Stand-By Time
Monday, June 26, 2017: 12:45 PM - 2:45 PM
Submission No:
1324
Submission Type:
Abstract Submission
On Display:
Monday, June 26 & Tuesday, June 27
Authors:
Sonja de Zwarte1, Rachel Brouwer1, Manon Hillegers1, Wiepke Cahn1, Hilleke Hulshoff Pol1, René Kahn1, Kathryn Alpert2, Lei Wang2, Elvira Bramon3, Fergus Kane4, Robin Murray4, Tomas Hajek5, Martin Alda5, Gloria Roberts6, Philip Mitchell6, Peter Schofield7, Janice Fullerton7, Anja Richter8, Oliver Gruber8, Aurora Bonvino9, Alessandro Bertolino9, Annabella Di Giorgio10, Xavier Caseras11, Ali Saffet Gonul12,13, Mehmet Cagdas Eker12,14, Fatma Simsek12,15,16, Scott Fears17,18, Carrie Bearden19,20, David Glahn21,22, Theo van Erp23, Paul Thompson24, Ole Andreassen25, Jessica Turner26, Neeltje van Haren1, ENIGMA Relatives Group27
Institutions:
1Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands, 2Department of Psychiatry & Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States, 3Neuroscience in Mental Health Research Department, Division of Psychiatry, University College London, London, United Kingdom, 4Psychosis Studies, Institute of Psychiatry, King's College London, London, United Kingdom, 5Department of Psychiatry, Dalhousie University, Halifax, Canada, 6School of Psychiatry, University of New South Wales, Sydney, Australia, 7Neuroscience Research Australia, Sydney, Australia, 8Experimental Psychopathology & Neuroimaging, Department of General Psychiatry, Heidelberg, Germany, 9Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy, 10Section of Psychiatry and Psychology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy, 11Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom, 12Ege University, School of Medicine, Department of Psychiatry, SoCAT LAB, Bornova, Izmir, Turkey, 13Mercer University School of Medicine, Department of Psychiatry and Behavioral Sciences, Macon, GA, United States, 14Stony Brook University, School of Medicine, Department of Psychiatry, Stony Brook, NY, United States, 15Cigli State Hospital, Department of Psychiatry, Izmir, Turkey, 16Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom, 17Department of Psychiatry and Biobehavioral Science, University of California, Los Angeles, Los Angeles, CA, United States, 18Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, United States, 19Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, United States, 20Department of Psychology, University of California, Los Angeles, Los Angeles, CA, United States, 21Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States, 22Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, CT, United States, 23Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, United States, 24Imaging Genetics Center, Keck School of Medicine of University of Southern California, Marina Del Rey, CA, United States, 25NORMENT, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway, 26Psychology Department & Neuroscience Institute Georgia State University, Atlanta, GA, United States, 27http://enigma.ini.usc.edu, ENIGMA-Schizophrenia and Bipolar Disorder Working Groups
First Author:
Sonja de Zwarte
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Lecture Information
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Contact Me
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht
Utrecht, Netherlands
Introduction:
Schizophrenia (SZ) and bipolar disorder (BD) are characterized by structural brain abnormalities. Smaller total brain (TB) and hippocampal volumes, and larger ventricle volumes are among the strongest findings (Arnone et al. 2009, Haijma et al. 2012, Hibar et al.2015, Van Erp et al. 2015). Both disorders share overlapping genetic liabilities (Lichtenstein et al. 2009), which are partly reflected in the brain (Hulshoff Pol et al. 2012). Family members of patients are of particular interest as they share part of the genetic and/or environmental risk for the disease but not confounding factors, such as medication use or duration of illness. Non-psychotic first-degree relatives of SZ patients have smaller brain volumes on average, particularly in the hippocampus, compared with controls without a family history of psychosis (Boos et al. 2007). In contrast, a review on BD relatives reported large discrepancies in findings across studies (Nery et al. 2013).
MRI studies of relatives have shown different results depending on the generational relationship of the first-degree relatives to the proband (Moran et al. 2013). A possible explanation could be that, although first-degree relatives share on average 50% of their common genetic variants with the proband (except for monozygotic (MZ) twins), they differ in relative risk (RR) for the disorder (Gottesman 1991, Lichtenstein et al. 2009). Through the ENIGMA SZ and BD Working Groups and beyond, we are analyzing data sets consisting of first-degree family members of SZ or BD patients (i.e., co-twins, siblings, offspring, parents), probands (if available), and matched healthy controls (HC). In this ENIGMA effort, we aim to compare the different types of relatives to HC on global and subcortical measures of the brain. We hypothesize that relatives show brain volume abnormalities and that the extent of brain volume abnormalities scales with the RR. In addition, we expect the same pattern in first-degree relatives of BD patients but with smaller effect sizes. In this abstract, we limit ourselves to TB and hippocampal volume.
Methods:
To date, the ENIGMA relatives study includes data from 3,033 individuals from 16 independent studies collected at 10 sites. T1-weighted MRI scans were processed with the FreeSurfer software package. Linear mixed model analyses were performed in R comparing TB and hippocampal volume of each type of relative to HC, while taking family relatedness into account. Centered age, age squared and sex (and lithium for BD) were included as covariates. Analyses of multiscanner studies included binary dummy variables for n – 1 scanners. Cohen's d effect size estimates were obtained at each site and then pooled using an inverse variance-weighted random-effects meta-analysis for each relative group separately and all relatives combined. All random-effects models were fitted using the restricted maximum likelihood method.
Results:
SZ siblings and offspring showed significantly lower TB volume (Cohen's d's were -0.19 and -0.83, respectively), and the SZ relatives combined also showed significant lower TB volume (d=-0.28) (figure 1). In addition, SZ offspring had smaller hippocampal volumes than HC (d=-0.65) and the SZ relatives combined showed a trend level significant decrease (d=-0.14, figure 2). SZ patients showed, as expected from the literature, both significantly lower TB and hippocampal volume. No significant differences were found between BD relatives and controls, and BD patients and controls.
Conclusions:
This ENIGMA collaboration, comparing structural brain measures in SZ and BD relatives to controls, is ongoing and larger sample sizes are expected. Our preliminary findings suggest that relatives of SZ patients have a smaller total brain volume, while relatives of BD patients do not. We are currently expending the analyses to investigate whether a DSM diagnosis in the relatives explains the differences found in brain volume and whether differences between the types of relatives can be explained by RR.
Disorders of the Nervous System:
Bipolar Disorder
Schizophrenia and Psychotic Disorders 1
Imaging Methods:
Anatomical MRI 2
Keywords:
Meta- Analysis
MRI
Schizophrenia
Other - Bipolar Disorder; First-Degree Relatives; Hippocampus; Total Brain Volume
1|2Indicates the priority used for review
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Yes
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Yes
Please indicate below if your study was a "resting state" or "task-activation” study.
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Healthy subjects only or patients (note that patient studies may also involve healthy subjects):
Patients
Internal Review Board (IRB) or Animal Use and Care Committee (AUCC) Approval. Please indicate approval below. Please note: Failure to have IRB or AUCC approval, if applicable will lead to automatic rejection of abstract.
Yes, I have IRB or AUCC approval
Please indicate which methods were used in your research:
Structural MRI
For human MRI, what field strength scanner do you use?
1.5T
3.0T
Which processing packages did you use for your study?
Free Surfer
Provide references in author date format
Arnone, D. et al. (2009), ‘Magnetic Resonance Imaging Studies in Bipolar Disorder and Schizophrenia: Meta-Analysis’, British Journal of Psychiatry, vol. 195, no. 3, pp. 194-201.
Boos, H.B.M. et al. (2007), ‘ Brain Volumes in Relatives of Patients with Schizophrenia’, Archives of General Psychiatry, vol. 64, pp. 297-304.
Gottesman, I.I. (1991), Schizophrenia Genesis – The Origins of Madness. New York, NY: W.H. Freeman and Company.
Haijma, S.V., et al. (2013), ‘Brain Volumes in Schizophrenia: a Meta-Analysis in over 18000 Subjects’, Schizophrenia Bulletin, vol. 39, no. 5, pp. 1129-1138.
Hibar D.P. et al. (2015), ‘Subcortical Volumetric Abnormalities in Bipolar Disorder’, Molecular Psychiatry (in press).
Hulshoff Pol, H.E. et al. (2012), ‘Overlapping and Segregating Structural Brain Abnormalities in Twins with Schizophrenia or Bipolar Disorder’, Archives of General Psychiatry, vol. 69, no. 4, pp. 349-359.
Lichtenstein, P. et al. (2009), ‘Common Genetic Determinants of Schizophrenia and Bipolar Disorder in Swedish Families: a Population-Based Study’, Lancet, vol. 373, pp. 234-239.
Moran, M.E. et al. (2013), ‘A Family Affair: Brain Abnormalities in Siblings of Patients with Schizophrenia’, Brain, vol. 136, pp. 3215-3226.
Nery, F.G. et al. (2013), ‘Gray Matter Abnormalities as Brain Structural Vulnerability Factors for Bipolar Disorder: a Review of Neuroimaging Studies of Individuals at High Genetic Risk for Bipolar Disorder’, Australian and New Zealand Journal of Psychiatry, vol.
47, pp. 1124-1135.
Van Erp, T.G.M. et al. (2015), ‘Subcortical Brain Volume Abnormalities in 2028 Individuals with Schizophrenia and 2540 Healthy Controls via the ENIGMA Consortium’, Molecular Psychiatry, vol. 21. pp. 547-553.