Biology subjects

Ophoff, R.

Publications and source records attributed to Ophoff, R..

3 recordsLinked to original sources

bioRxiv2018

Structural brain alterations in youth with psychosis and bipolar spectrum symptoms

ObjectiveAdults with established diagnoses of serious mental illness (bipolar disorder and schizophrenia) exhibit structural brain abnormalities, yet less is known about how such abnormalities manifest earlier in development.\n\nMethodsWe analyzed the data publicly available from the Philadelphia Neurodevelopmental Cohort (PNC). Structural magnetic resonance neuroimaging data (sMRI) were collected on a subset of the PNC (N=989, ages 9-22 years old). We calculated measures of cortical thickness (CT) and surface area (SA), along with subcortical volumes. Study participants were assessed for psychiatric symptomatology via structured interview and the following groups were created: typically developing (TD, N=376), psychosis spectrum (PS, N=113), bipolar spectrum (BP, N=117), and BP + PS (N=109). We examined group and developmental differences in sMRI measures. We also examined to what extent any structural aberration was related to neurocognition, global functioning, and clinical symptomatology.\n\nResultsIn comparison to all other groups, PS youth exhibited significantly reduced SA in orbitofrontal, cingulate, precentral, and postcentral regions. PS youth also exhibited reduced thalamic volume in comparison to all other groups. Strongest effects for precentral and posterior cingulate SA reductions were seen during early adolescence (ages 13-15) in PS youth. Strongest effects for reductions in thalamic volume and orbitofrontal and postcentral SA were observed in mid-adolescence (16-18 years) in PS youth. Across groups, better overall functioning was associated with increased lateral orbitofrontal SA. Increased postcentral SA was associated with better executive cognition and less severe negative symptoms in the entire sample.\n\nConclusionIn a community-based sample, we found that reduced cortical SA and thalamic volume are present early in adolescent development in youth with psychosis spectrum symptoms, but not in youth with bipolar spectrum symptoms, or with both bipolar and psychosis spectrum symptoms. These findings point to potential biological distinctions between psychosis and bipolar spectrum conditions, which may suggest additional biomarkers relevant to early identification.

neuroscience↗

bioRxiv2017

Genomewide association study identifies 30 loci associated with bipolar disorder

Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P<1x10-4 in an independent sample of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters (CACNA1C, GRIN2A, SCN2A, SLC4A1), synaptic components (RIMS1, ANK3), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes; ~73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes; ~17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.

genetics↗

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↗