Biology subjects

Rujescu, D.

Publications and source records attributed to Rujescu, D..

2 recordsLinked to original sources

bioRxiv2017

Genome-wide Association Study of Clinical Features in the Schizophrenia Psychiatric Genomics Consortium: Confirmation of Polygenic Effect on Negative Symptoms

Schizophrenia is a clinically heterogeneous disorder. Proposed revisions in DSM - 5 included dimensional measurement of different symptom domains. We sought to identify common genetic variants influencing these dimensions, and confirm a previous association between polygenic risk of schizophrenia and the severity of negative symptoms. The Psychiatric Genomics Consortium study of schizophrenia comprised 8,432 cases of European ancestry with available clinical phenotype data. Symptoms averaged over the course of illness were assessed using the OPCRIT, PANSS, LDPS, SCAN, SCID, and CASH. Factor analyses of each constituent PGC study identified positive, negative, manic, and depressive symptom dimensions. We examined the relationship between the resultant symptom dimensions and aggregate polygenic risk scores indexing risk of schizophrenia. We performed genome - wide association study (GWAS) of each quantitative traits using linear regression and adjusting for significant effects of sex and ancestry. The negative symptom factor was significantly associated with polygene risk scores for schizophrenia, confirming a previous, suggestive finding by our group in a smaller sample, though explaining only a small fraction of the variance. In subsequent GWAS, we observed the strongest evidence of association for the positive and negative symptom factors, with SNPs in RFX8 on 2q11.2 (P = 6.27x10-8) and upstream of WDR72 / UNC13C on 15q21.3 (P = 7.59x10-8), respectively. We report evidence of association of novel modifier loci for schizophrenia, though no single locus attained established genome - wide significance criteria. As this may have been due to insufficient statistical power, follow - up in additional samples is warranted. Importantly, we replicated our previous finding that polygenic risk explains at least some of the variance in negative symptoms, a core illness dimension.

genetics↗

bioRxiv2017

Placental gene expression mediates the interaction between obstetrical history and genetic risk for schizophrenia

Defining the environmental context in which genes enhance susceptibility can provide insight into the pathogenesis of complex disorders, like schizophrenia. Here we show that the intrauterine and perinatal environment modulates the association of schizophrenia with genomic risk, as measured with polygenic risk scores (PRS) based primarily on GWAS significant variants. Genomic risk interacts with intrauterine and perinatal complications (Early Life Complications, ELCs) in each of three independent samples from USA, Italy and Germany (overall n= 1693, p= 6e-05). In each sample, the liability of schizophrenia explained by PRS is nominally more than five times greater in the presence of a history of ELCs compared with its absence. In each sample, patients with positive ELC histories have higher PRS than patients without ELCs, which is further confirmed in two additional patient samples from Germany and Japan (overall n=2038, p= 1e-04). The gene set based on the schizophrenia loci interacting with ELCs is highly expressed in multiple placental compartments and dynamically regulated in placenta from complicated in comparison with normal pregnancies. The same genes are differentially up-regulated in placentae from male compared with female offspring. The interaction between genomic risk and ELCs is mainly driven by GWAS significant loci enriched for genes highly expressed in the various placenta samples. Molecular pathway analyses based on the genes not driving this interaction reflect previous analyses about schizophrenia risk-genes, while genes highly and differentially expressed in placentae implicate an orthogonal biology involving cellular stress. These results suggest that the most significant genetic variants detected by current schizophrenia GWAS contribute to risk in part by converging on a developmental trajectory sensitive to events affecting placentation, which may underlie the male preponderance of schizophrenia and offer new insights into primary prevention.

genetics↗