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The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder.

ABSTRACT: BACKGROUND:Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. METHODS:We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. RESULTS:FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. CONCLUSIONS:Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

SUBMITTER: de Zwarte SMC

PROVIDER: S-EPMC7068800 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder.

de Zwarte Sonja M C SMC Brouwer Rachel M RM Agartz Ingrid I Alda Martin M Aleman André A Alpert Kathryn I KI Bearden Carrie E CE Bertolino Alessandro A Bois Catherine C Bonvino Aurora A Bramon Elvira E Buimer Elizabeth E L EEL Cahn Wiepke W Cannon Dara M DM Cannon Tyrone D TD Caseras Xavier X Castro-Fornieles Josefina J Chen Qiang Q Chung Yoonho Y De la Serna Elena E Di Giorgio Annabella A Doucet Gaelle E GE Eker Mehmet Cagdas MC Erk Susanne S Fears Scott C SC Foley Sonya F SF Frangou Sophia S Frankland Andrew A Fullerton Janice M JM Glahn David C DC Goghari Vina M VM Goldman Aaron L AL Gonul Ali Saffet AS Gruber Oliver O de Haan Lieuwe L Hajek Tomas T Hawkins Emma L EL Heinz Andreas A Hillegers Manon H J MHJ Hulshoff Pol Hilleke E HE Hultman Christina M CM Ingvar Martin M Johansson Viktoria V Jönsson Erik G EG Kane Fergus F Kempton Matthew J MJ Koenis Marinka M G MMG Kopecek Miloslav M Krabbendam Lydia L Krämer Bernd B Lawrie Stephen M SM Lenroot Rhoshel K RK Marcelis Machteld M Marsman Jan-Bernard C JC Mattay Venkata S VS McDonald Colm C Meyer-Lindenberg Andreas A Michielse Stijn S Mitchell Philip B PB Moreno Dolores D Murray Robin M RM Mwangi Benson B Najt Pablo P Neilson Emma E Newport Jason J van Os Jim J Overs Bronwyn B Ozerdem Aysegul A Picchioni Marco M MM Richter Anja A Roberts Gloria G Aydogan Aybala Saricicek AS Schofield Peter R PR Simsek Fatma F Soares Jair C JC Sugranyes Gisela G Toulopoulou Timothea T Tronchin Giulia G Walter Henrik H Wang Lei L Weinberger Daniel R DR Whalley Heather C HC Yalin Nefize N Andreassen Ole A OA Ching Christopher R K CRK van Erp Theo G M TGM Turner Jessica A JA Jahanshad Neda N Thompson Paul M PM Kahn René S RS van Haren Neeltje E M NEM

Biological psychiatry 20190613 7

<h4>Background</h4>Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects ...[more]

PMID: 31443932

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Project description:Schizophrenia (SCZ) and bipolar disorder (BD) are associated with immunological dysfunctions that have been hypothesized to lead to clinical symptomatology in particular through kynurenine pathway abnormalities. The aim of this study was thus to investigate the impact of serum kynurenine metabolite levels on diagnosis, clinical state, symptom severity and clinical course in a large French transdiagnostic cohort of SCZ and BD patients. Four patient groups (total n = 507) were included in a cross-sectional observational study: 1) hospitalized acute bipolar patients (n = 205); 2) stable bipolar outpatients (n = 116); 3) hospitalized acute schizophrenia patients (n = 111) and 4) stable schizophrenia outpatients (n = 75), in addition to healthy controls (HC) (n = 185). The quantitative determination of serum kynurenine metabolites was performed using liquid chromatography-tandem mass spectrometry. Kynurenine levels were lower in all patients combined compared to HC while ANCOVA analyses did not reveal inter-diagnostic difference between SCZ and BD. Interestingly, hospitalized patients of both diagnostic groups combined displayed significantly lower kynurenine levels than stabilized outpatients. Psychotic symptoms were associated with lower quinaldic acid (F = 9.18, p=<.001), which is KAT-driven, whereas a longer duration of illness contributed to abnormalities in tryptophan (F = 5.41, p = .023), kynurenine (F = 16.93, p=<.001), xanthurenic acid (F = 9.34, p = .002), quinolinic acid (F = 9.18, p = .003) and picolinic acid (F = 4.15, p = .043), metabolized through the KMO-branch. These data confirm illness state rather than diagnosis to drive KP alterations in SCZ and BD. Lower levels of KP metabolites can thus be viewed as a transdiagnostic feature of SCZ and BD, independently associated with acute symptomatology and a longer duration of illness. Quinaldic acid has seldomly been investigated by previous studies and appears an important state marker in SCZ and BD. As serum samples are used in this study, it is not possible to extrapolate these findings to the brain.

Dataset Information

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder.

Publications

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder.

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