Allometric Analysis Detects Brain Size-Independent Effects of Sex and Sex Chromosome Complement on Human Cerebellar Organization

Mankiw, Catherine; Park, Min Tae M.; Reardon, Paul K.; Fish, Ari M.; Clasen, Liv S.; Greenstein, Deanna; Giedd, Jay N.; Blumenthal, Jonathan D.; Lerch, Jason P.; Chakravarty, M. Mallar; Raznahan, Armin

doi:10.1523/jneurosci.2158-16.2017

Cited by 69 publications

(64 citation statements)

References 54 publications

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“…Carriage of supernumerary X-and Y-chromosomes exert convergent effects on the volume and shape of the amygdala and hippocampus. This convergence across the entire family of SCAs echoes convergent effects previously identified in the cerebral cortex , striatum and thalamus (Reardon et al, 2016), and cerebellum (Mankiw et al, 2017). This robust pattern suggests that SCA influence on brain anatomy arises from the shared gene content between X-and Y-chromosomes (i.e.…”

Section: Discussionsupporting

confidence: 73%

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Carriage of Supernumerary Sex Chromosomes Decreases the Volume and Alters the Shape of Limbic Structures

Nadig

Reardon

Seidlitz

et al. 2018

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Sex chromosome aneuploidy (SCA) enhances risk for several psychiatric disorders associated with the limbic system, including mood and autism spectrum disorders. These patients provide a powerful genetics-first model for understanding the biological basis of psychopathology.Additionally, these disorders are frequently sex-biased in prevalence, further suggesting an etiological role for sex chromosomes. Here, to clarify how limbic anatomy varies across sex and sex chromosome complement, we characterize amygdala and hippocampus structure in a uniquely large sample of patients carrying supernumerary sex chromosomes (n = 132) and typically developing controls (n=166). After correction for sex-differences in brain size, karyotypically normal males (XY) and females (XX) did not differ in volume or shape of either structure studied.In contrast, all SCAs were associated with lowered amygdala volume relative to gonadallymatched controls. This effect was robust to three different methods for total brain volume correction, including an allometric analysis that derived normative scaling rules for these structures in a separate, typically developing population (n = 79). Hippocampal volume was insensitive to SCA after correction for total brain volume. However, surface based analysis revealed that SCA, regardless of specific karyotype, was consistently associated with a spatially specific pattern of shape change in both amygdala and hippocampus. In particular, SCA was accompanied by contraction around the basomedial nucleus of the amygdala and an area within the hippocampal surface that cuts across hippocampal subfields. These results demonstrate the power of SCA as a model to understand how genetic insults precipitate changes in brain systems relevant to psychiatric disease. SEX CHROMOSOME ANEUPLOIDY AND LIMBIC STRUCTURE Significance StatementIn approximately 1 per 500 live births, infants are born carrying extra X-or Y-chromosomes.These conditions, known as sex chromosome aneuploidies (SCA), are associated with elevated risk for psychiatric disorders such as depression, anxiety, and autism. In our study, we leverage a uniquely large dataset of brain scans from SCA patients to characterize how SCA influences the structure of the amygdala and hippocampus, which have been strongly implicated in many SCAlinked neuropsychiatric disorders. Across our different patient groups, we find converging evidence that SCA is associated with a decrease in amygdala volume, and spatially specific areal contractions in both the amygdala and hippocampus. Our findings help clarify how genetic copy number variation associated with psychiatric disease shapes brain organization.

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Section: Discussionsupporting

confidence: 73%

“…To account for sex-differences in the allometric fit β0 and β1 that have been observed in other brain structures (Mankiw et al, 2017;Reardon et al, 2016), we used our log-log regression framework to sequentially test three general linear models of amygdala and hippocampus allometry with decreasing complexity of sex differences.…”

Section: Statistical Analysesmentioning

confidence: 99%

Carriage of Supernumerary Sex Chromosomes Decreases the Volume and Alters the Shape of Limbic Structures

Nadig

Reardon

Seidlitz

et al. 2018

Preprint

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“…Recent work on sex-chromosome aneuploidy has indicated a dose effect of sex-chromosomes on gene expression (48) . Additional work from the same group has found effects of sex-chromosome dosage on brain structures (49,50) . These studies show sex-chromosomes influence both brain structure and gene-expression, however, further work is required to identify the underlying causes of the discrepancy in variability between males and females seen here and determine the relationship to genetic variability or gene expression.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in Variability of Brain Structure Across the Lifespan

Forde

Jeyachandra

Joseph

et al. 2019

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Several brain disorders exhibit sex differences in onset, presentation, and prevalence.Increased understanding of the neurobiology of sex-based differences across the lifespan can provide insight into potential disease risk and protective mechanisms. We focused on sex-related differences in variability, which may be indicative of both disease vulnerability and resilience. In n=3,069 participants, from 8-95 years of age, we first analyzed the variance ratio in females vs. males of cortical surface area and global and subcortical volumes for discrete brain regions, and found widespread greater variability in males. In contrast, variance in cortical thickness was similar for males and females. Multivariate analysis that accounts for structural covariance supported variance ratio findings. Findings were present from early life and stable with age. We then examined variability among brain regions by sex. We found significant age-by-sex interactions across neuroimaging metrics, whereby in very early life males had reduced among-region variability compared to females, while in very late life this was reversed. Overall, our findings of greater regional variability but less among-region variability in males in early life may aid our understanding of sex-based risk for neurodevelopmental disorders. In contrast, our findings in late life may provide a potential sex-based risk mechanism for dementia.

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“…National Institutes of Health -Bethesda, USA (NIH) Sex Chromosome Aneuploidies: This dataset has been described in detail previously [37][38][39] . Briefly, we included 297 patients with various supernumerary X-and/or Ychromosome counts and 165 healthy controls (79 females) ( Table S1).…”

Section: Cohorts Diagnostic Classification and Mri Acquisitionmentioning

confidence: 99%

“…Cell type decoding of AHBA microarray and CNV gene ranks. a) Regional median expression (Z-score) in the AIBS microarray dataset of cell-specific gene sets, aggregated across 5 single-cell sequencing studies and ordered according to 37 al ts, to hierarchical clustering (n=3 clusters based on gap statistic). Cell type abbreviations are maintained from the original study (see also Extended Data File 3).…”

Section: Defining Brain-specific Genesmentioning

confidence: 99%

Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders

Seidlitz¹,

Nadig²,

Liu³

et al. 2019

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Neurodevelopmental disorders are highly heritable and associated with spatially-selective disruptions of brain anatomy. The logic that translates genetic risks into spatially patterned brain vulnerabilities remains unclear but is a fundamental question in disease pathogenesis. Here, we approach this question by integrating (i) in vivo neuroimaging data from patient subgroups with known causal genomic copy number variations (CNVs), and (ii) bulk and single-cell gene expression data from healthy cortex. First, for each of six different CNV disorders, we show that spatial patterns of cortical anatomy change in youth are correlated with spatial patterns of expression for CNV region genes in bulk cortical tissue from typically-developing adults. Next, by transforming normative bulk-tissue cortical expression data into cell-type expression maps, we further link each disorder's anatomical change map to specific cell classes and specific CNV-region genes that these cells express. Finally, we establish convergent validity of this "transcriptional vulnerability model" by inter-relating patient neuroimaging data with measures of altered gene expression in both brain and bloodderived patient tissue. Our work clarifies general biological principles that govern the mapping of genetic risks onto regional brain disruption in neurodevelopmental disorders. We present new methods that can harness these principles to screen for potential cellular and molecular determinants of disease from readily available patient neuroimaging data.

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Allometric Analysis Detects Brain Size-Independent Effects of Sex and Sex Chromosome Complement on Human Cerebellar Organization

Cited by 69 publications

References 54 publications

Carriage of Supernumerary Sex Chromosomes Decreases the Volume and Alters the Shape of Limbic Structures

Carriage of Supernumerary Sex Chromosomes Decreases the Volume and Alters the Shape of Limbic Structures

Sex differences in Variability of Brain Structure Across the Lifespan

Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders

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