Eye Movements and Schizophrenia Risk Genes
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Eye movements and schizophrenia risk genes Associations of the putative schizophrenia risk genes COMT and NRG-1 with smooth pursuit and antisaccade eye movement endophenotypes in schizophrenia patients and healthy controls drawn from the homogenous Icelandic population Magnús Haraldsson, MD Supervisors Hannes Pétursson Ulrich Ettinger PhD committee: Hannes Pétursson (chair), Landspitali University Hospital, Reykjavik, Iceland Ulrich Ettinger, Ludwig-Maximilians-University, Munich, Germany Engilbert Sigurðsson, Landspitali University Hospital Hreinn Stefánsson, Decode Genetics, Reykjavik, Iceland Þórður Sigmundsson, Landspitali University Hospital HÁSKÓLI ÍSLANDS PhD Thesis Faculty of Medicine, School of Health Sciences University of Iceland May 2010 Magnús Haraldsson: Eye movements and schizophrenia risk genes - Associations of the putative schizophrenia risk genes COMT and NRG-1 with smooth pursuit and antisaccade eye movement endophenotypes in schizophrenia patients and healthy controls drawn from the homogenous Icelandic population The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Faculty of Medicine, School of Health Sciences, University of Iceland Reykjavik 2010 © Magnús Haraldsson e-mail: [email protected] Printing: Háskólaprent, Reykjavik ISBN 978-9979-9918-5-4 ÁGRIP Markmið: Meginmarkmið þessa verkefnis var að rannsaka tengsl innri svipgerða smooth pursuit (SPEM) og antisaccade augnhreyfinga við áhættuarfgerðir catechol- O-methyltransferasa ( COMT ) og neuregulin-1 ( NRG-1) gena í hópi íslenskra sjúklinga með geðklofa og í heilbrigðum samanburðarhópi. Breytileiki (val 158 met) í COMT geni kann að tengjast áhættu fyrir geðklofa vegna mismunandi áhrifa á niðurbrot dópamíns í framheila. Breytileikar í NRG-1 geni kunna að auka hættu á geðklofa vegna þess að NRG-1 gegnir margþættu hlutverki í þroskun taugakerfisins, en vísbendingar eru um að truflanir í taugaþroska eigi þátt í orsökum sjúkdómsins. Áhrif þessara gena á vitræna starfsemi heilans eru lítt þekkt. Finnist tengsl á milli frávika í augnhreyfingum og áhættuarfgerða geðklofa kunna þau að auka skilning á þætti erfðabreytileika í truflunum á vitrænni starfsemi heilans í geðklofa. Önnur markmið voru að rannsaka innra samræmi augnhreyfimælinga og breytileika í frammistöðu innan hverrar mælingar ásamt því að kanna tengsl alvarleika geðklofaeinkenna og tegund geðrofslyfja við frammistöðu á augnhreyfiprófum. Auk þess var rannsakað hvort fylgni væri á milli frammistöðu á SPEM og antisaccade prófum. Aðferðir: Prosaccade, antisaccade, fixation og SPEM augnhreyfingar voru mældar með innrauðri ljóstækni í 118 einstaklingum með geðklofa og 109 þátttakendum í samanburðarhópi. Allir þátttakandur voru arfgerðargreindir með tilliti til COMT val 158 met/rs4680 breytileika og tveggja áhættuarfgerða NRG-1 (SNP8NRG222662/rs4623364 og SNP8NRG243177/rs6994992). Frammistaða á augnhreyfiprófum var greind með sérhönnuðum hálfsjálfvirkum tölvuforritum. Niðurstöður: Einstaklingar með geðklofa höfðu marktækt afbrigðilegar SPEM og antisaccade augnhreyfingar samanborið við heilbrigða. Þátttakendur með geðklofa höfðu einnig marktækt meiri frávik á prosaccade og fixation prófum en heilbrigðir. Breytileiki val 158 met í COMT geni tengdist hvorki geðklofagreiningu né einkennum geðklofa. Ekki voru marktæk tengsl á milli COMT val 158 met og frammistöðu á SPEM prófi. COMT val 158 tengdist betri frammistöðu á antisaccade prófi en ekki voru marktæk víxlhrif á milli sjúklinga og heilbrigðra. Áhættuarfgerðir NRG-1 sýndu hvorki marktæk tengsl við frammistöðu á augnhreyfiprófum né við einkenni geðklofa. Þó var frammistaða þeirra sem höfðu NRG-1 áhættuarfgerð lítilega verri á iii flestum SPEM og antisaccade mælingum en hjá þeim sem ekki höfðu NRG-1 áhættuarfgerð (d= 0.1-0.3). Innra samræmi var hátt fyrir nánast allar augnhreyfibreytur (Cronbach’s α >0.85) og breytileiki í frammistöðu innan hverrar mælingar var svipaður hjá þátttakendum með geðklofa og heilbrigðum. Aldur við greiningu geðklofa, tímalengd veikinda, tegund geðrofslyfja og alvarleiki sjúkdómseinkenna sýndu almennt ekki fylgni við frammistöðu á augnhreyfiprófum. Fylgni á milli frammistöðu á SPEM og antisaccade prófum var lítil og ekki sambærileg hjá sjúklingum og heilbrigðum. Ályktanir: Rannsóknin staðfestir að frávik á SPEM og antisaccade augnhreyfiprófum eru til staðar í stóru íslensku þýði einstaklinga með geðklofa. COMT val 158 met breytileiki tengist ekki frammistöðu á SPEM prófi. Tengsl COMT val 158 við niðurstöður á antisaccade prófi bendir til þess að hraðara niðurbrot dópamíns í framheila bæti frammistöðu á prófinu og að áhrifin tengist ekki geðklofa. Þó að útiloka megi sterk áhrif NRG-1 áhættuarfgerða á frammistöðu á SPEM og antisaccade prófum er mögulegt að rannsóknina skorti tölfræðilegt afl til þess að greina væg áhrif áhættuarfgerða. Hátt innra samræmi og sambærilegur breytileiki í frammistöðu innan hverrar mælingar hjá sjúklingum og samanburðarhópi ásamt því að alvarleiki sjúkdómseinkenna og tegund geðrofslyfja tengist lítið frammistöðu á prófunum styður gildi þessara augnhreyfifrávika sem innri svipgerða. Veik fylgni á milli frammistöðu í SPEM og antisaccade prófum bendir til þess að prófin endurspegli ekki sömu erfðafræðilegu áhættuþætti sjúkdómsins. Lykilorð: Geðklofi, innri svipgerðir, áhættuarfgerðir, smooth pursuit, antisaccade iv ABSTRACT Aims: The main objective of this thesis was to investigate the association of smooth pursuit (SPEM) and antisaccade eye movement endophenotypes with polymorphisms in the putative schizophrenia risk genes, catechol-O-methyltransferase ( COMT ) and neuregulin-1 ( NRG-1), in schizophrenia patients and controls drawn from a homogenous Icelandic sample. A functional polymorphism (val 158 met) in the COMT gene may increase risk for schizophrenia through its effects on dopamine turnover in the frontal brain and NRG-1 may be associated with schizophrenia due to its involvement in several neurodevelopmental processes implicated in the pathogenesis of schizophrenia. However, the effects of these genes on neurocognitive functions are not well characterized. Associations between putative schizophrenia risk genes and eye movement endophenotypes may provide information on neural mechanisms by which these genes increase risk for schizophrenia or modulate the expression of the disorder. Secondary aims were to investigate internal consistency and intra-session performance variability of eye movement performance, to assess the association of schizophrenia symptom levels, illness duration and type of antipsychotic medication with eye movements and to examine the relationship between SPEM and antisaccade performance measures. Methods: Eye movements were measured in 118 schizophrenia patients and 109 healthy controls using infrared oculography. Each participant performed prosaccade, antisaccade, visual fixation and SPEM tasks and was genotyped for COMT val 158 met (rs4680) and two putative risk variants of NRG-1 (SNP8NRG222662/rs4623364 and SNP8NRG243177/rs6994992). Eye movement recordings were analyzed using semi- automated computer programs. Results: Schizophrenia patients performed worse on SPEM and antisaccade tasks than healthy controls. Patients also performed worse than controls on the prosaccade and visual fixation tasks. Allele frequencies of COMT val 158 met were neither associated with diagnosis of schizophrenia nor with symptoms of schizophrenia. COMT val 158 met was not associated with SPEM performance. The COMT val 158 allele was significantly associated with better performance on the antisaccade task, but there were no diagnosis-by-genotype interactions. The NRG-1 genotypes were v neither significantly associated with eye movement task performance nor with clinical measures of schizophrenia. However, NRG-1 risk carriers had numerically worse performance on most eye movement measures (d= 0.1-0.3). Internal consistency was high for most eye movement variables (Cronbach’s α >0.85) and systematic intra-session performance changes were similar in patients and controls. Age of illness onset, duration of illness, type of antipsychotic medication and schizophrenia symptom scores were generally not associated with eye movement task performance. Relationships between SPEM and antisaccade performance measures were weak and inconsistent between patients and controls. Conclusions: The study confirms the presence of SPEM and antisaccade deficits in schizophrenia in a homogenous Icelandic sample. COMT val 158 met was not associated with SPEM performance. The association of COMT val 158 with antisaccade performance indicates that more efficient dopamine degradation in the frontal cortex improves the task performance irrespective of diagnosis of schizophrenia. NRG-1 risk variants were not significantly associated with eye movement performance. However, while large NRG-1 genotype effects on SPEM and antisaccade eye movements can be excluded it is possible that the study lacks power to examine weak effects. High internal consistency, similar intra-session performance changes and limited associations between clinical measures and eye movement task performance support the use of these eye movement task deficits as endophenotypes. Weak relationships between SPEM and antisaccade performance indicate that deficits on the two tasks probably reflect separate sources of genetic risk. Key words: Schizophrenia, endophenotypes, risk genes, smooth pursuit, antisaccade vi ACKNOWLEDGEMENTS First