Research

Research areas

The National Center for Register-based Research (NCRR) was established in 2000 at Aarhus University under the leadership of Professor Preben Bo Mortensen and funded by the Danish National Research Foundation. Research activities at NCRR are mainly financed by external research grants.

During the last twenty years, NCRR has become a world-leading centre in psychiatric epidemiology, contributing to the integration of register-based research between health sciences and social sciences.  

Today, NCRR consists of approximately 35 staff members who cover a broad area of research expertise, ranging from medicine and statistics to pharmacology, sociology and psychology.

Over the years, research has been extended to include bio-banked samples, thereby expanding to large-scale population-based genetic studies, as well as studies of gene-environment interactions associated with developing psychiatric disorders.

The main perspective of studies carried out at NCRR is to provide a better life for each individual suffering from a mental disorder – and perhaps, in the future, even find ways to prevent the development of severe mental illnesses.

Research Projects 

Access to the unique various Danish registers makes Denmark one of the leading countries in the world with regard to register-based research. The Danish registers offer possibilities to study large nationwide samples, which are less biased than most other samples. This is possible because in Denmark, access to healthcare is free of charge for everyone, and there are virtually no private psychiatric hospitals.

Studies at NCRR have contributed to epidemiological research through work focusing on specific mental illnesses including schizophrenia, bipolar disorder, depression, autism and attention deficit hyperactivity disorder (ADHD). Moreover, research also includes combined studies on disorders as well as studies on mortality and suicide, eating disorders, psychopharmacology and many more.

Research at NCRR is interdisciplinary. We collaborate with research groups, and have frequent interactions with leading epidemiologists from the Danish and international research community. Currently, NCRR houses four major research projects cross-linking highly skilled researchers from Denmark and abroad:  

  • iPSYCH; a national psychiatric project anchored at Aarhus University
  • CIRRAU; a centre for interdisciplinary register-based research funded by Aarhus University
  • A European Stanley Research Centre supporting research on causes and treatment of schizophrenia and bipolar disorder
  • A Niels Bohr Professorship that follows up on recent discoveries linking neonatal vitamin D and the risk of schizophrenia and other mental disorders

 

iPSYCH

"The Lundbeck Foundation Initiative for Integrative Psychiatric Research"- iPSYCH - is a Danish psychiatric project anchored at Aarhus University. iPYSCH is a collaboration between leading researchers in the field of psychiatry from Aarhus University, University of Copenhagen, Central Region of Denmark, Capital Region of Denmark and the Danish State Serum Institute, Copenhagen.

The Lundbeck Foundation decided three times to fund the iPSYCH project: In 2012, with 121 million DKK for a three-year period starting on March 1, 2012; in 2015, with a new three-year funding of 120 million DKK; and recently, a new three-year funding of 120 million DKK, starting on March 1, 2018.

The iPSYCH project involves six research groups, covering areas within medicine, molecular biology, bioinformatics, statistics, psychology and many more. Each research group investigates aspects of five specific mental disorders: autism, ADHD, schizophrenia, bipolar disorder and depression. All mental disorders are studied from different angles, including environmental, genetic and psychological risk factors. Information ranging from fetal to adult life, gathered from population studies, allows researchers within iPSYCH to examine possible causes and symptoms of a given disorder.

More than 150 researchers are involved in research activities within iPSYCH – most of them based in Aarhus and Copenhagen. However, iPSYCH also collaborates with skilled researchers from centres in the international research community such as the Broad Institute of MIT and Harvard University, Beijing Genomics Institute (BGI), Psychiatric Genomics Consortium, deCode Genetics, Iceland and the Genetic Biobank of the Faroe Islands.   

For more information, please visit the iPSYCH-website 

iPSYCH2012

One of iPSYCH’s greatest achievements is the establishment of the iPSYCH2012 case-cohort sample, which provides researchers with unprecedented access to study the environmental and genetic risk factors associated with mental disorders.  

The iPSYCH2012 sample includes the entire Danish Population born between 1981 and 2005, including 1,472,762 persons. Representative cases are identified within the sample, involving persons with the specific mental disorders: Schizophrenia, autism, affective disorders and attention-deficit/hyperactivity disorder (ADHD).

The iPSYCH2012 sample provides a solid foundation for a range of studies to be conducted for decades to come: Not only is it a rich and unique database for research in its current version, but it also constitutes a logistic and organizational framework for future studies. Access to the iPSYCH2012 sample will accelerate epidemiological research on preventing and treating severe mental disorders for the benefit of patients, their families, and society in general.

Moreover, future studies will benefit from the continued dialogue between epidemiological research projects within the iPSYCH consortium and large-scale studies available only through collaboration with leading international research communities.

For more info: The iPSYCH2012 case–cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders 

 CIRRAU

“Centre for Integrated Register-based Research” – CIRRAU - was established at Aarhus University in 2012. CIRRAU facilitates interdisciplinary register-based research in the academic areas of social sciences, health sciences and elements from natural sciences.

Records on the entire Danish population from cradle to grave have been collected for decades. Most of this information has been recorded for administrative purposes. However, Danish legislation also allows Danish researchers to utilize data to perform research of public relevance and importance.

Researchers within CIRRAU have acquired permission to establish a database at Statistics Denmark. This database provides the necessary data infrastructure to support and conduct register-based studies. In addition, the research potential of CIRRAU is further enhanced by linkage to collections of biological material and genetic information on 80,000 Danes from the Danish Neonatal Screening Bank located at Statens Serum Institute, Copenhagen. 

CIRRAU provides a data solution that constitutes the foundation of register-based analyses carried out in scientific programs, supported financially by the Lundbeck Foundation, TrygFonden, The Stanley Medical Research Institute, EU, The Simon Foundation and NordForsk.

For more information please visit the CIRRAU-website 

Stanley Medical Research Institute

NCRR participates in the “Stanley Program for Epidemiology, Prevention and Treatment of Schizophrenia” (SPECTS), supported by the Stanley Medical Research Institute.

The SPECTS Program consists of eight international leading laboratories, examining Gene-Environment interactions that may increase the risk of developing psychiatric disorders. These studies are important for the understanding of how both genetic disposition and environmental exposure play an important role in the development of mental illnesses.

The SPECTS Program is dedicated to developing biomarkers used to predict onset and progression of these mental illnesses. This is achieved by analysing the samples and data from various population registers, and by collecting data and samples from patients at various stages of their mental illness to examine the Gene-Environment Interaction.  

In addition to NCRR, other leading international research centres are involved in the SPECTS Program located at John Hopkins University, Karolinska Institute, WRAIR, University of Cambridge, Sheppard Prad, University of Michigan and University of Pittsburgh.  

For more information, please visit the SMRI-website

Niels Bohr Professorship

In 2016, Professor John McGrath from the University of Queensland, was awarded a Niels Bohr Professorship, with a grant of 30 million DKK from the Danish National Research Foundation.

In 2010, John McGrath published a paper based on information from Danish registers that described a link between neonatal vitamin D concentration and risk of mental disorders in the offspring. This discovery was achieved in close collaboration with Professor Preben Bo Mortensen and other leading Danish researchers at NCRR and Statens Serum Institute in Copenhagen.

The Niels Bohr Professorship makes it possible to follow up on this research, and to explore new innovative methods related to psychiatric epidemiology.

In addition to a close collaboration with iPSYCH, the Niels Bohr Professorship strengthens NCRR’s collaboration with top researchers from the international research community, including researchers from University of Queensland, senior investigators at the Institute for Health Metrics and Evaluation, and the WHO World Mental Health Survey Initiative at Harvard University.

Cross-linking researchers from these international research centres provides a variety of new opportunities for research and innovation in the field of psychiatric epidemiology. Along with other collaborative projects, neonatal vitamin D concentration will be measured in the iPSYCH2012 case-cohort sample.

For more information, please visit the NBP-website

NCRR RESEARCH

The academic staff at NCRR consists of Professors, Senior Researchers, Postdocs, PhD Students and Research Assistants; and a non-academistrative staff of 3 persons. Their main practise of expertise is to identify and pursue ways of using information stored in the Danish population-based registers. The registers allow research to address questions related to the epidemiology of psychiatric disorders, such as:

  • How many people have a particular mental disorder?
  • Do mental disorders occur differently in men and women?
  • When do different mental disorders emerge across the lifespan?
  • What are the risk factors for mental disorders – for example, do we inherit risk factors from our parents (e.g. genetic factors) or risk factors that we face during life (e.g. trauma, stress, low parental vitamin D)
  • How disabling are mental disorders, and how can we best measure this burden?

Although the causes of most mental disorders are unknown, it has been found that different biological, psychological, and environmental factors can all contribute to the development or progression of mental disorders. Most mental disorders are a result of a combination of several different factors rather than just a single factor.

For researchers at NCRR, the overriding hypothesis is that environmental risk factors contribute to the etiology of a range of mental disorders through their impact on neurodevelopment during fetal life, infancy and childhood. According to this hypothesis, the early exposures may interact with later risk factors such as social adversity or physical illness, as well as genetic risk. 

Over the last decade, genetic and other biological data have, thus, been added to the studies, anticipating that a combination of biological, health and social data will allow the discovery of interacting genetic and environmental etiologies of mental disorders. The section below provides an insight into current research at NCRR and previous research results.

Schizophrenia

Schizophrenia remains a poorly understood mental illness that impacts perception and cognition. It affects approximately one out of 100 individuals and leads to much suffering in the affected individuals and their relatives. Schizophrenia is associated with a substantial disability and has huge economic costs for society.

Access to various Danish registers has allowed researchers to document key risk factors associated with schizophrenia and other mental disorders. The risk factors associated with schizophrenia includes e.g. psychiatric family history, urban birth, paternal age, lifetime risk, infections, socio-economic adversity, and neonatal vitamin D deficiency. Furthermore, researchers at NCRR have studied different outcome measures associated with schizophrenia, such as treatment resistant schizophrenia, suicide, excess mortality, and pharmacological treatment.

Researchers at NCRR are currently involved in projects investigating the genetic background of schizophrenia. Through iPSYCH and together with international colleagues, they have identified some of the genetic variants that may increase the risk of developing schizophrenia. This research has shed new light on biological processes involved in the development of schizophrenia and other mental disorders, which, in time, will have crucial preventative and clinical implications for the future treatment of people with mental illnesses.

Regarding causes of schizophrenia and other severe mental illnesses, novel methods in psychiatric research provides new opportunities to take both environment and genes into consideration. These studies will strongly benefit from the iPSYCH2012 case-cohort sample, that further enhances possibilities to combine genetic, environmental and phenotypic data in aiming at predicting the emergence and development of schizophrenia and other mental illnesses.

Currently, NCRR is involved in projects that examine research questions like:

  • Can levels of neonatal vitamin D that are associated with an increased risk of developing schizophrenia also be connected to an increased risk of the development of other mental illnesses?
  • What particular genetic architecture increases the risk of schizophrenia?  
  • How is schizophrenia connected to the risk of gaining physical illnesses such as obesity, diabetes and infections? 
  • Can we identify genes particularly associated with the risk of developing schizophrenia, and genes particularly predicting a chronic course?
  • What are the genetic similarities between schizophrenia and other mental illnesses such as affective disorders, autism and ADHD? Can we identify a genetic overlap in the various mental disorders?

 For further reading

Pedersen CB et al. (2017) The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders. Molecular Psychiatry: http://rdcu.be/zk9N

Wimberley, T., et al. (2016). "Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study." Lancet Psychiatry: http://dx.doi.org/10.1016/S2215-0366(15)00575-1

Agerbo, E. et al. (2015) “Polygenic risk score, parental socioeconomic status, family history of psychiatric disorders, and the risk for schizophrenia: a Danish population-based study and meta-analysis.” JAMA Psychiatry: 10.1001/jamapsychiatry.2015.0346

McGrath, J. J., et al. (2014). "A comprehensive assessment of parental age and psychiatric disorders." JAMA Psychiatry: 10.1001/jamapsychiatry.2013.4081

Petersen, L., et al. (2011). "Paternal age at birth of first child and risk of schizophrenia." Am J Psychiatry: https://www.ncbi.nlm.nih.gov/m/pubmed/20952457/

McGrath, J. J., et al. (2010). "Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study." Arch Gen Psychiatry: 10:1001/archgenpsychiatry.2010.110

Dean, K., et al. (2010). "Full spectrum of psychiatric outcomes among offspring with parental history of mental disorder." Arch Gen Psychiatry: 10.1001/archgenpsychiatry.2010.86

Pedersen, C. B. and P. B. Mortensen (2006). "Why factors rooted in the family may solely explain the urban-rural differences in schizophrenia risk estimates."Epidemiologia E Psichiatria Sociale: https://pdfs.semanticscholar.org/626d/1469257c61296972bffd307cb4f1809e2998.pdf.

Pedersen, C. B. (2006). "No evidence of time trends in the urban-rural differences in schizophrenia risk among five million people born in Denmark from 1910 to 1986." Psychol Med: 10.1017/S003329170500663X

Mortensen, P. B., et al. (1999). "Effects of family history and place and season of birth on the risk of schizophrenia." New England Journal of Medicine: 10.1056/NEJM199902253400803

Mortality and suicide

People with severe mental disorders such as schizophrenia and bipolar affective disorder die 15-20 years earlier than the general population. Four general factors help explain this unacceptably high mortality rate among mentally ill patients: Suboptimal health-related behaviour, adverse effects of medicine, increased risk of suicide and high levels of somatic/mental comorbidities, including insufficient treatment.

It is a well-known fact that persons with severe mental disorders have an excess mortality as a result of accidents or suicide. However, the main explanation for early death in patients suffering from severe mental disorders is that they are more often affected by physical illness, for which they are treated poorly or too late compared to the general population. Actually, in many cases, physical illness is not discovered at all, and may be side effects of medicine. Moreover, persons with severe mental disorders also have a lifestyle characterised by lack of exercise, and therefore have a higher risk of complications from obesity.

Access to various Danish Registers makes it possible for researchers at NCRR to follow up on decades of data in order to examine the high excess mortality and to suggest causes, with the possibility to reduce them. As an example, researchers at NCRR have contributed to studies showing that persons with mental disorders are less likely to be treated for heart disease and use less medication for cardiovascular diseases, even though they are more vulnerable compared to the general population.

Recently, NCRR has extended its research to large-scale population-based genetic studies as well as studies of gene-environment interactions (GxE interaction). This has created new opportunities to take both genes and environment into consideration when studying the excess mortality in people with mental disorders.

Moreover, NCRR recently entered into collaboration with Professor John McGrath from the University of Queensland in a Niels Bohr professorship, which, among other interesting projects, will involve NCRR in the Global Burden of Disease project  and the WHO World Mental Health Survey Initiative examining the treatment of mental disorders worldwide. 

Currently, NCRR is involved in projects that examine research questions like: 

  • How do genes affect the high mortality rate among people with schizophrenia?
  • Do genes that increase risk of schizophrenia also increase risk of early death?
  • How does air-pollution affect mortality?
  • How does the presence of multiple mental illnesses affect mortality?
  • What causes of death may explain the excess mortality among mentally ill patients (Percentage of mortality caused by suicide, cardiovascular disease, cancer, etc.)?

For further reading

Erlangsen., et al. (2017) “Cause-specific life-years lost in people with mental disorders: a nationwide, register-based cohort study.” Lancet Psychiatry: https://doi.org/10.1016/S2215-0366(17)30429-7

Laursen, T., et al. (2017) Mortality and Self-Harm in Association with Clozapine in Treatment-Resistant Schizophrenia.” The American Journal of Psychiatry:https://doi.org/10.1176/appi.ajp.2017.16091097

Liu, Nancy H., et al (2017) Excess mortality in persons with severe mental disorders: a multilevel intervention framework and priorities for clinical practice, policy and research agendas. World Psychiatry:10.1002/wps.20384

Laursen, T., et al. (2016). ”Association of the polygenic risk score for schizophrenia with mortality and suicidal behaviour – a Danish population-based study”. Schizophrenia Research: http://dx.doi.org/10.1016/j.euroneuro.2016.09.578

Ribe, Anette Rissgaard., et al (2016) Ten-Year Mortality after a Breast Cancer Diagnosis in Women with Severe Mental Illness : A Danish Population-Based Cohort Study.  PloS one: https://doi.org/10.1371/journal.pone.0158013

Laursen, T. M., et al (2016) Mortality and life expectancy in persons with severe unipolar depression. Journal of Affective Disorders: 10.1016/j.jad.2015.12.067

Dalsgaard, S., et al (2015). “Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study”. The Lancet: http://dx.doi.org/10.1016/S0140-6736(14)61684-6

Laursen, T., et al (2014). “Excess early Mortality in Schizophrenia”. Annual Review of Clinical Psychology: https://doi.org/10.1146/annurev-clinpsy-032813-153657

Nordentoft, M., et al. (2011). "Absolute risk of suicide after first hospital contact in mental disorder." Arch Gen Psychiatry: 10.1001/archgenpsychiatry.2011.113

Laursen, T., et al. (2011). “Life expectancy among persons with schizophrenia or bipolar affective disorders”. Schizophrenia Research: 10.1016/j.schres.2011.06.008. 

Affective disorders (bipolar disorder, depression and anxiety disorder)

Affective disorders are a set of psychiatric diseases characterized by abnormalities of emotional state. The main types of affective disorders are depression, bipolar disorder and anxiety disorder. These illnesses are disruptive for the individual and have social and economic effects such as functional impairment, disability or lost work productivity, and increased need of health services. 

The numerous Danish National registers are a remarkable resource for epidemiological research because they include longitudinal data on the entire population of Denmark, including information on psychiatric diagnoses, other medical diagnoses, demographic information, income and labour market affiliation and other variables. 

Researchers at NCRR have studied the epidemiology of affective disorders by utilizing and analysing data from the Danish National Registers. Unique data are used to investigate research questions that would be difficult or even impossible in other research samples; for example, the distribution of information and determinants of more rare outcomes in disorders such as bipolar disorders, and the long-term causes and outcomes of more common disorders such as depression.

Access to complete information on large and representative samples of persons with and without affective disorders allows for sound conclusions to be made from results. For example, a recent study documented that despite having the same diagnosis, patients with severe depression receive treatment of very different duration in the Danish psychiatric system. Another study of approximately one million Danish children showed that mothers’ use of antidepressants during pregnancy increases the risk of children being diagnosed with a psychiatric illness later in life.


Affective disorders are heritable to varying degrees, meaning that a portion of the risk for depression or bipolar disorder can be attributed to genetic factors. However, studies also show that a large proportion of the population-level variation in affective disorders is due to environmental factors such as early adversity and socioeconomic status. Current research focuses on gaining a better understanding of the relationships between genes, environment and affective disorders within the Danish population. This research is crucial for a better understanding of the etiology of affective disorders, and hopefully thereby improving prediction, prevention and treatment.

Currently, NCRR is involved in projects that examine questions like: 

  • To which extent does genetic risk affect the onset, course and outcome of affective disorders within the Danish population?
  • How do early adverse life events interact with genetic risks associated with affective disorders?
  • Do genes associated with increased risk of schizophrenia also predispose to affective disorders such as depression?

 For further reading

Liu X., et al. (2017) ”Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study.” British Medical Journal: https://doi.org/10.1136/bmj.j3668 

Liu X, et al (2017) ”Depression and Anxiety in the Postpartum Period and Risk of Bipolar Disorder: A Danish Nationwide Register-Based Cohort Study.” J Clin Psychiatry: 10.4088/JCP.16m10970

Musliner, K. L., et al (2017) ”Vascular pathology and trajectories of late-life major depressive disorder in secondary psychiatric care.” The American Journal of Geriatric Psychiatry: https://doi.org/10.1016/j.jagp.2017.07.006

Musliner, K., et al. (2017) “Progression from unipolar depression to schizophrenia.” Acta Psychiatrica Scandinavica: 10.1111/acps.12663

Musliner, K. L., et al (2016) ”Heterogeneity in 10-year course trajectories of moderate to severe major depressive disorder: A Danish national register-based study” JAMA Psychiatry: 10.1001/jamapsychiatry.20

Dahl, S. K., et al. (2016) “Early adversity and risk for moderate to severe unipolar depressive disorder in adolescence and adulthood: A register-based study of 978,647 individuals.” Journal of Affective Disorders: http://dx.doi.org/10.1016/j.jad.2017.03.014

Laursen, T. M., et al (2016) Mortality and life expectancy in persons with severe unipolar depression. Journal of Affective Disorders: 10.1016/j.jad.2015.12.067

Bergink, V., et al (2016) “Childhood adverse life events and parental psychopathology as risk factors for bipolar disorder.” Transl Psychiatry: 10.1038/tp.2016.201

Musliner, K., et al. (2015) Parental history of psychiatric diagnoses and unipolar depression: a Danish National Register-based cohort study. Psychological Medicine:  10.1017/S0033291715000744

Mortensen, P. B., et al. (2011). "Neonatal antibodies to infectious agents and risk of bipolar disorder: a population-based case-control study." Bipolar Disord: 10.1111/j.1399-5618.2011.00962.x

Autism

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviour. Symptoms arise in the first years of life and, although treatment often improves functioning and daily living, ASD is generally a life-long disorder, and can be very disabling and cause significant economic costs for society.

Although ASD affects 1-2 % of children, it is still relatively rare compared to more common chronic child health conditions like asthma or obesity. Therefore, large, population-based studies with complete information on pregnancy and early life are needed in order to accurately identify important risk factors and discover the causes of ASD. Large, population-based studies with complete longitudinal information are also needed to better understand the life course of persons with ASD in order to develop interventions and improve quality of life.

NCRR has the data resources to make important and unique contributions to epidemiological research in ASD. Examples of research focusing on ASD specifically include work on family and pregnancy risk factors, such as parental age and occupational exposures during pregnancy, obstetric, pregnancy and new-born complications, family medical history and urbanity at birth or through childhood. Studies of ASD along with other severe mental disorders include contrasting time trends in incidence, risk factors such as parental age, antidepressant use in pregnancy and family history of related disorders.

Both genetic and non-genetic environmental factors, like maternal illness during pregnancy, are important contributors to ASD. It is likely that the interplay between genetics and environmental factors during critical periods of development is a key factor. Future investigations of ASD will need to combine genetic and environmental factors in the same studies. NCRR houses the largest assembly of genetic, biological and longitudinal data on persons with ASD in the world. Therefore, NCRR will be a crucial partner in ASD etiologic studies in the years to come.

Currently, NCRR is involved in projects that examine questions like:   

  • How do genes influence the risk for ASD from exposures like traffic-related air pollution? Are risk patterns different or the same for ASD and ADHD?
  • Is risk for ASD influenced by environmental factors during pregnancy that can change the ways genes are expressed?
  • Are there any significant gene-environment interactions in the risk of ASD from pregnancy conditions like maternal smoking or diabetes?
  • What is the overlap between genes increasing risk for ASD and disorders like schizophrenia and ADHD? Do any shared genes belong to a biologic pathway that sheds light on shared causes across these disorders?

For further reading

Singer AB, et al. (2017) ”Parental exposure to occupational asthmagens and risk of autism spectrum disorder in a Danish population-based case-control study.” Environmental Health: https://doi.org/10.1186/s12940-017-0230-8

St Pourcain B., et al (2017) “ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social communication difficulties.” Mol Psychiatry: 10.1038/mp.2016.198

Robinson, E. B., et al (2016) “Genetic risk for autism spectrum disorders and neuropsychiatric variation on the general population.” Nat Genet: 10.1038/ng.3529

Schendel DE., et al (2016) “”Association of psychiatric and neurologic comorbidity with mortality among persons with autism spectrum disorder in a Danish Population.” Jama Pediatrics: 10.1001/jamapediatrics.2015.3935

Christensen J et al. (2016) “Risk of epilepsy and autism in full- and half-siblings – a population-based cohort study.” Epilepsia: 10.1111/epi.13595

Sandin S, et al. (2015) “A. Autism risk associated with parental age and with increasing difference in age between the parents.” Molecular Psychiatry: 10.1038/mp.2015.70

Hansen, S. N., Schendel D.E. and Parmer E.T. (2015)” Explaining the increase in the prevalence of autism spectrum disorders: the proportion attributable to changes in reporting practices”. Jama Pediatrics: 10.1001/jamapediatrics.2014.1893

Atladottir HO, et al (2014)” The increasing prevalence of reported diagnoses of childhood psychiatric disorders: a descriptive multinational comparison.” Eur Child Adoles Psychiatry: 10.1007/s00787-014-0553-8

Christensen J, et al (2013) “Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism – a population-based study.” JAMA Pediatrics: 10.1001/jama.2013.2270

Grønborg TK, et al (2013) “The recurrence of autism spectrum disorders in Danish families: a population-based cohort study.” Jama Pediatrics: 10.1001/jamapediatrics.2013.2259

ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder, the most common mental disorder in children. The disorder is associated with severe impairments throughout the lifespan, and with many different adverse outcomes.

Danish registers allow long prospective follow-up studies of all individuals in Denmark, without attrition. This is especially important when studying ADHD, because the disorder is associated with a high drop out in follow-up studies. Register-based studies can provide a follow-up of 100 % of the original sample, even after 30 years.

For instance, researchers at NCRR were the first to document that ADHD is associated with an increased risk of premature death. In addition, NCRR has contributed to other long-term follow-up studies, documenting that persons with ADHD have an increased risk of developing other mental disorders later in life, including substance use disorders, affective disorders, and psychosis; and also that children with ADHD have an increased risk of injuries and emergency ward visits, teenage parenthood, and criminality in adulthood.  

Moreover, NCRR was first-mover in studies that included large samples of females with ADHD, providing important information on sex differences in ADHD, such as patterns of treatment, comorbidity and other characteristics and long-term prognosis. Finally, NCRR has also performed studies, investigating associations between ADHD and prenatal exposure to asthma-medication, maternal autoimmune diseases, and risk factors in early childhood, such as social adversities, febrile seizures and epilepsy.

Although the exact etiology of ADHD is still unknown, we know that both genetic and environmental risk factors are important: In a meta-analysis of 20 twin studies, the heritability of ADHD was 75 %. Currently, Denmark is probably the only place, where it is possible to perform prospective studies using nationwide cohorts, including large samples of patients with ADHD and random controls, on whom both genetic and environmental data is available.

Recently, NCRR contributed to a study identifying SNP’s in 12 loci genome-wide significantly associated with ADHD. These molecular genetic data now allow direct measurements of genetic liability of ADHD, by for instance a polygenic risk score (PRS). NCRR researchers will combine PRS for ADHD and environmental data to learn more about the etiology and outcome of ADHD. 

Currently, NCRR is involved in projects that examine questions like:      

  • Does exposure to air pollutants early in life increase the risk of ADHD?
  • Are xenobiotic and geogenic substances in drinking-water risk factors for ADHD?
  • How does genetics and air- and drinking-water borne substances interact in the etiology of ADHD?
  • How well does genetics and adversities in parent-child interactions predict adult adverse health outcomes of childhood ADHD?

For further reading:

Gundel LK, et al (2017) “Longitudinal association between mental disorders in childhood and subsequent depression - a nationwide prospective cohort study. J. Affect. Disord: https://doi.org/10.1016/j.jad.2017.10.023

Liang H, et al (2017) “In utero exposure to beta-2-adrenergic receptor agonist and attention-deficit/hyperactivity disorder in children. Eur Child Adolesc Psychiatry: https://doi.org/10.1007/s00787-017-0956-4

Demontis D, et al (2017) “Discovery Of The First Genome-Wide Significant Risk Loci For ADHD.” bioRxiv: https://doi.org/10.1101/145581

Nielsen PR, et al (2016) “Associations Between Autoimmune Diseases and Attention-Deficit/Hyperactivity Disorder: A Nationwide Study” J Am Acad Child Adolesc Psychiatryhttps://doi.org/10.1016/j.jaac.2016.12.010

Riglin L, et al (2016) ”Investigating the contribution of genetic risk variants to Attention Deficit/Hyperactivity Disorder trajectories in the general population” JAMA Psych: https://doi.org/10.1001/jamapsychiatry.2016.2817

Butt JH, et al (2016) “Beta-blockers for Exams Identify Students at High Risk of Psychiatric Morbidity.” J Child Adolesc Psychopharmacol: https://doi.org/10.1089/cap.2016.0079

Bertelsen EN, et al (2016) “Childhood Epilepsy, Febrile Seizures, and Subsequent Risk of ADHD. Pediatrics: https://doi.org/10.1542/peds.2015-4654

Ottosen C, et al (2016) Gender differences in associations between attention-deficit/hyperactivity disorder and substance use disorder. J Am Acad Child Adolesc Psychiatr: https://doi.org/10.1016/j.jaac.2015.12.010

Dalsgaard S, et al (2015) “Effect of Drugs On the Risk of Injuries in Children with Attention-Deficit/Hyperactivity Disorder - A Prospective Cohort Study.” Lancet Psychiatry. https://doi.org/10.1016/S2215-0366(15)00271-0

Dalsgaard S, et al (2015). Mortality in Children, Adolescents and Adults with Attention Deficit Hyperactivity Disorder - a nationwide cohort study. Lancet Psychiatry: https://doi.org/10.1016/s0140-6736(14)61684-6

Psychopharmacology

Patients with mental disorders like depression, schizophrenia, ADHD, bipolar disorder, psychosis, anxiety etc. are often treated with psychotrophic drugs. Psychopharmacologic research examines the impact of different drugs on patients with mental disorders and how different compounds may affect people’s behaviour by altering thought patterns and emotions; and documents potential long-term effects on physical condition.

Besides academia, psychopharmacology and the safe use of drugs are naturally also of general public health concern and of interest to pharmaceutical companies. Therefore, collaborations between the domains are common.

Pharmacoepidemiology relies on a large amount of data in order to detect rare events, and researchers at NCRR utilize data from the Danish registers to study courses and outcomes of pharmacological treatment in psychiatric patients. In recent years, NCRR has been involved in EU-funded research projects, CRESTAR and PROTECT, that allowed researchers to work relatively independent of drug companies’ financial aid. 

In the CRESTAR project, that officially ended on 31st October 2015, researchers analysed samples of more than 11,000 patients with treatment resistant schizophrenia, involving nearly 25,000 controls, identifying 10 genetic loci associated with treatment resistant schizophrenia - and clozapine treatment failure. Moreover, the researchers used epigenetic analyses with the purpose to develop a model that may predict the effect of clozapine use in patients with schizophrenia, with high specificity and sensitivity. This research has important clinical implications, because the earlier patients are offered the correct medical treatment, the better the long-term outcome may be.  

The EU-project, PROTECT, contains several work programmes, where the researchers compare and develop new methods in the field of pharmacoepidemiology to quantify and communicate the risks and benefits of pharmacological treatment. NCRR contributes to the PROTECT project as a leading force concerning performance combining register data, genetic data and other biological data in order to conduct studies of interacting genetic and environmental factors influencing risk, course and outcome of mental disorders.

In addition to the involvement in CRESTAR and PROTECT, NCRR is also involved in other research projects on anti-depressive treatment response, sickness absence in users of anti-depressants, pharmacological treatment of patients with dementia, and much more.

Currently, NCRR is involved in research projects that examine questions like:  

  • How does clozapine treatment effect mortality and self-harm in individuals with treatment-resistant schizophrenia?
  • What is the prevalence of drug prescription for high-risk pregnancies in Danish women with a psychiatric history compared to Danish women in general?

For further Reading:

Horsdal, Henriette T, et al (2017): “Association between global functioning at first schizophrenia diagnosis and treatment resistance”. Early Intervention in Psychiatry: 10.1111/eip.12522

Ingstrup, Katja G, et al (2017): ”Prescribtion drug use in pregnancy and variations according to prior psychiatric history”. Pharmacoepidemiology and Drug Safety: 10.1002/pds.4355

Wimberley, Theresa, et al (2017): ”Polygenic Risk Score for Schizophrenia and Treatment-Resistant Schizophrenia” Schizophrenia Bulletin: 10.1093/schbul/sbx007

Horsdal, Henriette Thisted, et al (2017): ”C-reactive protein levels and treatment resistance in schizophrenia – A Danish population-based cohort study” Human Psychopharmacology: Clinical and Experimental: 10.1002/hup.2632

Bjørklund, Louise B, et al (2017): ”Psychopharmacological treatment of psychotic mania and psychotic bipolar depression compared to non-psychotic mania and non-psychotic bipolar depression Bipolar disorders: 10.1111/bdi.12504

Wimberley, Theresa, et al (2016): ”Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study” Lancet Psychiatry:  10.1016/S2215-0366(15)00575-1

Köhler, Karl Ole, et al (2016): ”The effect of Concomitant Treatment with SSRIs and Statins: A Population-based Study”: The American Journal of Psychiatry: 10.1176/appi.ajp.2016.150

Dalsgaard S, et al (2015) “Effect of Drugs On the Risk of Injuries in Children with Attention-Deficit/Hyperactivity Disorder - A Prospective Cohort Study.” Lancet Psychiatry. https://doi.org/10.1016/S2215-0366(15)00271-0

Other Projects

NCRR primarily utilizes data from numerous Danish registers to investigate long-term causes and outcomes of severe mental disorders. This work has documented several key factors within psychiatric epidemiology, including urban birth, paternal age, psychiatric family history, lifetime risk, infections, neonatal vitamin D deficiency, socio-economic adversity, treatment resistant schizophrenia and pharmalogical treatment, and many more.     

However, researchers at NCRR also conduct projects that shine light on other important public areas. For example, they are involved in register-based projects investigating health consequences of air pollution, connection between school, education and social mobility, connection between lifestyle and health issues such as cancer, and many others.    

Moreover, the new-established iPSYCH2012 sample enables researchers to provide a continuous measure of reliability, which greatly enhances the possibility to combine genetic, environmental and phenotypic data in a broad range of studies. Since the initiation of the iPSYCH2012 sample, many related Danish projects are built on the same framework as projects within iPSYCH. This includes disorders like anorexia, obsessive-compulsive disorder, conduct disorder, and hyperkinetic conduct disorder.

For further Reading:

Zerwas S, et al (2017): Eating Disorders, Autoimmune, and Autoinflammatory Disease. Pediatrics 10.1542/peds.2016-2089

Pedersen CB et al. (2017): The iPSYCH2012 case-cohort sample: new directions for unraveling genetic and environmental architectures of severe mental disorders. Molecular Psychiatry: http://rdcu.be/zk9N

Mohr-Jensen C, et al (2016). The validity and reliability of the diagnosis of hyperkinetic disorders in the Danish Psychiatric Central Research Registry. European Psychiatry http://dx.doi.org/10.1016/j.eurpsy.2016.01.2427

Zerwas S et al. (2015): The incidence of eating disorders in a Danish register study: Associations with suicide risk and mortality. Journal of Psychiatric Research: http://dx.doi.org/10.1016/j.jpsychires.2015.03.003

Sorensen CJ et al (2014): Combined oral contraception and obesity are strong predictors of low-grade inflammation in healthy individuals: results from the Danish Blood Donor Study (DBDS). PLos One: https://doi.org/10.1371/journal.pone.0088196

Tjonneland A, et al. (2007): Study design, exposure variables, and socioeconomic determinants of participation in Diet, Cancer and Health: a population-based prospective cohort study of 57,053 men and women in Denmark. Scand J Public Health: https://doi.org/10.1080/14034940601047986

Danish Registers

Records on the entire Danish population from cradle to grave have been collected for decades. Most of this information has been recorded for administrative purposes. However, Danish legislation also allows Danish researchers to utilize data to perform research of public relevance and importance.

The researchers at NCCR have outstanding expertise in all aspects of population-based epidemiology using Danish registers, including legislative and ethical aspects, database management, security and implementation of epidemiological research. By appointment, researchers at NCRR can give advice and practical assistance in relation to register-based research, and participate in research collaboration.