NEWSLETTER N°11 – SEPTEMBER 2019 © Christophe Moratal © Christophe

EDITORIAL The Synapy group Villars, March 2019 by Alexandre Dayer Synapsy and : an Adventure Ahead

From a historical perspective, early determined whether PRS will have suf- working under the supervision of Prof. hypotheses about risk genes in psy- ficient power to stratify Synapsy clinical Dermitzakis and Reymond will inter- chiatry were based on candidate gene cohorts in a biologically relevant man- act with Synapsy clinicians and begin approaches and were largely incor- ner and whether they could contribute to interrogate the use of PRS in clini- rect. These studies were performed in to delineate high-risk states and predict cal cohorts. The focus on genetics will small-sized cohorts and led to a repli- disease conversion. initially be put on Axis-1 cohorts, which cation crisis. However, in the past few For Phase 3, Synapsy has decided to are more genetically-driven than those years, genome-wide association studies tackle these timely questions and this found in Axis-2. of psychiatric phenotypes have been will be the topic of the current news- Finally, Synapsy has continued performed in large-scale collaborative letter. By teaming up with Emmanouil to grow and has recently incorpo- cohorts and led to the successful identi- Dermitzakis, Director of the Genome rated into its network new affiliated fication of polygenetic risk scores (PRS). Center at Campus Biotech (University members. In this newsletter, you will PRS are the result of the combination of of Geneva) and Alexandre Reymond, discover six additional profiles of psy- hundreds of common variants and are Director of the Center for Integrative chiatric researchers in the Lemanic considered to be robust. Whether PRS (University of Lausanne) area working in the fields of genetics, derived from large-scale cohorts can Synapsy will have sufficient method- brain development, early-life stress and be used successfully in smaller cohorts ological support to begin to investi- high-risk states. These newcomers will such as the ones studied within Synapsy gate genetic variants in clinical cohorts. continue to enrich the network in the research groups remains an open ques- More specifically, new postdoctoral coming years and hopefully lead to new tion. More specifically it remains to be researchers trained in genetics and synergies. ●

N°11 – SEPTEMBER 2019 (ENGLISH) NEWSLETTER Bringing Together Brain Research and Psychiatry NATIONAL CENTRE OF COMPETENCE IN RESEARCH (NCCR) SYNAPSY Naonal Centre of Competence in Research

Editor Contact NCCR-Synapsy NCCR-Synapsy Texts Campus Biotech Y. Bernardinelli – lesmotsdelascience.ch Ch. des Mines 9 Layout 1202 Geneva C. von Tobel – lacivette.ch Switzerland Print +41 21 379 11 21 Reprographie UNIMAIL [email protected] nccr-synapsy.ch as diabetes or cancer. He has been an been hascancer. He or diabetes as suchdiseases complex with link sality works on geneticvariants and theircau laboratory Emmanouil’s Medicine. of Faculty the in Development and MedicineGenetic of Department the in professor full a as 2009 in Geneva to returning before Cambridge, near based center genomics leading a own laboratory at the Sanger Institute, set up hisin to 2001 left the City Swiss Emmanouil Antonarakis. Stylianos by led laboratory the in fellow doctoral post- a as Geneva of University the at Penn State University. He then joined Emmanouil completed a PhD in genetics Crete, of University the at studying After Greece. in Heraklion “Producing Something Together issoRewarding!” Emmanouil Dermitzakis NCCR-SYNAPSY.CH 2 NEWSLETTER N°11 – SEPTEMBER 2019 INTERVIEW – AFFILIATED MEMBER © E. Dermitzakis maoi Drizks s from is Dermitzakis Emmanouil - where you can study this, and the brain brain the and this, study can you where ing to find the simplestpossible model modified by genetic variants. try I was and how is thatfunction DNA function studies concentrated on thinking about initial My DNA! is interest “organ”of brain? was goingics to my focus. be primary I decided on biology, and I knew genet why that’s So, amazing. this found I ture, architec and biology between tating with DNA was possible! Since I was hesi engineering doing that realized I flies. vectors and how to transform cells and that described how to clone genes into middle the in pages two were There engineering.genetic about book a on of high school, I focused all my attention DNA structure. When I was in last year genetics? the during annuallast retreat in Villars. met him onthemargins of his seminar variants. We genetic on expertise his and is keen to help the consortium with affiliated member ofSynapsy since 2018 everywhere, braineverywhere, included. cists study genomes. But the genome is a cardiologist studies the heart, geneti thatcancer.wayand ease same the In dis cardiovascular diabetes, 2 type on while a for working been I’ve organs. and tissues with progressively, and, lines cell with done were lab our in ments experi first The of samples. availability the or complexity of terms in either model, possible simplest the not is Does working on psychiatric psychiatric on working Does My honest. be particularly, to Not the in any have you interest Do I have always been very interested in study to Why choose you did ------stantly intellectually challenged. I am I challenged. intellectually stantly need to be in a group where you’re con Youroom. the in person smartest the you’rewhen good not it’s but obvious the I’mstating just expertise. mentary comple and ideas complementary havewho people of lot a with work to like I excited. very I’mrewarding, so inspire you? members Synapsy with disorders that’s the way you can make the money more people to work together because force organizations should other and SNSF The enough. large not it’s because good as been not has SNSF the from grant Synergia the Even problem. gle sin a on together work to has team a not traditionallyfunded projects where comes to team . Switzerland has it when strong so notindividuality, is and science basic in strong extremely good thing. The Swiss community, while a actually it’s but money” here’sthe and fruitful is collaboration your that me “Show saying: for approach down top- of kind money.a It’sthe get they where that’s because together work to people force theythings; doing for them? stimulate to done be should more research; for what important tist’s intention, my intention. scien the always is learning more, and very excited because I’m going to learn I’mlanguage. same the share won’t we because hard very be to going are Initially,table. things the to bring can people information the and expertise intelligence about but about not talking Producing something together is together something Producing Funds are always a good motivation synergies and are Collaborations - - - - do team science. when you massively increases results these get can you which at speed However,amazing! the is seen ever in a cell that nobody in the world has something of shot adrenaline seeing The something. discover to first the be to them push instincts their and selfish, are it!of Scientists out more get you and perspectives different bring together, they minds different produce more knowledge. You bring ● ized that genetics actually offered the could have chosen zoology but I real I studies, my For step.natural a just was genetics sense, that In works. been quite puzzled about how alwaysI’ve nature. of facets ferent dif the by fascinated watcher, mal develop?genetics the current CIG director. Alexandre is now a full professor and professor. track tenure a as 2004 in for Integrative Genomics (CIG) at UNIL Center the joining before Geneva of University the at Medicine Genetic of Department the to Switzerland to back went Alexandrethere, From genetics. human studying was he Medicine, Genetic Institute of where the Telethon Italy, at in lab first his built He School. Medical Harvard at tinuing with apost-doctoral fellowship (ISREC)Researchcon Cancer before on Experts of Institute Swiss the at Alexandre entered research via a PhD (UNIL).Lausanne of University the at studies undergraduate with ground back biological and biochemical genetics, keeping aszoology a hobby. was more intellectually challenged by best tool for zoologists. At that time,I Alexandre Reymond Puzzled AbouttheWay Nature Works INTERVIEW – AFFILIATED MEMBER I am a passionate bird and mam and birdpassionate a am I for fascination your did How dual a has Reymond Alexandre

- - - - - cognition. of and brain the of functioning proper the for important are genes of lot a because frequent quite are disability intellectualcausing mutations fact, In disability. intellectual of aspects ics genet the on working to used am I relatedto the brain. More particularly, psychiatry? and sciences questions. challenging and new ask to us allowing advancing, is technology because ing chang always It’s job. this doing are we why alsothat’s think I one. fun a and neurologists.trists psychia psychologists, neuroscientists, of work the facilitate will we because this, we will certainly be perceived well step in the right direction. If wecan do differentis another,from a be might it patient one why understand to begin really to us allows it If perspective. new psychiatrists? and by neuroscientists perceived well © YB NEWSLETTER N°11 – SEPTEMBER 2019 e, hv awy rn projects run always have I Yes, neuro in any have you interest Do Yes, it is a challenging approach but Is this an ambitious approach? a bring we course, Of so. think I approach variant genetics the Is ● CRSNPYC 3 NCCR-SYNAPSY.CH - - - - people adjust, cope and carry on. adjust,people and cope carry as the protectivefactors that might help well as illnesses post-traumatic of ment develop the to contributemight that factors interestedin very been always I’ve time. any at anybody to happen can event of type This event. traumatic a and, in particular, how they respond to function humanshow understanding I’ve because always interestedbeen in brain develop? major national trauma centers. UK’sthe of one researchclinicalin and between work time hersplit She undertook her doctoral training at University,Oxford where she Humboldt University in Berlin and the University of Toronto, Canada. fromgraduated training, by psychologist clinical a is who Horsch, Professor(CHUV). Hospital University Lausanne at Department Children’sand Women the in (UNIL)and Lausanne of University the at Care Health in Research and Education Higher of Institute Transmission of Stress andTrauma Deciphering theInter-Generational Antje Horsch NCCR-SYNAPSY.CH 4 trauma. and stress of transmission andtry interrupt this intergenerational early intervention protocols inorder to mechanisms. social and physiological including sion, transmis this of mechanisms lying under the of understanding better a We’retrauma.and in interestedfirstly stress of transmission intergenerational the call we what is This child? the of well-being and development health, mental the with link the is what and parents, on pregnancy of impact the mentalily health. example,For what is fam on trauma and stress of impact the studying are We period. natal NEWSLETTER N°11 – SEPTEMBER 2019 INTERVIEW – AFFILIATED MEMBER Secondly, my group is developing is group mySecondly, peri the interestedin is group My interests? research your are What psychology study to decided I the for fascination your did How the at professor assistant of position the holds Horsch Antje - - - - - approach? family. temic approach that looks at the whole sys a have to crucial is it thatmeans This generation. future the with work also we parents, the treating When instance, we asked mothers following mothers asked we instance, For disorders. stress post-traumatic these of development the prevent to childbirth traumatic a after hours few first the during do to what tigating We’rethird.inves one to up be can rates prevalencebaby, theand/or her mother the of life the to threat a there’s no obstetric complications. However, if are there when disorder stress matic post-trau a develop women of cent per 6 and 3 between birth, preterm a or caesarean emergency an as such Following a traumatic childbirth, traumatic a Following your about more us tell you Could

©-SAM CHUV - - - - types of traumatictypes events. otherofrange wide a across out it roll pursue in the future, to see if we could This is something we would also like to work. daily their in events traumatic to hospital professionals who are exposed example, For events. traumatic enced othertopopulations who haveexperi relevant be also could It intervention. applicable to traumatic childbirth? in the month afterwards. develop post-traumaticstress disorder tolikely less were and weekfollowing the in intrusions traumatic less icantly control group, these had mothers signif hours after the birth. In comparison toa six first the within task spatial visual a in engage to caesarean emergency an No, we think it could be a universala be No,couldthinkwe it only intervention of kind this Is - - NEWSLETTER N°11 – SEPTEMBER 2019

INTERVIEW – AFFILIATED MEMBER

Denis Jabaudon Synapsy is Developing a Common Culture

How could your affiliation with Denis Jabaudon is a professor of neuroscience and current director of the Synapsy help your research? Department of Basic Neuroscience at the University of Geneva. He is also an attend- I’m very excited to be an affiliated ing physician in the Department of Neurology at the University Hospital of Geneva member and I’m hoping that this (HUG). Professor Jabaudon trained as a medical doctor at the University of Lausanne might open opportunities for future before doing a PhD at the University of Zurich. He subsequently undertook his collaborations with the Synapsy internal medicine and neurology residency before becoming a post-doctoral fel- network. I’m also very interested to low at Harvard University. Denis came back to Switzerland in 2008 to launch his hear more about the very impres- own lab, trying to combine his interest in neuronal circuits, synaptic physiology sive amount of work that has been and brain development. carried out.

I think that the way forward in clinical research is interdisciplinar- ity. I firmly believe that all of the projects I’m working on can only be carried out with the collaboration of different professionals from different backgrounds. If we want to address complex questions, such as mental health, we need to join forces. So, I’m very committed to the mission of the NCCR-Synapsy. That’s where the future lies in achieving the transla- tion from fundamental to clinical and applied sciences. There’s no doubt about it! ● Lüscher © Christian

What are your research interests? can emerge. The aim is to understand My lab is interested in the devel- not just how genes control the genera- opment of the cerebral cortex. More tion of different neurons and circuit specifically, we’re trying to understand types but also the other way around. and identify the genetic programs that It’s a two-directional interaction: genes generate neuronal diversity in the cere- influence the building of circuits but the bral cortex. This is a cellularly highly wiring of circuits influences the expres- heterogeneous structure. Neurons sion of genes also. project from one part of the cortex to What is the link with psychiatric the other, to the spinal cord and other disorders? regions of the brain. Neuronal projec- I think it relates to the interactions tions are very specifically wired and between genetic and environmental this is defined by gene expression. My factors, I mean susceptibility genes and lab is trying to understand how, from their interactions with the environment. a seemingly relatively homogeneous pool of progenitor cells, this diversity (continued on next page)

NCCR-SYNAPSY.CH 5 NEWSLETTER N°11 – SEPTEMBER 2019

(continued from previous page) to a more cellular point of view as Nathalie Ginovart uses neuroim- well as in terms of a network and a aging as a research tool to investi- Of course, there’s more and more cognitive point of view. I think that’s gate mental disorders and as a way evidence that the cell death that what’s exciting about the field we’re of bringing the clinical and funda- occurs at relatively late ages in neu- in. What’s more, you can interact mental worlds closer together. rodegenerative diseases might reflect with very different kinds of people the susceptibility factors that are from very different backgrounds. present very early on, maybe even That brings a lot! Nathalie Ginovart started by study- during embryonic or early postnatal What do you expect from your ing biology before continuing with a development. affiliation with Synapsy? master’s in pharmacology followed by What does your work as a I’m learning a lot from the patient- a M.Phil. in integrated biological sys- clinician bring to your research cohort type of approach that I’m tems – which is when her interest in the approach? not particularly familiar with. In the brain began to deepen. “I was exposed A few years ago, as a pure clini- same way, it’s important that clini- to studies on epilepsy, depression and cian, I was always interested in basic cians learn how things are going on schizophrenia. I soon wanted to do research so that I could have a big- in basic research. I think it’s impor- neuroscience so I could have a better ger picture. While interacting with tant, for those of us who are not understanding of the brain mechanisms patients, I really felt the need to go a directly exposed to basic research, involved. The brain seemed to me to be little bit deeper into the mechanisms to understand the limitations of the like a black box that wasn’t very acces- of what was going on. That’s what cohort approaches, the diversity of sible.” A thorough training combined drives my research interest today. I patients and the type of information with a passion for the brain meant that still have a 20% clinical commitment that can be gathered – even in single Nathalie decided to undertake a doctor- but it has no direct relationship with case studies as proof of principle or ate in neuroscience at the University of my research work. I believe that this examples of what can happen in a Lyon in France. is a strength in that it gives me two disease. perspectives to ask questions from. Synapsy is quite rich and, again, Clinic-based biologist Also, from the point of view of the it’s developing a common culture. Even as a young doctoral student, clinics, I get a realistic idea about how The development of this culture – in Nathalie was aware of the difficul- drugs could be translationable as a the “neuroworld” in particular and, I ties involved in translational research. therapeutic approach. From the basic would say, in medical studies in gen- “There were problems in dialoguing research point of view, I get a realistic eral – is absolutely critical and under- with each other: most basic researchers understanding of what we can actu- valued. A good way to promote don’t understand the challenges of clini- ally do with human beings. scientific progress is to promote cal research and most clinicians don’t How did your fascination for the human interactions – very simple have the time, training and resources to brain develop? human interactions, so that people venture into basic research.” Ginovart Compared to other fields of medi- feel comfortable with each another adds that she has always been inter- cine, the exciting part is that you and confident about what the other ested in neuropsychiatric research can study the same organ from a person is saying. I think Synapsy does because it can be used to apply basic very detailed molecular perspective that in a remarkable way. ● research concretely. And that’s why Nathalie decided, as part of her post- doctoral internship, to do a clinical neuroscience training at the Karolinska Institute in Sweden where she was trained in clinical positron emission tomography (PET) imaging.

6 NCCR-SYNAPSY.CH drug exposure.” As a result, Ginovart Ginovart result, a As exposure.” drug abnormalities that arisefrom repeated they’re if or abuse drug pre-exist tors fac these whether knowdon’t we ity, correlated with high levels of impulsiv are receptors dopaminergic in deficits instance,”“For Nathalie,says “although individuals. addicted of characteristics prominent are novelty for search the and decision-taking risky Impulsivity, involved. circuits neuronal the and mechanisms neurochemical their tify iden to and behaviors addictive to individuals predispose that factors the of understanding better a gain to understand addiction approach tohelp Using atranslational the animals and human studies”. vides the translational bridge between pro imaging PET and parallel, in out carried are humans in studies Clinical models. animal in chemogenetics and operant behavioral testing, PET imaging andconduct approach multidisciplinary a have “We areas. clinical the ment comple to modelsanimal developing surrounded by clinicians and worked on psychiatricBelle-Idée hospital, she was HUG’sat Based Medicine. of Faculty UNIGE’s in Psychiatry of Department the joining before professor assistant an as years Torontofive infor stayed interface between the two worlds. She the more as once file, act could she so pro of kind her for looking was which Toronto,of University the at Health to the Center for Addiction and Mental appliedthenShe it. work,”puts sheas fundamental and clinical between gap the “bridge to CNRS, torate,Lyon doc her done had she where place Translational Research UsingNeuroimaging Nathalie Ginovart INTERVIEW – AFFILIATED MEMBER She was later called back to the to back called later was She In particular, her research goal is goal research particular, her In ------mon to these two types of addiction of types two these to mon com and potentialbrain abnormalities aim theto predisposingextract factors because, as Ginovart points out:sufferingfrom “We internet gaming disorder nabis use disorder and in young people can with patients in underway also are studies clinical Department, the from psychiatrists with collaborations tight to Thanks addiction.” to vulnerability increase to that’sthought And young. were they when behavior parenting sufferednegligent abuseor experienced have lived in a poor social environment, environmental tendeffects: to “Addicts later in adulthood. She is studying early that may reveal pathological behaviors factors environmental into research as such issues, relevant clinically at ing made in humans. observations of help the with factors these determine to model nerability vul addiction an as used RLA) / (RHA strain rat a researchon out carrying is Ginovart and her team Ginovart are also look

- - - - collaborations. field as well as to develop new research the in advances recent of informed be to her help will and community neuroscience Lemanic the in visibility with Synapsy since it will give her more relationship closer her with delighted also is Nathalie Furthermore, events.” lunch and meetings seminars, as such events through neuroscientists with interacting closely for opportunities new students my and me gives this as network in Geneva. “I’m really delighted neuroscience the to access easier and 2019, with the promise of having closer in CenterUNIGE’s Medical University the to moved and Neuroscience Basic of Department the to affiliated network Gaining accesstothe drug-taking.” to linkedthose dissociatefrom them and NEWSLETTER N°11 – SEPTEMBER 2019 Nathalie’s research group got co- got group research Nathalie’s ● CRSNPYC 7 NCCR-SYNAPSY.CH

© Nathalie Ginovart Studying self-regulation mental disorders. for programs children with parents with in detection, prevention and treatment and Tourette’ssyndrome (TS), as well as (ADHD) disorder Deficit/Hyperactivity Attention-especiallyinterestedin trist psychia child a is Kerstin University. Copenhagen and Bergen of University career spent at Columbia University, the in Norway followed by an international MD-PhD an and school medical after 2017in CHUV / UNIL joined Plessen von Professor CHUV. at Psychiatry of Department (SUPEA), Psychiatry Adolescent and Child of Division the of director is Plessen von Kerstin (UNIL), Lausanne of University the at Medicine and Biology of Faculty the lational approach. trans a require that areas - illnesses neurodevelopmental treating for ways Treatments Based onSelf-Regulation Kerstin Von Plessen NCCR-SYNAPSY.CH 8 other and training cognitive specific subject even though we could develop tive outcome.There are few data on the nega a of riskhigh a with adversity or trauma a of spite in normally develop to ability the is which resilience, of part important an is Self-regulation capacities. self-regulation reduced have illness neurodevelopmental a with children of “Lots abilities. nitive cog certain recover to help that tors self-regulatingthe fac studying alsois Plessen von treatment.Professor and stage in order to enable early diagnosis and factors endophenotypes at an early biomarkers, genetic identify to is goal ment in a transdiagnostic approach. Her develop during basis neurobiological their investigating by illnesses mental NEWSLETTER N°11 – SEPTEMBER 2019 INTERVIEW – AFFILIATED MEMBER The clinical researcher aims to study study to aims researcher clinical The in professor full a being as well As Kerstin von Plessenstudies earlybiomarkers andpotential resilience path - - - - - child to regulate him orherself. backand any approach that allows the neurofeed mediation, cognitive cates advo Plessensocially.” von Professor and academically both disadvantaged are they because development ing dur problems neurodevelopmental with children these strengthen to tant mentalhealthfuture.the in It’s impor theirdetermine know we which tors fac these develop them help can we and life in “sense” and relationships strong of importance the as such tors, importance of orself-efficacy other fac the control, cognitive master,as such to learn could children the factors are “These development. brain during factors resilienceexamine tointends the professor. explains malfunctions,” the correct to approaches facilitating general more To do this, Professor von Plessen von Professor this, do To ------ents that I noticed at a very ageyoung very that a noticed entsat I encouragement I received from my par logopedist). “It’s definitely down to the a and psychiatrist a of daughter the is child (she young a as medicine tice lives is what motivated Kerstin toprac their of control back take can they so Treating withoutdisrupting importance of their experiences”.their The of importance the and has child a that potential the to ment of a child– this appeals to me due important impact on the brain develop an have and lifetime a during happen can that things small Many psychiatry. brain, which is why I took an interest in human development and related to the standing that those are related to their under when discovery great a was it Later,about. were they what knowing reallyanyone without problems, ioral that some of my classmates had behav Finding a way to care for childrenfor care to way a Finding - - - - © Eric Déroze SAM / CHUV - concludes. sheequation,” common a formulate and together data the all put can we so branches different mix to have We silos! separate in work can’tSynapsy. “We with affiliation her justifies own its on to treat children. Translational research approachesclinical the in place in put being accumulatedwithout been has knowledge fundamental much since work translational extensive requires Mixing disciplines of behavioralability approaches. sustain superior a show approaches, and because studies that compare both medication on the brain’s development of effects the about sufficiently know caring for children, because, we do not be given to treatmentsnon-drug when should priority that thinks researcher Kerstin von Plessen’s approach Plessen’s von Kerstin

© YB ● - Three Questions Empowerment for Bita Moghaddam Geneva and took time to answer our questionsabout gender bias inacademia. of University the of Neurosciences Basic of Department the of students with atric disorders. Last March, she participated in the Synapsy-LWiNcareer lunch the past 26 years, she focused her research on the modeling ofaspects psychi where she holds the Chair of the Department of Behavioral Neuroscience. In and speak about out inequalities. fight to you for comfortable that are ways find And you. support to – plural the potential become to researcherssuccessful and mentor thembetter. younger Wewomenidentify to need find out why women are leaving research and find ways of them. supporting papers in high profile journals, and many more things. research? Pleasedonot leave research! We need you! Find mentors emphasis– on researchers? women of generation next the to say you would What to need Wethings. many do to need we but answer good a had I wish I research? in women of quota the improve to done be to needs What resources, research awards, positions, academiclevels: all at Inclusion world of the in inequalities gender obvious most the are What Bita Moghaddam is a full professor at Oregon Health and Science University

● EQUAL OPPORTUNITIES – and not just a tokenhavea whojust fewnotand – ­–

NEWSLETTER N°11 – SEPTEMBER 2019 CRSNPYC 9 NCCR-SYNAPSY.CH

© Christian Lüscher - of psychiatric illnesses. illnesses. psychiatric of prevention and diagnosis the improve its clinicalify and cohorts thus possibly of strat analysis to to begin genetically acquired the resources to use this type recently Synapsy subtypes. illness of stratification better a relationships for genotype-phenotype analyzing and predicting therisks ofcomplex illnesses (GWASs)studies haveinproveduseful culated from genome-wide association (PRSs)cal scores risk polygenic years, collected thoughout the years. In recent been has that data clinical of range wide to begin to apply genetic analyses to the two Synapsy phases, the time has come phenotypes. illness psychiatric with association their at look detailed a taking is Synapsy the EnormousHeterogeneity of Patients Using Genetic Variants to Stratify Genetics andpsychiatry 10 © Shutterstock NEWSLETTER N°11 – SEPTEMBER 2019 REPORT NCCR-SYNAPSY.CH Following the success of the first the of success the Following Geneticvariants have an oneffect ourappearance, and functioning health. - - basis of various assumptions relatedassumptions various of basis dategenes, which were chosenthe on candi on focusingapproach an from derived werehypotheses these that is reasons the of “One incorrect. largely were psychiatry in genes risk about eses hypoth early the perspective, historical a (UNIGE),from Genevathat, explains of University the at Neurosciences Basic sor in the Department of Psychiatry and profes and Synapsy of Dayer,director Alexandre cohorts? clinical in analysis geneticimplement to program the of has Synapsy waited for the third phase Why development. brain influence that factors biological the assessing by disorders mental to vulnerability in has aimed to identify the genes involved Revamped geneticapproach to the biological foundations of foundations biological the to Sincebeing upset in 2010, Synapsy psychiatric phenotypes, rather rather phenotypes, psychiatric than on unbiased associa unbiased on than tion studies.” This meth studies.”This tion odology gave rise to a to rise gave odology substantial number substantial f publications of that concentrated on the potentialthe on significance of significance a given poly given a cations, it has it cations, morphism in a hs publi these complexpsy majority of of majority withthe vast However, chiatric trait.

------pancreas for diabetes. “Althoughdiabetes.that for pancreas for or instance, the illnesses, psychiatric for brain the affected: was that organ occurred the in only geneticthe effect that supposed conventional approach this that professor,adds UNIGE and Center Genome 2030 Health the of could false actually positives. be genes in studies used candidate earlier discoveries, suggesting that most of the not been possible to theverify reported ersin ec Tee categories, These etc. depression, schizophrenia,disorder,bipolar major (ASD), disorder spectrum autistic as currently grouped into categories such Stratifying by generisk director. Synapsy’s says implications.” clinical possible with factor risk genetic eral gen more a constitute can thatgenes risk of variety wide a of combination It’sthe trait. given a of variancethe of smallfraction very a for accounts only variant has only a very small effect and phisms. Taken individually, each genetic polymor common of variety wide a includes and complex is phenotypes psychiatric of architecture genetic the that is view current “The psychiatry. to applied be to guarantees enough given now have and crisis, genetic ine have changed in response to this genu wheneverything it comes to diabetes.” forisn’t responsiblepancreas the that meaningappetite, controls it because diabetes for tissue causative a is brain theexample, For tissue. diseased the initialcause does not alwayscome from “the explains, he part,” in correct was Emmanouil Dermitzakis, director director Dermitzakis, Emmanouil People with psychiatric disorders are approaches and vision overall The - - - NEWSLETTER N°11 – SEPTEMBER 2019

A C T A C C T C T A T G A A G G G T T G G A A G T T G G T G C C A A A C A C G A C G T T T C C

© CvT C however, are composed of highly het- director of the Center for Integrative GWASs, which correlate a position on erogeneous patients suggestive of Genomics at the University of Lausanne. the genome with the phenotype vari- several subcategories or possibly dif- The idea is then to analyze the ants. Researchers can extract probabili- ferent types of illnesses. Patients in genetic variants that are common to ties and risk factors — PRSs — for the each category clearly share common patients. In fact, each human cell con- development of an illness by employing behavioral traits but probably have tains the entire genome, which is made genotyping on large cohorts consisting further phenotypes that are not yet up of 6.54 billion nucleic bases. There of tens of thousands of individuals. sufficiently understood to differentiate are on average 20,000 single nucleo- “Once this work has been carried out, them in biologically relevant categories. tide variants between individuals, 500 it’s theoretically possible to return to If researchers could better understand of which are rare and half linked to a the patient and identify his or her vari- the etiology of these illnesses — which loss of function. “It’s estimated that ant alleles to diagnose a disease or iden- may be genetic, environmental or a 50% of the risk of developing an ill- tify a predisposition. It’s also a way of combination of both — it would be pos- ness stems from the variability of the stratifying patients,” points out profes- sible to better stratify patients and iden- genome”, says professor Dermitzakis. sor Reymond. tify biological pathways differentially These genetic variants can be used, The second approach is based on affecting distinct subgroups of patients. therefore, to understand the illnesses. rare variants that have a significant “We’d then be in a position to under- effect on cognition. “They can only be stand what differentiates one subgroup Common or rare rare from an evolutionary point of view, of patients from another. Using genetics There are two main ways to proceed because the carriers will tend to have as a starting point, we’ll obtain the first depending on the extent of the effect fewer children than normal,” continues unbiased indication about what isn’t of the variants on the body. Genetic working properly because a given gene variants with limited effects can be is affected”, adds Alexandre Reymond, identified through large studies called → continued on next page

NCCR-SYNAPSY.CH 11 NEWSLETTER N°11 – SEPTEMBER 2019

CONTENT

(continued from previous page) and analyzed, and the clinical vari- Editorial ables including high-quality multi- Synapsy and genetics 1 professor Reymond. “In a situation modal imaging data are available” like that, you can’t only examine says professor Dermitzakis. In the Interviews – Affiliated members unique positions on the genome first instance, it will be necessary to Emmanouil Dermitzakis 2-3 through genotyping to derive a PRS determine whether imaging can be Alexandre Reymond 3 but all the positions in detail, including integrated into PRSs to define the Antje Horsch 4-5 in non-coding regions.” risks and predict the onset of dis- Denis Jabaudon 5-6 ease. Finally, “the modest size of the Nathalie Ginovart 6-7 A special situation for Synapsy cohorts, a hundred or so Kirsten Von Plessen 8-9 Synapsy patients compared to several thou- Both approaches will be used sand for the GWAS, could be an obsta- Equal opportunities by Synapsy with a common goal in cle,” tempers professor Dayer. Bita Moghaddam 9 mind: to identify the genetic origins The Synapsy researchers, with the of the clinical phenotypes observed help of a post-doctoral fellow super- Report in patients and to derive risk fac- vised by the two affiliated geneti- Genetics and psychiatry 10-12 tors for each individual. “That means cists, will compute PRS profiles and there will be a personalized vision of stratify the genetic risk in the 22q11 risk, as opposed to the average for deletion syndrome cohorts (WP 1), Home the population,” explains professor early psychoses (WP 2) and ASD (WP Institutions Dermitzakis. 3). Genetic data from the WP 1 and The question of whether PRSs WP 2 clinical cohorts are already avail- are clinically useful is still very able through international consortia. open according to professor Dayer. Finally, additional private funding Synapsy’s clinical cohorts will contrib- has been obtained by Marie Schaer, Partners ute to answer this question, he says. a UNIGE professor and Synapsy “Synapsy clinical cohorts are particu- member, to carry out whole genome larly attractive since the genomes sequencing on the ASD cohort. ● can obviously be extracted from the blood of patients to be sequenced

26-27-28 FEBRUARY 2020

rd 3 Conference on the Bringing Together Brain Research and Psychiatry Neurobiology of Mental Health Naonal Centre of Competence in Research nccr-synapsy.ch/conference2020

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