Genetic Schizophrenia Risk Variants Jointly Modulate Total Brain and White Matter Volume

Scheltinga, Afke F. Terwisscha van; Bakker, Steven C.; Haren, Neeltje E.M. van; Derks, Eske M.; Buizer-Voskamp, Jacobine E.; Boos, Heleen B. M.; Cahn, Wiepke; Pol, Hilleke E. Hulshoff; Ripke, Stephan; Ophoff, Roel A.; Kahn, René S.

doi:10.1016/j.biopsych.2012.08.017

Cited by 103 publications

(113 citation statements)

References 32 publications

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“…[ [15][16][17][18]. This patient sample consisted of ARMS and FEP patients, but without schizophrenia and bipolar disorder patients or healthy controls.…”

Section: Discussionmentioning

confidence: 99%

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Impact on the Onset of Psychosis of a Polygenic Schizophrenia-Related Risk Score and Changes in White Matter Volume

Harrisberger

Smieskova

Egli

et al. 2018

Cell Physiol Biochem

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Background: Reductions in the volume of brain white matter are a common feature in schizophrenia and bipolar disorder while the association between white matter and polygenic schizophrenia-related risk is unclear. To look at the intermediate state between health and the full-blown disorder, we investigated this aspect in groups of patients before and after the onset of psychosis. Methods: On a 3 Tesla scanner, total and regional white matter volumes were investigated by structural magnetic resonance imaging (MRI) in the following groups: 37 at-risk mental state patients (ARMS), including 30 with no transition to psychosis (ARMS-NT) and 7 with a transition to psychosis (ARMS-T) pooled with 25 first episode psychosis (FEP) patients. These T₁-weighted images were automatically processed with the FreeSurfer software and compared with an odds-ratio-weighted polygenic schizophrenia-related risk score (PSRS) based on the publicly available top white matter single-nucleotide polymorphisms. Results: We found no association, only a trend, between PSRS and white matter volume over all groups (β = 0.24, p = 0.07, 95% confidence interval = [-0.02 – 0.49]). However, a higher PSRS was significantly associated with a higher probability of being assigned to the ARMS-T + FEP group rather than to the ARMS-NT group (β = 0.70, p = 0.02, 95% confidence interval = [0.14 – 1.33]); there was no such association with white matter volume. Additionally, a positive association was found between PSRS and the Brief Psychiatric Rating Scale (BPRS) total score for the pooled ARMS-NT/ARMS-T+FEP sample and for the ARMS-T + FEP group also, but none for the ARMS-NT group only. Conclusion: These findings suggest that at-risk mental state patients with a transition and first-episode psychosis patients have a higher genetic risk for schizophrenia than at-risk mental state patients with no transition to psychosis; this risk was associated with psychopathological symptoms. Further analyses may allow polygenic schizophrenia-related risk scores to be used as biomarkers to predict psychosis.

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“…[ [15][16][17][18]. This patient sample consisted of ARMS and FEP patients, but without schizophrenia and bipolar disorder patients or healthy controls.…”

Section: Discussionmentioning

confidence: 99%

“…PSRS calculation PSRS were calculated, following the suggestions of Wray et al [34], by taking LD pruned loci associated with white matter volume identified by Terwischa van Scheltinga et al, 2013 [15]. All 186 SNPs could be used to calculate the PSRS.…”

Section: Mri Acquisitionmentioning

confidence: 99%

Impact on the Onset of Psychosis of a Polygenic Schizophrenia-Related Risk Score and Changes in White Matter Volume

Harrisberger

Smieskova

Egli

et al. 2018

Cell Physiol Biochem

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“…41,118,119 Moreover, because a polygenic contribution to MDD with psychotic features can be expected, future genomewide association studies on representative samples MDD with psychotic features may afford quantitative risk scores to be subsequently used in studies investigating the relationship between robust imaging phenotypes and polygenic risk scores. 120,121 Finally, there should also be neuroimaging studies applying a dimensional approach to the evaluation of psychosis associated with MDD, with both subthreshold and full-blown psychotic experiences rated along a continuum of severity, on a background of major depressive symptoms. There is a significant prevalence of subthreshold psychotic-like experiences in the general population 122 and in subjects with less severe major depressive episodes, 123 and there is a growing recognition that psychotic symptoms may best be viewed as falling along a continuum of severity in MDD rather than solely as a subcategory of severe MDD.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Structural and Functional Neuroimaging Studies in Major Depressive Disorder With Psychotic Features: A Critical Review

Busatto

2013

Schizophrenia Bulletin

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The relationship between major depressive disorder with psychotic (MDDP) features and schizophrenia has long been recognized, and the neurobiological boundaries between these disorders can nowadays be investigated using neuroimaging techniques. This article provides a critical review of such studies, addressing how they support a dimensional approach to the nosology and pathophysiology of psychotic disorders. A proportion of neuroimaging studies carried out to date indicate that MDDP subjects display structural and functional abnormalities in some brain regions specifically implicated in the pathophysiology of mood disorders, such as the subgenual cingulate cortex. This reinforces the validity of the classification of MDDP in proximity to major depression without psychosis. There is some neuroimaging evidence that MDDP may be associated with additional brain abnormalities relative to nonpsychotic major depression although less prominently in comparison with findings from the neuroimaging literature on schizophrenia. Brain regions seen as critical both to emotional processing and to models of psychotic symptoms, such as the hippocampus, insula, and lateral prefrontal cortex, have been implicated in separate neuroimaging investigations of either schizophrenia or major depression, as well as in some studies that directly compared depressed patients with and without psychotic features. These brain regions are key targets for future studies designed to validate imaging phenotypes more firmly associated with MDDP, as well as to investigate the relationship between these phenotypes and possible etiological influences for MDDP.

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“…Examination of the cumulative effects of inheriting multiple risk alleles—each of which are significantly or nominally associated with disease risk—has been able to powerfully differentiate groups of cases from controls in independent population‐based studies [Purcell et al, 2014, 2009; Patel et al, 2010; Ayalew et al, 2012; Terwisscha van Scheltinga et al, 2012]. However, despite phenotypic aggregation within families [McGuffin et al, 2003; Lichtenstein et al, 2009], no studies have so far examined polygenic risk incorporating these common genetic factors in a family context in adults, with only one group to date reporting on polygenic risk in adolescent offspring of individuals with BP [Whalley et al, 2012, 2013].…”

Section: Introductionmentioning

confidence: 99%

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

Fullerton

Koller

Edenberg

et al. 2015

American J of Med Genetics Pt B

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Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European‐ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12–30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty‐two disease‐associated SNPs from the PGC‐BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10−5, AUC = 0.60). In families with a high‐polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at‐risk youth, regardless of affected status, compared to unrelated controls (GEE‐χ2 = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease‐associated variants than unrelated controls and first‐degree relatives, and illustrate the potential utility of PRS assessment in a family context. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

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Genetic Schizophrenia Risk Variants Jointly Modulate Total Brain and White Matter Volume

Cited by 103 publications

References 32 publications

Impact on the Onset of Psychosis of a Polygenic Schizophrenia-Related Risk Score and Changes in White Matter Volume

Impact on the Onset of Psychosis of a Polygenic Schizophrenia-Related Risk Score and Changes in White Matter Volume

Structural and Functional Neuroimaging Studies in Major Depressive Disorder With Psychotic Features: A Critical Review

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

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