Biology subjects

Olde Loohuis, L. M.

Publications and source records attributed to Olde Loohuis, L. M..

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↗

bioRxiv2018

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To evaluate this hypothesis, we conducted genetic analyses in 26 Colombian (CO) and Costa Rican (CR) pedigrees ascertained for BP1, the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 856 individuals and high-coverage whole-genome sequencing of 454 individuals. Compared to their unaffected relatives, BP1 individuals had higher polygenic risk scores estimated from SNPs associated with BP discovered in independent genome-wide association studies, and also displayed a higher burden of rare deleterious single nucleotide variants (SNVs) and rare copy number variants (CNVs) in genes likely to be relevant to BP1. Parametric and non-parametric linkage analyses identified 15 BP1 linkage peaks, encompassing about 100 genes, although we observed no significant segregation pattern for any particular rare SNVs and CNVs. These results suggest that even in extended pedigrees, genetic risk for BP appears to derive mainly from small to moderate effect rare and common variants.

genetics↗

bioRxiv2017

A longitudinal model of human neuronal differentiation for functional investigation of schizophrenia disease susceptibility

There is a pressing need for in vitro experimental systems that allow for interrogation of polygenic psychiatric disease risk to study the underlying biological mechanisms. We developed an analytical framework that integrates genome-wide disease risk from GWAS with longitudinal in vitro gene expression profiles of human neuronal differentiation. We demonstrate that the cumulative impact of risk loci of specific psychiatric disorders is significantly associated with genes that are differentially expressed across neuronal differentiation. We find significant evidence for schizophrenia, which is driven by a longitudinal synaptic gene cluster that is upregulated during differentiation. Our findings reveal that in vitro neuronal differentiation can be used to translate the polygenic architecture of schizophrenia to biologically relevant pathways that can be modeled in an experimental system. Overall, this work emphasizes the use of longitudinal in vitro transcriptomic signatures as a cellular readout and the application to the genetics of complex traits.

genetics↗