Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination.

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.

The hippocampus is a complex structure consisting of subregions with specialized cytoarchitecture and functions. Magnetic resonance imaging (MRI) studies in psychotic disorders show hippocampal subfield abnormalities, but affected regions differ between studies. We here present an overview of hippocampal anatomy and function relevant to psychosis, and the first systematic review and meta-analysis of MRI studies of hippocampal subfield morphology in schizophrenia and bipolar disorder. Twenty-one MRI studies assessing hippocampal subfield volumes or shape in schizophrenia or bipolar disorder were included (n 15-887 subjects). Nine volumetric group comparison studies (total n = 2593) were included in random effects meta-analyses of group differences. The review showed mixed results, with volume reductions reported in most subfields in schizophrenia and bipolar disorder. Volumetric studies using ex-vivo based image analysis templates corresponded best with the shape studies, with CA1 as the most affected region. The meta-analyses showed volume reductions in all subfields in schizophrenia and bipolar disorder compared to healthy controls (all p < .005; schizophrenia: d = 0.28-0.49, bipolar disorder: d = 0.20-0.35), and smaller left CA2/3 and right subiculum in schizophrenia than bipolar disorder. In conclusion, the hippocampal subfields appear to be differently affected in psychotic disorders. However, due to the lack of control for putative confounders such as medication, alcohol and illicit substance use, and illness stage, the results from the meta-analysis should be interpreted with caution. Methodological subfield segmentation weaknesses should be addressed in future studies.

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.