The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder.
de Zwarte SMC, Brouwer RM, Agartz I, Alda M, Aleman A, Alpert KI, Bearden CE, Bertolino A, Bois C, Bonvino A, Bramon E, Buimer EEL, Cahn W, Cannon DM, Cannon TD, Caseras X, Castro-Fornieles J, Chen Q, Chung Y, De la Serna E, Di Giorgio A, Doucet GE, Eker MC, Erk S, Fears SC, Foley SF, Frangou S, Frankland A, Fullerton JM, Glahn DC, Goghari VM, Goldman AL, Gonul AS, Gruber O, de Haan L, Hajek T, Hawkins EL, Heinz A, Hillegers MHJ, Hulshoff Pol HE, Hultman CM, Ingvar M, Johansson V, Jönsson EG, Kane F, Kempton MJ, Koenis MMG, Kopecek M, Krabbendam L, Krämer B, Lawrie SM, Lenroot RK, Marcelis M, Marsman JC, Mattay VS, McDonald C, Meyer-Lindenberg A, Michielse S, Mitchell PB, Moreno D, Murray RM, Mwangi B, Najt P, Neilson E, Newport J, van Os J, Overs B, Ozerdem A, Picchioni MM, Richter A, Roberts G, Aydogan AS, Schofield PR, Simsek F, Soares JC, Sugranyes G, Toulopoulou T, Tronchin G, Walter H, Wang L, Weinberger DR, Whalley HC, Yalin N, Andreassen OA, Ching CRK, van Erp TGM, Turner JA, Jahanshad N, Thompson PM, Kahn RS, van Haren NEM. The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder. Biological psychiatry. 2019 Oct 1; 86(7):545-556.
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.
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.
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.
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.