X-chromosome influences on neuroanatomical variation in humans

Mallard, Travis T.; Liu, Siyuan; Seidlitz, Jakob; Ma, Zhiwei; Moraczewski, Dustin; Thomas, Adam G.; Raznahan, Armin

doi:10.1038/s41593-021-00890-w

Cited by 35 publications

(35 citation statements)

References 68 publications

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“…Girls typically displayed increased N0, ND, and NT compared to boys, on average, suggesting increased cell and neurite density in girls. Given that our results remained consistent when statistically controlling for puberty, these observed microstructure sex differences in late childhood may be due to the impact of X chromosome genes and/or the organizational effects of intrauterine testosterone (Lentini, Kasahara, Arver, & Savic, 2013;Mallard et al, 2021;Salminen et al, 2022).…”

Section: Discussionsupporting

confidence: 67%

“…The current study has a number of important strengths, including the unprecedented sample size, the use of both conventional and advanced microstructure models, the narrow age range of the sample, and the demonstrated reproducibility and robustness of our results. Our findings provide an important foundation for future work dissecting the mechanisms driving sex differences in white matter microstructure, including the potential impact of pubertal development, sex hormones, genetic factors, and environmental contributors (Herting et al, 2017; Herting et al, 2012; Mallard et al, 2021; Nabulsi et al, 2020; Salminen et al, 2022). These findings also lay the groundwork for future studies examining how white matter sex differences may relate to individual variability in brain function and behavior, including how such neural differences may relate to clinical sex differences in adolescent-onset neuropsychiatric disorders (Meyer & Lee, 2019; Paus et al, 2008; Salminen et al, 2022; van Eijk et al, 2021).…”

Section: Discussionmentioning

confidence: 84%

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White matter microstructure shows sex differences in late childhood: Evidence from 6,797 children

Lawrence

Abaryan

Laltoo

et al. 2021

Preprint

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Sex differences in white matter microstructure have been robustly demonstrated in the adult brain using both conventional and advanced diffusion-weighted magnetic resonance imaging (dMRI) approaches. However, the effect of sex on white matter microstructure prior to adulthood remains poorly understood, with previous developmental work focusing on conventional microstructure metrics and yielding mixed results. Here we thoroughly and rigorously characterized sex differences in white matter microstructure among over 6,000 children from the Adolescent Brain Cognitive Development (ABCD) Study who were between 9 and 10 years old. Microstructure was quantified using both the conventional model - diffusion tensor imaging (DTI) - and an advanced model, restriction spectrum imaging (RSI). DTI metrics included fractional anisotropy (FA) and mean, axial, and radial diffusivity (MD, AD, RD). RSI metrics included normalized isotropic, directional, and total intracellular diffusion (N0, ND, NT). We found significant and replicable sex differences in DTI or RSI microstructure metrics in every white matter region examined across the brain. The impact of sex on FA was regionally specific. Across white matter regions, boys exhibited greater MD, AD, and RD than girls, on average. Girls displayed increased N0, ND, and NT compared to boys, on average, suggesting greater cell and neurite density in girls. Together, these robust and replicable findings provide an important foundation for understanding sex differences in health and disease.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 84%

White matter microstructure shows sex differences in late childhood: Evidence from 6,797 children

Lawrence

Abaryan

Laltoo

et al. 2021

Preprint

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“…For example, a recent study highlights the X-chromosome's privileged influence on neuroanatomical variation. 87 Regions linked to enriched X-chromosome morphological influence overlap with the "sex-typical" right anterior cingulate/anterior parahippocampus and the "sex-atypical" precuneus nodes linked to camouflaging in this study. It is plausible that processes like X inactivation/escape may preserve function in sex-related pathways affected by ASD risk genes.…”

Section: Sex-related Biological Mechanismsmentioning

confidence: 55%

Sex-Related Neurocircuitry Supporting Camouflaging in Adults with Autism: Female Protection Insights

Walsh

Pagni

Monahan

et al. 2021

Preprint

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The male preponderance in autism led to the hypothesis that aspects of female biology are protective against autism. Females with autism report engaging in more compensatory behaviors (i.e., “camouflaging”) to overcome autism-related social differences, which may be a downstream result of protective pathways. No studies have examined sex-related brain pathways supporting camouflaging in females with autism, despite its potential to inform mechanisms underlying the sex bias in autism.This case-control design included 45 non-intellectually-disabled adults with autism (male/female: 21/24) and 40 neurotypical adults (male/female: 19/21) ages 18-71. We used group multivariate voxel pattern analysis to conduct a data-driven, connectome-wide characterization of “sex-atypical” (sex-by-diagnosis) and “sex-typical” (sex) brain functional connectivity features linked to camouflaging, and validated findings in females with autism multi-modally via structural connectometry. Exploratory associations with cognitive control, memory, emotion recognition, and depression/anxiety examined the adaptive nature of functional connectivity patterns supporting camouflaging in females with autism.We found 1) “sex-atypical” functional connectivity patterns predicting camouflaging in the hypothalamus and precuneus and 2) “sex-typical” patterns in the anterior cingulate and right anterior parahippocampus. Higher hypothalamic functional connectivity with a limbic reward cluster was the strongest predictor of camouflaging in females with autism (a “sex-atypical” pattern), and also predicted better cognitive control/emotion recognition. Structural connectometry validated functional connectivity results with consistent brain pathways/effect patterns implicated across multi-modal findings in females with autism.This data-driven, connectome-wide characterization of “sex-atypical” and “sex-typical” brain connectivity features supporting compensatory social behavior in autism suggests hormones may play a role in the autism sex bias. Furthermore, both “male-typical” and “female-typical” brain connectivity patterns are implicated in camouflaging in females with autism in circuits associated with reward, emotion, and memory processing. “Sex-atypical” results are consistent with the fetal steroidogenic hypothesis, which would result in masculinized brain features in females with autism. However, female genetics/biology may contribute to “female-typical” patterns implicated in camouflaging.

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“…This growth in absolute brain size is accompanied by an increase in the variability of brain size among humans that also peaks in adolescence, and arises from differential contributions of underlying tissue types with discrete growth trajectories 4 . Many studies have demonstrated high twin-based and single nucleotide polymorphism (SNP) heritability of brain morphology, with many global brain size indices reaching above 50% (twin) and 25% (SNP) of interindividual variance explained by genetic factors [4][5][6][7] . Brain size has also been implicated in myriad clinically relevant contexts, including case-control differences in both neuropsychiatric and neurodegenerative diseases, as well as dimensional associations with anthropometric and cognitive traits 4,8 .…”

Section: Introductionmentioning

confidence: 99%

The molecular genetic landscape of human brain size variation

Seidlitz

Mallard

Vogel

et al. 2022

Preprint

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Human brain size increases dynamically through early development, peaks in adolescence, and varies up to two-fold among adults. Although previous studies have elucidated changes in brain size across evolution, development, traits, and diseases, the molecular underpinnings of interindividual variation in brain size remain unknown. Here, we leverage postmortem brain RNA sequencing and estimates of brain weight (BW) in 2,531 individuals across three independent datasets, to identify 928 genes that show genome-wide significant associations with either higher or lower BW (BW+, BW-, respectively). These BW gene sets showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto developmental, functional and cellular axes of brain organization. Expression differences among evolutionarily conserved BW genes were predictive of interspecies differences in brain size, and functional annotation of BW genes revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses of in vivo neuroimaging phenotypes confirmed that the genetic regulation of BW- transcripts influences cortical surface area and volume, as well as behavioral traits related to brain function and disease. Cumulatively, our study represents a major step towards the goal of delineating the causal mechanisms of human brain size variation in health and disease.

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X-chromosome influences on neuroanatomical variation in humans

Cited by 35 publications

References 68 publications

White matter microstructure shows sex differences in late childhood: Evidence from 6,797 children

White matter microstructure shows sex differences in late childhood: Evidence from 6,797 children

Sex-Related Neurocircuitry Supporting Camouflaging in Adults with Autism: Female Protection Insights

The molecular genetic landscape of human brain size variation

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