RESUMEN
Major depressive disorder (MDD) is a clinically and genetically heterogeneous disorder. To reduce heterogeneity, large-scale genome-wide association studies have recently identified genome-wide significant loci associated with seven MDD subtypes. However, it was unclear in which tissues the genes near those loci are specifically expressed. We investigated whether genes related to specific MDD subtypes would be preferably expressed in a specific tissue. At 14 novel subtype-specific loci related to seven MDD subtypes-(1) non-atypical-like features MDD, (2) early-onset MDD, (3) recurrent MDD, (4) MDD with suicidal thoughts, (5) MDD without suicidal thoughts, (6) MDD with moderate impairment, and (7) postpartum depression, we investigated whether 22 genome-wide significant genetic variant-mapped genes were tissue-specifically expressed in brain, female reproductive, male specific, cardiovascular, gastrointestinal, or urinary tissues in the Genotype-Tissue Expression (GTEx) subjects (n ≤ 948). To confirm the tissue-specific expression in the GTEx, we used independent Human Protein Atlas (HPA) RNA-seq subjects (n ≤ 95). Of 22 genes, nine and five genes were tissue-specifically expressed in brain and female reproductive tissues, respectively (p < 2.27 × 10-3). RTN1, ERBB4, and AMIGO1 related to early-onset MDD, recurrent MDD, or MDD with suicidal thoughts were highly expressed in brain tissues (d = 1.19-2.71), while OAS1, LRRC9, DHRS7, PSMA5, SYPL2, and GULP1 related to non-atypical-like features MDD, early-onset MDD, MDD with suicidal thoughts, or postpartum depression were expressed at low levels in brain tissues (d = -0.17--1.48). DFNA5, CTBP2, PCNX4, SDCCAG8, and GULP1, which are related to early-onset MDD, MDD with moderate impairment, or postpartum depression, were highly expressed in female reproductive tissues (d = 0.80-2.08). Brain and female reproductive tissue-specific expression was confirmed in the HPA RNA-seq subjects. Our findings suggest that brain and female reproductive tissue-specific expression might contribute to the pathogenesis of MDD subtypes.
RESUMEN
BACKGROUND: Patients with schizophrenia and bipolar disorder have an overlapping polygenic architecture and clinical similarities, although the 2 disorders are distinct diagnoses with clinical dissimilarities. It remains unclear whether there are specific differences in subcortical volumes between schizophrenia and bipolar disorder, and whether the subcortical differences are affected by any clinical characteristics. We investigated differences in subcortical volumes bilaterally among patients with schizophrenia, patients with bipolar disorder and healthy controls. We also investigated the influences of clinical characteristics on specific subcortical volumes in these patient groups. METHODS: We collected 3 T T 1-weighted MRI brain scans from 413 participants (157 with schizophrenia, 51 with bipolar disorder and 205 controls) with a single scanner at a single institute. We used FreeSurfer version 6.0 for processing the T 1-weighted images to segment the following subcortical brain volumes: thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala and nucleus accumbens. Differences in the 7 subcortical volumes were investigated among the groups. We also evaluated correlations between subcortical volumes and clinical variables in these patient groups. RESULTS: Of 7 subcortical regions, patients with schizophrenia had significantly smaller volumes in the left thalamus (Cohen d = -0.29, p = 5.83 × 10-3), bilateral hippocampi (left, d = -0.36, p = 8.85 × 10-4; right, d = -0.41, p = 1.15 × 10-4) and left amygdala (d = -0.31, p = 4.02 × 10-3) than controls. Compared with controls, patients with bipolar disorder had bilateral reductions only in the hippocampal volumes (left, d = -0.52, p = 1.12 × 10-3; right, d = -0.58, p = 0.30 × 10-4). We also found that patients with schizophrenia had significantly smaller volumes in the bilateral amygdalae (left, d = -0.43, p = 4.22 × 10-3; right, d = -0.45, p = 4.56 × 10-3) than patients with bipolar disorder. We did not find any significant volumetric differences in the other 6 subcortical structures between patient groups (p > 0.05). Smaller left amygdalar volumes were significantly correlated with younger onset age only in patients with schizophrenia (r = 0.22, p = 5.78 × 10-3). LIMITATIONS: We did not evaluate the differences in subcortical volumes between patients stratified based on clinical bipolar disorder subtype and a history of psychotic episodes because our sample size of patients with bipolar disorder was limited. CONCLUSION: Our findings suggest that volumetric differences in the amygdala between patients with schizophrenia and those with bipolar disorder may be a putative biomarker for distinguishing 2 clinically similar diagnoses.