VINTER / FORÅR · Social cognition Michael Benros: Subphenotypes and inflammatory mechanisms WP2 Francesco Lescai: Whole exome and whole genome sequencing of Faroese samples Anders

FORSLAG 1VINTER / FORÅR

FORSLAG 2FORÅR / SOMMER

FORSLAG 3SOMMER / EFTERÅR

PROGRAMMEiPSYCH AnnuAl Meeting 21 – 23 MAy 2014




WELCOME TO THE iPSYCH AnnuAl Meeting21-23 MAy 2014

Dear i PSYCH employee or collaborator.

Welcome to the i PSYCH Annual Meeting 2014.

The aim of our meeting is to discuss and develop our scientific plans and the related activities in the i PSYCH project in all five work packages, to meet each other and take part in scientific discussions – in order to secure future collaboration across projects and heighten the quality and outcome of the studies and other activities.

We are very pleased that the programme again this year features distin-guished speakers from some of our main collaborators. A new initiative will be the poster session, which will be held in the evening on Wednesday 21 May. Also we will include working group sessions allowing more active and in-depth discussions of a number of topics.

We are looking forward to spending time with you in the beautiful surround-ings of Sandbjerg Estate.

Best regards,i PSYCH PIs Merete NordentoftAnders BørglumPreben Bo MortensenThomas WergeOle Mors




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PROGRAMMEWeDneSDAY 21 MAY

PROGRAMMEtHuRSDAY 22 MAY

11.30 – 13.00 Arrival and Lunch

13.00 –13.45 Preben Bo Mortensen: Welcome, update of i PSYCH, recent developments and future plans

13.45 – 14.45 Mary Cannon: Psychosis-like experiences in Childhood. Rationale for intervention in the premorbid phase?

14.45 – 15.15 Coffee/tea break

15.15 – 16.15 Naomi Wray: Analyses of data sets that are informative for both genetic and environmental risk factors

16.15 – 17.15 John McGrath: Vitamin D and schizophrenia – update on recent developments and future directions

18.30 – 19.30 Dinner

19.30 – 22.00 Poster session including snack food & beer/wine Location: “Brænderiet” SEE PAGE 16-17

07.30 – 08.30 Breakfast

08.30 – 10.00 Work package presentations and discussions

WP1 Camilla Christiani: ViA 7, the Danish High Risk and Resilience Study: Social cognition

Michael Benros: Subphenotypes and inflammatory mechanisms

WP2 Francesco Lescai: Whole exome and whole genome sequencing of Faroese samples

Anders Lade Nielsen & Nicklas Staunstrup: epigenetics in i PSYCH discovery samples

Thomas Sparsø: Discovery and disease risk of pathogenic CnVs in the i PSYCH gWAS sample WP3 Søren Dalsgaard: The effect of medication on the risk of injuries in children with Attention-Deficit/Hyperactivity Disorder

10.00 – 10.30 Coffee/tea break




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13.00 – 16.00 Parallel Working Group Sessions SEE PAGE 18-22

1. Opportunities and challenges of sequencing technologies in i PSYCH Chairs: Francesco Lescai, Ditte Demontis & Thomas Sparsø

2. g x e interactions Chairs: Liselotte Petersen & Jakob Grove

3. epigenetics, the molecular link between inheritance, environment and phenotype? Chairs: Anders Lade Nielsen & Nicklas Staunstrup

4. transgenic and Functional genomics Chairs: Michael Didriksen & Jane H. Christensen

5. network medicine and systems biology Chairs: Marcelo Bertalan & Manuel Mattheisen

6. Phenotyping individuals at high risk for developing serious psychiatric disorders Chairs: Anne Thorup & Kerstin Plessen

16.15 – 17.30 Working Group presentations

18.30 – 19.30 Pre-dinner social event Location: “Staldauditorium”

19.30 Gala dinner

PROGRAMMEtHuRSDAY 22 MAY (CONTINUED)

PROGRAMMEtHuRSDAY 22 MAY (CONTINUED)

10.30 – 12.00 Work package presentations and discussions

WP3 Christiane Gasse: Defining pharmacological treatment response in psychiatric disorders based on register data: feasibility and challenges WP4 Anto Praveen Rajkumar Rajamani/ Per Qvist: RNA-seq of specific brain regions of BRD1 +/- mice.

Veerle Paternoster: Histone modifications in BRD1 KO mice

Marcelo Bertalan: RnA-seq and metabolome analysis of selected brain areas in the 22q11 deletion mouse strain

Julie L Hentze: Modeling and functional characterization of CnV genes in Drosophila flies

WP5 Manuel Mattheisen: Integrated data analysis identifies ZNF323 to be associated with schizophrenia and suggests recent positive selection based on compensatory advantage on pulmonary function

12.00 – 13.00 Lunch

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PROGRAMMEFRiDAY 23 MAY

08.00 – 09.00 Breakfast

09.00 – 09.45 Stephan Beck: insights from methylome analyses

09.45 – 10.30 Brad Pearce: the infection connection in schizophrenia

10.30 – 11.00 Coffee/tea Break

11.00 – 11.45 Merete Nordentoft: Possibilities for early intervention and intensive treatment in psychotic disorders

11.45 – 12.00 Closing remarks

12.00 – 13.00 Lunch

13.00 Departure

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EXTERNAL SPEAKERS

PhD Mary Cannon

WeDneSDAY 21 MAY 2014, 13.45–14.45:PSycHOSIS-lIKE ExPERIENcES in CHilDHOOD. RAtiOnAle FOR INTERvENTION IN THE PREmORBID PHASE?

Mary Cannon trained in psychiatry at St John of God Hospital Dublin and the Institute of Psychiatry, London. She holds a Masters degree in Epidemiology from the London School of Hygiene and Tropical Medicine and was awarded her PhD from University of London in 2002, supervised by Professors Robin Murray

and Peter Jones. She is Associate Professor in Psychiatry at the Royal College of Surgeons in Ireland, Dublin, and is the holder of a Clinician Scientist Fellow-ship from the Health Research Board Ireland.

Her research area of interest is developmental psychiatric epidemiology, in particular the study of childhood and adolescent risk factors for schizophrenia such as obstetric complications, developmental delay and cannabis use, and the interaction of environmental and genetic risk factors for psychosis. She has worked with longitudinal birth cohort and register data from New Zealand, UK and Finland.

Her current research programme focuses on psychotic symptoms in childhood and adolescence, which she believes, can inform us about the risk trajectory to later psychotic illnesses and could provide a significant opportunity for prevention.

She is co-chair of the publications committee of the Schizophrenia Interna-tional Research Society and is a member of the Editorial Boards of Schizophre-nia Bulletin, The British Journal of Psychiatry and Irish Journal of Psychological Medicine.




Professornaomi Wray

WeDneSDAY 21 MAY 2014, 15.15–16.15:AnAlYSeS OF DAtA SetS tHAt ARe INFORmATIvE FOR BOTH gENETIc AND ENvIRONmENTAl RISK FAcTORS

Naomi Wray is Professor of statistical neurogenetics at the Queensland Brain Institute of the University of Queensland. She is an Australian National Health and Medical Research Council Senior Research Fellow and an Australian Re-search Council Future Fellow. Her early training was in quantitative genetics

with application in livestock, which provides a strong theoretical foundation for her research today. She holds a BSc in Animal Science from the University of Edinburgh, an MS in Animal Breeding and Statistics from Cornell and a PhD in Quantitative Genetics from the University of Edinburgh.

Her career path from livestock genetics through epidemiology of childhood leukaemia to psychiatric genetics has been underpinned at each stage by a strong interest in underlying theory and practical applications. She moved to Australia in 2005 to join the Queensland Institute of Medical Research where she established and led the Psychiatric Genetics Laboratory. She joined QBI in 2011 where she is co-director of the newly formed Centre of Neurogenetics and Statistical Genomics.

Her recent research has provided empirical evidence for a polygenic architecture of psychiatric disorders including the shared genetic structure between disorders. This work has been conducted through collaboration with the Psychiatric Genomics Consortium.

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EXTERNAL SPEAKERS (CONTINUED)

Professor Stephan Beck

FRiDAY 23 MAY 2014, 09.00–09.45:inSigHtS FROM MetHYlOMe AnAlYSiS

Stephan Beck is Professor of Medical Genomics at the University College London (UCL) Cancer Institute. He received his PhD in 1985 from the University of Konstanz where he studied DNA structure. After appointments at the MRC Laboratory of Molecular Biology in Cambridge, Millipore Corporation in Boston and the Imperial Cancer

Research Fund in London, he joined the Wellcome Trust Sanger Institute in 1996.

Using experimental and computational approaches, his laboratory has broad interests in the genomics and epigenomics of phenotypic plasticity in health and disease.

During his tenure as Head of Human Sequencing (1998-2006), he played a leading role in the sequencing and analysis of the human, mouse and ze-brafish genomes.

He has co-founded and led a number of international efforts, including the Human Epigenome Project and the UK Personal Genome Project.




ProfessorJohn Mcgrath

WeDneSDAY 21 MAY 2014, 16.15–17.15:vITAmIN D AND ScHIZOPHRENIA – uPDAte On ReCent DeVelOPMentS AnD FutuRe DiReCtiOnS

John McGrath is the Director of the Queensland Centre for Mental Health Research and conjoint Professor at the Queensland Brain Institute.

His research aims to generate and evaluate nongenetic risk factors for schizophrenia. He has forged produc-

tive cross-disciplinary collaborations linking risk factor epidemiology with developmental neurobiology. In addition, he has supervised major systematic reviews of the incidence, prevalence, recovery and mortality of schizophrenia.

He has won several national and international awards including the Premier’s Award for Medical Research, a Rockefeller Foundation Bellagio Residency, the Organon Senior Research Award, and the Founders’ Medal from the Australasian Society for Psychiatric Research. In 2007 he was appointed a Member of the Order of Australia (AM). In 2013 he was awarded a prestigious John Cade Fellowship, by the National Health and Medical Research Council (NHMRC).

He is an Associate Editor for Schizophrenia Bulletin, and is on the editorial boards of several international journals. He has published approx. 300 peer-reviewed articles. He is a member of the NHMRC Research Committee and the Australian Health Ethics Committee. He is a Director of Research Australia.

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PhDBrad Pearce

FRiDAY 23 MAY 2014, 09.45–10.30:tHe inFeCtiOn COnneCtiOn in ScHIZOPHRENIA

Brad D. Pearce received his PhD in pharmacology from the University of Miami in 1990, and completed postdoc-toral training in molecular genetics and immunology at the Scripps Research Institute in La Jolla, California.

He currently directs a vigorous neuroim-munology laboratory and research

group at Emory University, where he holds appointments in the Department of Epidemiology (Research Associate Professor), the Graduate Division of Biological and Biomedical Sciences, and the Center for Translational Social Neuroscience.

A major emphasis of his research group is to elucidate the cellular and molecular mechanisms by which infections and immune molecules mediate long-term changes in neuronal circuitry.

As Principal Investigator on several NIH and private foundation-funded projects, he has blended his interests in pregnancy disorders, neuropsychi-atric illnesses, and molecular biomarkers to investigate etiological pathways for schizophrenia, autism, and mood disorders. His recent and ongoing collaborative projects include the analysis of gene-infection interactions in schizophrenia, and a longitudinal assessment of the dynamic changes in the human microbiome during pregnancy and the risk for preterm delivery.

EXTERNAL SPEAKERS (CONTINUED)




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Neurocognitive profiles in 7-year-old offspring of parents with schizophrenia or with bipolar disorder: Nicoline Hemager

Predictors of treatment resistance in schizophrenia: Christiane Gasse

Psychiatric disorders in childhood and the risk of later major depressive disorder: Louise Gundel

Psychopathology in Offspring of Parents with Schizophrenia or Bipolar Disorder – Associations with neurodevelopmental Disturbances and Childhood Stress. Part of the Danish High Risk and Resilience Study – ViA 7: Ditte Ellersgaard

Social cognition, language, and social functioning in offspring, age 7, with familial high risk for developing schizophrenia and bipolar disorder: Camilla Christiani

Substance use disorders in patients with psychiatric disorders: A nationwide Danish population-based study: Nanna Gilliam Toftdahl

the Danish High Risk and Resilience Study - ViA 7 -attachment style, home environ-ment and emotional climate among 7- year- old children with familiar high risk of developing schizophrenia spectrum disorder or bipolar disorder: Anne Thorup

The Schizophrenia and Bipolar Disorder Associated Brd1 gene Affects the global Histone modification Pattern in mouse Brain: Veerle Paternoster

The Schizophrenia and Bipolar Disorder Associated BRD1 Promoter SNP rs138880 Affects DNA methylation and Transcription: Mads Dyrvig

Whole genome sequencing – new possibilities, new dilemmas: Anna Sundby

15q13 microdeletion syndrome – Characterization of homozygous knockout mice: Annika Forsingdal




A Drosophila functional evaluation of candidate genes from human CnVs in schizophrenia: Julie Hentze & Kim Rewitz

Associations between social cognition in parents and offspring - A study of parents with schizophrenia or bipolar disorder and their 7-year old offspring: Aja Neergaard Greve

Attention Deficit Hyperactivity Disorder in childhood and the Risk of later Substance use Disorder: Cæcilie Ottosen

Childhood epilepsy and risk of ADHD: Elin Næs Bertelsen

cNv identification from DNA extracted from blood spots: Thomas Sparsø

Depression and BmI influences the serum vascular Endothelial growth Factor level: Henriette Buttenschøn

Dual diagnosis and mortality: Carsten Hjorthøj

Effect of anti-inflammatory treatment on depression, depressive symptoms and side effects: A systematic review and meta-analysis of randomized clinical trials: Ole Köhler

Effects of different register-based definitions of schizophrenia: Janne Tidselbak Larsen

emotion regulation in children at high genetic risk for bipolar disorder or schizophrenia: Katrine Spang

Family Based linkage and Sequence Analysis of Thought Disorder in Schizophrenia: Johan Thygesen

Home environment in families with parents diagnosed with schizophrenia or bipolar disorder: Ditte Lou Gantriis

miRnAs in the Aetiology of Schizophrenia: Mads Engel Hauberg

Mortality in persons with autism spectrum disorders: a Danish population-based cohort study: Diana Schendel

Mortality in women with postpartum psychiatric disorders: Benedicte Johannsen

POSteR SeSSiOnWEdNEsdAy 21 MAy, 19.30 – 22.00

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THE AIM OF THE WORKING GROUP SESSIONS IS TO DISCUSS OPPORTUNITIES, CHALLENGES AND RECOMMENDATIONS FOR THE NExT THREE-YEAR PROJECT PERIOD. THE GROUP IS ExPECTED TO PRODUCE A 10 MINUTES POWER-POINT PRESENTATION OF THE MAIN FOCUS POINTS, TO BE PRESENTED AT THE PLENUM SESSION FROM 16.15-17.30.

1. Opportunities and challenges of sequencing technologies in i PSYCH

Working Group outline: A recent exome-sequencing study revealed that the polygenic burden of schizophrenia includes many ultra-rare nonsense mutations distributed across many genes. A scenario, which may also hold for other psychiatric diseases. Using whole exome sequencing, it is also possible to locate individuals carrying large disease causing structural varia-tions. These individuals will be matched with non-carriers, which will enable a powerful incidence-based analysis (survival analysis). This scenario is very different from the conventional cross-sectional case-control analysis and we will be able to address many new scientific questions.

A the same time, innovations in whole-genome sequencing technologies allow a dra-matic reduction of costs, and “long read fragments” technology introduces the capability to sequence a whole-genome from just 10-20 cells, or as low as 100pg. Whole-genome sequencing on larger scale will allow to address new questions on regulatory regions, better characterise different types of variations and even gather information about the microbiome.

What is the contribution i PSYCH can give in the next years? What can we do more, compared to other research initiatives in the world? How can each researcher involved in NGS within i PSYCH give a contribution to the existing challenges and propose new activities?

This workshop will address these questions, by identifying the main challenges and op-portunities in the areas of exome-based association studies, structural variation analyses and whole-genome sequencing. The session will have a highly interactive structure, and each participant is expected to contribute to the guided brainstorming and collection of ideas.

Please have your smartphone, tablet or laptop: the interaction with the participants will be ensured by the use of Socrative (http://b.socrative.com).

2. g x e interactions

Working Group outline: The GxE workshop will facilitate discussions of various aspects of gene-environment interactions. The aim is to consider possibilities within i PSYCH to contribute to this field of research, and also to consider what challenges lies ahead for us in i PSYCH when plan-ning GxE studies, and how to deal with these challenges. The possible questions to discuss may include• Which environmental factors should be included in future GxE studies?• How do we sufficiently and most effectively control for confounders in these types of studies?• When are polygenic scores well suited for GxE studies?• How to deal with rare variants in the context of GxE?• How to conduct genomewide analysis of GxE? The workshop will include short introductions to some of above mentioned considera-tions followed by joint discussions. We invite everybody interested in the topic to join the workshop regardless of training and previous experience with GxE analyses.

3. epigenetics, the molecular link between inheritance, environment and phenotype?

Working Group outline: Epigenetics is an umbrella term for reversible gene modulating effects mediated by chemical groups attached to DNA or the histone tails as well as the non-coding RNA environment.

It is becoming increasingly evident that epigenetic variation either trans-generational inherited or due to pre- and post-natal exposures plays a significant role in the etiology of mental disorders. Furthermore, the epigenetic landscape is constantly changed over time per se and in response to environmental exposures modulating disease risk.

Our working hypothesis is that the susceptibility to mental disorders is in part associated with a specific epigenetic imprint at birth as well as the epigenetic changes acquired later in life. This can for example be examined in umbilical cord blood and PKU cards from newborn children as well as in blood or saliva samples and postmortem brains from mental disorder affected individuals.

We expect that epigenetics will be able to explain a part of the susceptibility to mental disorders, and that epigenetic modifications will have importance as novel biomarkers and as targets for pharmaceutical intervention.

PARAllEl WORKINg gROuP SESSIONSTHuRsdAy 22 MAy, 13.00 – 16.00




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We will discuss the pipelines being established at TNU, Aarhus University for agnostic genome-wide analyses of epigenetic marks (MeDIP-Seq and ChIP-Seq), the use of ar-chived (e.g. from SSI, brainbanks, etc) as well as collected samples and possible integra-tion with e.g. genetic and microbiomic data.

4. transgenic and Functional genomics

Working Group outline: The overall objective of the subprojects in functional genomics in i PSYCH is to inform on disease mechanisms through the functional characterization of established disease mutations. The molecular aspects of these activities involved studies on RNA expression and metabolites in selected tissues and cell types but will be covered by another work group. A major challenge in studying disease mechanisms in psychiatric disorders is to achieve animal models with high construct and face validity. Disease mutations exert their pathogenic effect in interaction with other risk alleles and environmental factors, making it important to develop standards for strategic approaches to the generation and study of animal models of disease. Currently i PSYCH researchers have pursued two different approaches to model psychi-atric disorders in animals. The first includes mouse models based on highly penetrant human CNVs and the second includes the polygenic-like BRD1 mouse model. Also, i PSYCH has initiated the modeling in mice and fruit flies of GxE interactions, using as G the already established mouse strains. The work group will initiate with a few short presentations simply presenting state-of-the-art for the various projects. We will thereafter aim to discuss current challenges in the various branches of the projects and together explore common opportunities in this field. A suite of topics will guide these discussions:

• What is the principal deliverable that we can generate from working with animal model of disease?• What is a useful animal model of mental disorders; i.e. what’s required for construct and face validity?• How can we interpret data from “animal models of mental disorders”?• Where to focus our experiments?• Which risk/protective factors (incl. polygenecity) to model in animals, and in which animals?• How to think about going beyond animals to cellular models of disease?

5. network medicine and systems biology

Working Group outline: The network medicine and systems biology projects in i PSYCH will try to bridge the gap between the exhaustive, hypothesis-free and functional studies. They are the fundamen-tal part of an iterative loop in i PSYCH that is aimed to provide new insights into mental disorders. The underlying question asked in this project is whether integration of multiple (trait specific) layers of -omics data leads to an increased power in detection of both spe-cific disease associated risk factors (genes and others) and broader disease modules?

Two main tasks, each with multiple subprojects, are key to the proposed project: (i) data integration and (ii) context-dependent data extraction. Task one is aimed at building a database for the subsequent research in the second task of the project. While such da-tabases already exist, they are neither tailored towards the need of research into mental disorders nor do they integrate well with the overall iterative design of i PSYCH. We pro-pose to use a graph database that is both easy to iteratively update and perfectly suited to facilitate subsequent analyses. In order to succeed we will need to study both new scoring functions and measurements that will allow us to integrate information from the registers with different layers of molecular data. In the second task we will study context-dependent data-extraction methods and use them to built disease modules for mental disorders. Identification of these modules and their interconnectivity (across phenotypes) will help to understand more about the so far identified risk factors and also allow for identification of new risk factors. We will extend current tools in use to integrate with our graph database and develop new methods that are specifically designed to comply with the needs in i PSYCH. The proposed project has the opportunity to extend our knowledge about the psychiatric diseasome and its bearing in the human diseasome.

Our workshop will provide an introduction to the data integrated in the graph database, the methods used in the project, and outline some of the challenges that this project will face. All i PSYCH researchers with an interest in the topic are invited regardless of training and previous experience with network and systems biology approaches.

PARAllEl WORKINg gROuP SESSIONSTHuRsdAy 22 MAy, 13.00 – 16.00 (CONTINUED)




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WHeReThe Sandbjerg EstateSandbjergvej 102DK-6400 Sønderborg

Location for the meeting “Staldauditorium”.

tRAnSPORtAtiOnWednesday 21 May

FROM AARHUSDeparture at 09.00 from Arhus University Campus, Wilhelms Meyers Allé 4, 8000 Aarhus C. in front of the Bartholin Building, No. 1242

FROM COPENHAGENDeparture at 07.30 from the main entrance at Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV

Friday 23 MayDeparture at 13.00 from the Sandbjerg Estate

COntACtIf you have any questions please contact project coordinator Annette Bang Rasmussen at:

Mail: [email protected]: +45 2326 6332

PRACTICALinFORMAtiOn

6. Phenotyping individuals at high risk for developing serious psychiatric disorders

Workshop outline: Aim: The overall objective of the workshop is to discuss approaches that help to inves-tigate young individuals at high genetic risk for developing serious mental disorders in a longitudinal and developmental perspective. This includes mapping genetic liability, neuropsychology, brainmapping, psychiatric symptoms and environmental influences in a large cohort of young people at risk, which will firstly provide a unique, longitudinal perspective for early detection of serious mental disorders. Secondly, we aim to further shed light on specific domains of development, such as motor development, impaired coordination, and poorer cognitive and social cognition in groups of children at high risk. It is unclear to date if these impairment in development continue do decrease of if they stabilize at a specific, lower level.

Background: Abundant literature documents the genetic vulnerability in children of individuals with schizophrenia and with bipolar disorder, but also for individuals who themselves have known genetic variants that lead to a higher risk for mental disorders. Recently a possible genetic overlap between the different serious mental disorders has been suggested, which is why it is relevant to study genetic liability in a trans-diagnostic perspective. Neither developmental pathways of psychopathology in children at risk, nor the implications of specific resilience factors have been assessed sufficiently in a cross diagnostic perspective and longitudinal studies in individuals with genetic variants are scarce.

Perspective: The “high-risk” approach is well-known, but since treatment approaches and possibilities to map underlying dimensions of mental health have developed further, the study will contribute to a better understanding of the development of psychopathol-ogy in this group. Given their genetic liability, it will also focus on underlying potential endophenotypes and map the development of endophenotypes parallel to understand-ing the trajectories of psychopathology. An important and novel part of this perspective is the combination of environmental factors, which will give us insight into resilience factors when this cohort is being followed up. This type of data will allow analysing the implica-tions of resilience factors, such as intelligence, emotional regulation, quality of life, parent involvement and familial interaction patterns. Finally, Danish registers offer a unique pos-sibility to use data from registers to further explore the influence of risk factors and their interaction with genetic and clinical measures in this national cohort.

Researchers from VIA 7 and from the 22q11 project will present at the workshop.

PARAllEl WORKINg gROuP SESSIONSTHuRsdAy 22 MAy, 13.00 – 16.00 (CONTINUED)







LUNDBECKFONDEN

Documents

VINTER / FORÅR · Social cognition Michael Benros: Subphenotypes and inflammatory mechanisms WP2 Francesco Lescai: Whole exome and whole genome sequencing of Faroese samples Anders