ENIGMA-Relatives – Brain Volumes in First-Degree Relatives of Schizophrenia and Bipolar Patients

1324 

Abstract Submission 

Monday, June 26 & Tuesday, June 27 

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 Gonul^12,13, Mehmet Cagdas Eker^12,14, Fatma Simsek^12,15,16, Scott Fears^17,18, Carrie Bearden^19,20, David Glahn^21,22, Theo van Erp²³, Paul Thompson²⁴, Ole Andreassen²⁵, Jessica Turner²⁶, Neeltje van Haren¹, ENIGMA Relatives Group²⁷

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

Sonja de Zwarte    -  Lecture Information | Contact Me
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht
Utrecht, Netherlands

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.

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.

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.

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.

Bipolar Disorder

Schizophrenia and Psychotic Disorders ¹

Anatomical MRI ²

Meta- Analysis

MRI

Schizophrenia

Other - Bipolar Disorder; First-Degree Relatives; Hippocampus; Total Brain Volume