.1] at the lower extreme (∼12.5 nmol/L) with a higher risk for men [2.5 (95% CI 2.2–2.9)] than for women [1.7 (95% CI 1.5–1.9)]. At the higher extreme (∼125 nmol/L), the hazard ratio of cardiovascular disease mortality was 1.3 (95% CI 1.2–1.4), with a similar risk among men and women. Results were similar for stroke and acute myocardial subgroups.Conclusions:In this large observational study, low and high levels of 25(OH)D were associated with cardiovascular disease, stroke, and acute myocardial mortality in a nonlinear, reverse J-shaped manner, with the highest risk at lower levels. Whether this was a causal or associational finding cannot be determined from our data. There is a need for randomized clinical trials that include information on the effects of 25(OH)D levels greater than 100 nmol/L.

Previous studies have suggested that dopamine agonists have an antidepressant effect in Parkinson's disease (PD) patients. We examined whether fewer PD patients used antidepressant medication, when they were first treated with a dopamine agonist compared to other PD medications. PD patients diagnosed in Denmark were identified, and the diagnosis was confirmed by a review of the medical record. Antidepressant medication was assessed using the Danish National Prescription Registry. We used Cox proportional hazards regression to model the association between PD medications and time to antidepressant prescription. The type of PD medication first prescribed did not affect the subsequent use of antidepressants.

The MCHR1gene encoding the melanin-concentrating hormone receptor 1 is located on chromosome 22q13.2 and has previously been associated with schizophrenia in a study of cases and controls from the Faroe Islands and Scotland. Herein we report an association between variations in the MCHR1gene and schizophrenia, based on analyses of a larger sample and an increased number of single nucleotide polymorphisms (SNPs) than used in the previous study.

The serine/threonine kinase Akt (PKB) is activated in response to growth factors, cytokines and other growth promoting stimuli and is involved in the regulation of a number of cellular processes including metabolism, cell growth, proliferation and survival. To study intracellular metabolic effects of left ventricular hypertrophy (LVH) induced by chronic aortic banding in a recently established swine model, protein arrays can be used to analyze changes in cytosolic protein phosphorylation levels such as cell signal transduction and protein kinase pathways. Miniaturized sandwich immunoassays allow the simultaneous analysis of several parameters in a single experiment. Bead-based protein array systems or suspension microarrays are well-established multiplex sandwich immunoassay formats. Cytosolic proteins were extracted from pig hearts. Using the bead-based Luminex system, multiplexed sandwich immunoassays have been developed to analyze the phosphorylated proteins IR[pYpY1162/1163], IGF-1R[pYpY1135 /1136], IRS-1[pS312], Akt[pS473], PRAS40[pT246], p70S6K[pTpS421/424], and GSK-3[pS9], which were measured simultaneously in extracted myocardial tissue homogenates with the Akt Pathway Phospho 7-Plex Panel using a Luminex 100 IS system. Using this assay, tissue homogenates derived from myocardial tissue samples from 28 individual porcine in vivo model experiments in normal hearts (n17) and LVH hearts (n11) were analyzed for phosphorylated protein concentrations. Results obtained allowed grouping of myocardial tissue samples into a LVH and a normal group. Two candidate molecules: PRAS40 (normal vs. LVH two-tailed probability P 0.0022) and GSK-3 (P0.003), had lower concentrations in LVH pigs than in normal animals, suggesting loss of GSK-3 inhibitory activity and contributing to speculation of altered insulin sensitivity associated with LVH.

The XVII World Congress of Psychiatric Genetics, sponsored by The International Society of Psychiatric Genetics (ISPG) took place in San Diego, California from 4 to 8 November 2009. Approximately 550 participants gathered to discuss the latest molecular genetic findings relevant to serious mental illness, including schizophrenia, mood disorders, substance abuse, autism, and attention deficit disorder. Recent advances in the field were discussed, including the genome-wide association studies results, copy number variation (CNV) in the genome, genomic imaging, and large multicenter collaborations. The following report, written by junior travel awardees who were assigned sessions as rapporteurs represents some of the areas covered in oral presentation during the conference, and reports on some of the notable major new findings described at this 2009 World Congress of Psychiatric Genetics.

X-linked congenital nephrogenic diabetes insipidus (CNDI) is characterized by a defective renal response to the antidiuretic hormone (AVP) due to variations in the arginine vasopressin receptor 2 (AVPR2) gene. In a unique group of patients, the renal insensitivity to the effects of AVP is incomplete resulting in a partial phenotype. To investigate the molecular defects, two previously published variations in the AVPR2gene, known to cause a partial CNDI phenotype, were expressed in transiently transfected human embryonic kidney cells. One variation (p.Arg104Cys) is located in the first extracellular loop and the other variation (p.Ser329Arg) is located in the intracellular COOH terminal of the receptor protein. Western blotting showed almost equal amounts of WT-V2R and Arg104Cys-V2R protein at steady state, whereas the level of Ser329Arg-V2R protein was lower. Confocal microscopy established that WT-V2R and Arg104Cys-V2R are localized on the cellular surface while the Ser329Arg-V2R primarily accumulates within the endoplasmic reticulum resulting in reduced surface expression. Ligand binding analysis demonstrated that the Bmaxfor cells expressing Arg104Cys-V2R and Ser329Arg-V2R were 14.8- and 2.5-fold lower than Bmaxfor WT-V2R, respectively. AVP affinity (1/Kd) for WT-V2R and the Ser329Arg-V2R was similar while 1/Kdfor Arg104Cys-V2R was increased. cAMP assay revealed that cells expressing p.Arg104Cys-V2R or p.Ser329Arg-V2R produced 1.7- and 6.8-fold lower amounts of cAMP compared with WT-V2R, respectively. In conclusion, ligand binding and signal transduction capability are dependent on localization of the amino acid variation. Striking divergences at the level of receptor functionality may thus underlie similar clinical phenotypes in CNDI.

The incidence rate of breast cancer in first-degree relatives of women with breast cancer has been hypothesized to become constant at a predetermined age in accordance with observations of a high, roughly constant incidence rate of contralateral breast cancer by age. We attempted to test this hypothesis in the Danish population with cancer registry data.

Lung cancer risk was investigated in relation to single nucleotide polymorphisms in genes involved in the inflammatory response. The aim was to see if polymorphisms modifying the inflammatory response are associated with risk of lung cancer and if there were interactions between the same polymorphism and factors, which modify an inflammatory response, such as smoking status, duration, and intensity, and use of NSAID. The functional SNPs IL-1B T-31C, IL6 G-174C, IL8 T-251A, IL10 C-592T, COX2 C8473T, COX2 A-1195G and PPARγ2 Pro12Ala were included.

We investigated the risk of basal cell carcinoma (BCC) in relation to a number of single nucleotide polymorphisms in genes involved in the inflammatory response. A case–control study including 322 BCC cases and a similar number of controls was nested in a population-based prospective study of 57,053 individuals (aged 50–64 at inclusion) in Denmark. NSAID use was associated with a slightly decreased risk of BCC (IRR=0.85, 95% CI=0.66–1.10). We found that two polymorphisms in COX-2, COX-2 A-1195G and T8473C were associated with risk of BCC. Carriers of the variant allele of COX-2 A-1195G had lower risk of BCC than homozygous wild type carriers (IRR=0.54, 95% CI=0.47–0.89). Homozygous carriers of the variant allele of COX-2 T8473C were at 2.27-fold higher risk of BCC (95% CI=1.31–3.92) than homozygous wild type allele carriers.

Abstract: Objective: To investigate the effects of occupational activity and leisure time activity on incident colon cancer risk in a Danish middle-aged population. Methods: In the cohort, Diet, Cancer and Health, which included 28,356 women and 26,122 men aged 50–64 years at baseline, 140 women and 157 men were diagnosed with colon cancer from 1993 to 2003. The associations between occupational and leisure time activity in terms of a MET-score and the single activities, sports, cycling, walking, gardening, housework and do-it-yourself work, and incident colon cancer were investigated. Leisure time activity was investigated in two ways using the Cox proportional hazards model: by comparison of active versus non-active and by investigating a possible dose–response relationship while allowing a separate association for non-active individuals. Results: No associations were found between risk of colon cancer and occupational activity, MET-hours per week of total leisure time activity, residuals from a regression of each activity on the total MET-hours or the time spent on any of the six types of leisure time activities. However, a borderline significant association was found with the number of activities in which the participants were active. For each additional activity IRR = 0.87 (0.76–1.00) for women and IRR = 0.88 (0.78–1.00) for men. Conclusion: Our data do not support the evidence of an inverse association between colon cancer risk and occupational activity or leisure time activity, but avoiding a sedentary lifestyle by participating in different activities may reduce colon cancer risk.

AbstractObjective: To assess the importance of body fat mass (BFM) and fat free mass (FFM) for the established positive association between BMI and breast cancer among post-menopausal women.Research Methods and Procedures: A prospective cohort of 23,788 postmenopausal women included in the Danish study Diet, Cancer, and Health during 1993 to 1997 was linked to the Danish Cancer Registry to identify all cases of breast cancer occurring during 1993 to 2002. Breast cancer incidence rate ratios for anthropometric measurements with adjustment for known risk factors for breast cancer were calculated by Cox regression analyses.Results: Among the most commonly used anthropometric measurements, BMI was positively associated with breast cancer among never users of hormone replacement therapy (HRT). By splitting BMI into two indices, BFM index and FFM index, we found that the incidence rate ratio with each 1 kg/m2among never users of HRT was 0.98 (95% confidence interval, 0.93 to 1.03) for BFM index and 1.12 (95% confidence interval, 1.00 to 1.26) for FFM index after mutual adjustment.Discussion: The finding for BMI was in accordance with previous findings. Our results indicate that the FFM component of BMI may play a role for development of breast cancer among never users of HRT.

Although molecular research has contributed significantly to our knowledge of familial neurohypophyseal diabetes insipidus (FNDI) for more than a decade, the genetic background and the pathogenesis still is not understood fully. Here we provide a review of the genetic basis of FNDI, present recent progress in the understanding of the molecular mechanisms underlying its development, and survey diagnostic and treatment aspects. FNDI is, in 87 of 89 kindreds known, caused by mutations in the arginine vasopressin(AVP) gene, the pattern of which seems to be largely revealed as only few novel mutations have been identified in recent years. The mutation pattern, together with evidence from clinical, cellular, and animal studies, points toward a pathogenic cascade of events, initiated by protein misfolding, involving intracellular protein accumulation, and ending with degeneration of the AVP producing magnocellular neurons. Molecular research has also provided an important tool in the occasionally difficult differential diagnosis of DI and the opportunity to perform presymptomatic diagnosis. Although FNDI is treated readily with exogenous administration of deamino-D-arginine vasopressin (dDAVP), other treatment options such as gene therapy and enhancement of the endoplasmic reticulum protein quality control could become future treatment modalities.

Objective: The influence of the vitamins A, C, and E on breast cancer development has not been clarified. An effect of a vitamin per seimplicates similar patterns for the effects of the vitamin from dietary and supplemental sources. We examined how the breast cancer incidence rate among postmenopausal women was related to intake of vitamins A, C, and E from diet and supplements. Methods: Data was sampled as case–control nested within the Danish ‘Diet, Cancer and Health’ cohort. Data on vitamin intakes were collected at entry into the cohort by means of self-administered questionnaires. Women eligible for the nested case–control study were postmenopausal at entry into the cohort. The analyses were based on 418 cases of incident breast cancer and 394 controls (including two cases). Results: Breast cancer was not significantly related to the intakes of vitamin A or E, whereas a monotonic dose–response relation was seen for the intake of vitamin C. The estimated rate ratio per 100 mg vitamin C was: 2.06 (95% CI: 1.45–2.91) for dietary intake and 1.06 (95% CI: 1.01–1.13) for supplemental intake. Conclusions: We found no evidence of an association between breast cancer and intake of vitamin A or E for postmenopausal women. For vitamin C we found an increase in breast cancer rate with increasing intake.

Objective: The available epidemiological evidence indicates that drinking alcohol per seis associated with breast cancer. However, it has not been investigated how the breast cancer risk for a given total alcohol consumption depends on the drinking frequency. Methods: Within the prospective study on ‘Diet, Cancer and Health’, we examined the relationship between breast cancer, intake of total alcohol and frequency of drinking among 23,778 postmenopausal women, among whom 425 cases of breast cancer accrued during a median follow-up of 4.8 years. Results: The dose–response relationship between total alcohol intake and breast cancer showed an increase in the rate ratio of 1.10 per 10 g/day (95% CI: 1.04–1.16) with no evidence for differences by type of alcohol beverage. No interaction was found between drinking frequency and total alcohol intake in the risk of breast cancer (p= 0.40). Conclusions: The present study supports previous ones in showing a monotonic increase in the risk of breast cancer among postmenopausal women with increasing average daily intake of alcohol, and this relationship with alcohol intake did not depend on drinking frequency.

Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.

BackgroundFew studies have considered source-specific micronutrient intake in relation to mortality under the consideration that dietary and supplemental intake could exhibit different effects.ObjectiveTo evaluate the association between intake of vitamin C, E, folate, beta-carotene from diet and supplements, and overall mortality. Furthermore, to examine effect modification by smoking, alcohol intake, and BMI and to investigate if the effect of supplement use differs with dietary micronutrient intake.Methods and MaterialIn a prospective cohort study of 55,453 middle-aged Danes, information regarding diet, supplement use, and lifestyle was collected through questionnaires. During follow-up, 6,767 deaths were identified and incidence rate ratios (IRRs) of mortality related to micronutrient intake were calculated using Cox proportional hazards models.ResultsThe present study found no effect of dietary vitamin C, E, folate, or beta-carotene in relation to mortality. In contrast, supplemental folic acid was associated with a significantly increased mortality, whereas no other micronutrient supplement was associated with mortality. Effect modification by smoking and alcohol intake, but not BMI, was suggested in relation to some dietary micronutrients. The effect of supplements did not differ in groups defined by dietary micronutrient intake.ConclusionThis study suggests no effect of dietary micronutrients in relation to overall mortality. Supplemental folic acid was found to be associated with increased mortality, but further studies are required. No other supplemental micronutrient was associated with mortality.