Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept

Franke, Barbara; Stein, Jason L.; Ripke, Stephan; Anttila, Verneri; Hibar, Derrek P.; Hulzen, K.J.E. van; Arias-Vásquez, Alejandro; Smoller, Jordan W.; Nichols, Thomas E.; Neale, Michael C.; McIntosh, Andrew M.; Lee, Phil; McMahon, Francis J.; Meyer‐Lindenberg, Andreas; Mattheisen, Manuel; Andreassen, Ole A.; Gruber, Oliver; Sachdev, Perminder S.; Roiz-Santiáñez, Roberto; Saykin, Andrew J.; Ehrlich, Stefan; Mather, Karen A.; Turner, Jessica A.; Schwarz, Emanuel; Thalamuthu, Anbupalam; Yao, Yin; Ho, Yvonne; Martin, Nicholas G.; Wright, Margaret J.; O’Donovan, Michael; Thompson, Paul M.; Neale, Benjamin M.; Medland, Sarah E.; Sullivan, Patrick F.

doi:10.1038/nn.4228

Cited by 214 publications

(241 citation statements)

References 42 publications

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“…To mitigate some of these issues, cohorts of individuals with shared genetic risk factors have been assembled to minimize the noise introduced by etiologic and biological heterogeneity (9). Such a "genetic-first" study design provides the opportunity to investigate a given neurodevelopmental risk (and associated mechanism) shared by individuals who carry the same genetic etiology irrespective of the psychiatric diagnosis.…”

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confidence: 99%

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

Martin

Rodríguez-Herreros

Nielsen

et al. 2018

Biological Psychiatry

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BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure. METHODS: Using voxel-and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV. RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion . control . duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion . control; Cohen's d . 1), the superior and middle temporal gyri (deletion , control; Cohen's d , 21), and the caudate and hippocampus (control . duplication; 20.5 . Cohen's d . 21). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results. CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria. Autism spectrum disorder (ASD) and related neurodevelopmental disorders are defined behaviorally and characterized by a significant clinical and etiologic heterogeneity. As a consequence, investigating ASD under the assumption of an underlying homogeneous condition has resulted in controversial findings in the field of neuroimaging (1). Increased brain growth early in development (2-4) and alterations of many regional brain volumes (5) have been implicated in ASD, but results have proven difficult to replicate (1,(6)(7)(8).To mitigate some of these issues, cohorts of individuals with shared genetic risk factors have been assembled to minimize the noise introduced by etiologic and biological heterogeneity (9). Such a "genetic-first" study design provides the opportunity to investigate a given neurodevelopmental risk (and associated mechanism) shared by individuals who carry the same genetic etiology irrespective of the psychiatric diagnosis.Copy number variants (CNVs) at the 16p11.2 (breakpoints 4-5, 29.6-30.2 Mb-hg19) (10) are among the most frequent risk factors for neurodevelopmental and psychiatric conditions.

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mentioning

confidence: 99%

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

Martin

Rodríguez-Herreros

Nielsen

et al. 2018

Biological Psychiatry

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“…[1][2][3][4][5][6][7][8][9][10][11] Structural alterations commonly found in these studies are volumetric alterations in the anterior cingulate, frontal and temporal regions; hippocampus; amygdala; thalamus; and insula. 2,8,[12][13][14][15] Decreases, increases and negative findings were found, with most studies reporting reduced total and regional grey matter volumes. A comprehensive meta-analysis of these studies indicated the progressive nature of most of these brain structural alterations.…”

Section: Introductionmentioning

confidence: 99%

Age-related brain structural alterations as an intermediate phenotype of psychosis

Dukart

Smieskova

Harrisberger

et al. 2017

JPN

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“…A recent study integrating common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects) found no evidence of genetic overlap between schizophrenia risk and brain volume measures either at the level of common variant genetic architecture or for single genetic markers (95). There are several potential neurobiological reasons that might underlie such an absence, notably the fact that schizophrenia is a neurodevelopmental process where several neural longitudinal changes may map in opposite fashion onto regional volumes (for example, cortical pruning as a mechanism of maturation in adolescence and pathology-induced neuronal loss both may lead to cortical thinning; antipsychotic treatment and neural plasticity may both lead to samedirection volume changes in the striatum).…”

Section: The Future Of Structural Neuroimaging In Psychosismentioning

confidence: 99%

Forty years of structural imaging in psychosis: promises and truth

Fusar‐Poli

Meyer‐Lindenberg

2016

Acta Psychiatr Scand

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MethodWe present here a critical review of studies involving structural magnetic resonance imaging techniques in psychotic patients published between the 1976-2015 in selected journals of relevance for the field. For each study we extracted summary descriptive variables.Additionally we qualitatively described the main structural findings of each articles in summary notes and we employed a biomarker rating system based on quality of evidence (scored 1-4) and effect size (scored 1-4). Results80 studies meeting the inclusion criteria were retrieved. The number of studies increased over time, reflecting an increased structural imaging research in psychosis. However, quality of evidence was generally impaired by small samples and unclear biomarker definitions. In particular, there was little attempt of replication of previous findings. The effect sizes ranged from small to modest. No diagnostic or prognostic biomarker for clinical use was identified. ConclusionsStructural neuroimaging in psychosis research has not yet delivered on the clinical applications that were envisioned.

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Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept

Cited by 214 publications

References 42 publications

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

Age-related brain structural alterations as an intermediate phenotype of psychosis

Forty years of structural imaging in psychosis: promises and truth

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