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X-chromosome influences on neuroanatomical variation in humans

Abstract

The X-chromosome has long been hypothesized to have a disproportionate influence on the brain based on its enrichment for genes that are expressed in the brain and associated with intellectual disability. Here, we verify this hypothesis through partitioned heritability analysis of X-chromosome influences (XIs) on human brain anatomy in 32,256 individuals from the UK Biobank. We first establish evidence for dosage compensation in XIs on brain anatomy—reflecting larger XIs in males compared to females, which correlate with regional sex-biases in neuroanatomical variance. XIs are significantly larger than would be predicted from X-chromosome size for the relative surface area of cortical systems supporting attention, decision-making and motor control. Follow-up association analyses implicate X-linked genes with pleiotropic effects on cognition. Our study reveals a privileged role for the X-chromosome in human neurodevelopment and urges greater inclusion of this chromosome in future genome-wide association studies.

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Fig. 1: Regional patterning of X-chromosome dosage compensation and links to sex differences in anatomical variance for cortical SA.
Fig. 2: Regional patterning of XIs on cortical SA.
Fig. 3: Topographic annotation of XIs on cortical SA.
Fig. 4: X-linked genes associated with regional SA phenotypes with enriched XIs.

Data availability

No data were collected as part of this study. All genetic and phenotypic data (including neuroimaging data) are available from the UKB via their standard data access procedure, as described at https://www.ukbiobank.ac.uk/register-apply. The Neurosynth data for topic-based meta-analyses are available at https://neurosynth.org/analyses/topics/. The PsychENCODE data for developmental expression analyses are available at http://development.psychencode.org. XWA summary statistics are available at https://osf.io/cqxdj/.

Code availability

No custom software was used in this study. All relevant software and code are described in the text and can be found at the URLs or references cited.

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute of Mental Health (NIH annual report number ZIA MH002949-04), and conducted using the UKB resource under application number 22875. We thank the UKB participants for making this study possible.

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Authors

Contributions

T.T.M. and A.R. conceived and designed the study. A.R. oversaw the study. T.T.M. was the lead analyst responsible for conducting all genetically informative analyses. S.L. conducted the topographic annotation analyses and spin tests. J.S. assisted with the expression analyses in the PsychENCODE dataset. T.T.M. and S.L. prepared the figures and tables. T.T.M. prepared the genetic data, while J.S., Z.M., D.M. and A.T. prepared the neuroimaging data. T.T.M. and A.R. led the writing of the manuscript, and all authors provided valuable feedback and advice during its preparation.

Corresponding author

Correspondence to Armin Raznahan.

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The authors declare no competing interests.

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Peer review information Nature Neuroscience thanks Jason Stein and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Distributions of X-linked heritability in males and females for regional measures of brain anatomy.

Raincloud-style plot that considers all regional measures of brain anatomy where the full dosage compensation model was the best fitting model (n = 1,840 sex-stratified heritability estimates). X-linked heritability for males and females was independently estimated within each sex in a model-naïve manner (Methods). The median X-linked heritability in males is 2.37 times larger (bootstrapped 95% CI = 1.70-3.25) than the median X-linked heritability in females (two-sided Wilcoxon P = 1.18e-23). Summary statistics for males: minimum = 1e-6, Q1 = 3.98e-4, median = 6.34e-3, Q3 = 1.3e-2, maximum = 3.64e-2. Summary statistics for females: minimum = 1e-6, Q1 = 1e-6, median = 2.67e-3, Q3 = 7.48e-3, maximum = 3.34e-2.

Extended Data Fig. 2 Regional patterning of X-chromosome dosage compensation for cortical volume (CV).

a, Categorical map showing the best-fitting X-chromosome dosage compensation model for each cortical region. NDC = no dosage compensation, EV = equal variance, FDC = full dosage compensation. b, Continuous map showing regional variation in the strength of statistical evidence for X-chromosome dosage compensation on CV, as indexed by ΔAICDC (Methods). ΔAICDC equals zero when the EV model fits best, and departures from zero reflect quantitative evidence for either NDC or FDC. Values ≤ -10 are indicative of strong evidence for NDC while values ≥ +10 are indicative of strong evidence for FDC. Any values less than −10 or greater than 10 were set to −10 and 10, respectively, for illustration.

Extended Data Fig. 3 Regional patterning of X-chromosome dosage compensation for cortical thickness (CT).

a, Categorical map showing the best-fitting X-chromosome dosage compensation model for each cortical region. NDC = no dosage compensation, EV = equal variance, FDC = full dosage compensation. b, Continuous map showing regional variation in the strength of statistical evidence for X-chromosome dosage compensation on CT, as indexed by ΔAICDC (Methods). ΔAICDC equals zero when the EV model fits best, and departures from zero reflect quantitative evidence for either NDC or FDC. Values ≤ -10 are indicative of strong evidence for NDC while values ≥ +10 are indicative of strong evidence for FDC. Any values less than −10 or greater than 10 were set to −10 and 10, respectively, for illustration.

Extended Data Fig. 4 Regional patterning of X-chromosome influences (XIs) on cortical volume (CV).

a, Continuous map of total SNP heritability \((h_{\mathrm{g}}^2)\) for regional CV. b, Continuous map of X-linked heritability \((h_{\mathrm{x}}^2)\) for regional CV. c, Continuous map of regional ratio between the observed proportion of total heritability assigned to the X-chromosome, and the expected proportion from X-chromosome size (XI ratio). Values greater than one reflect enriched XIs and values less than one reflect depleted XIs (Methods).

Extended Data Fig. 5 Regional patterning of X-chromosome influences (XIs) on cortical thickness (CT).

a, Continuous map of total SNP heritability \((h_{\mathrm{g}}^2)\) for regional CT. b, Continuous map of X-linked heritability \((h_{\mathrm{x}}^2)\) for regional CT. c, Continuous map of regional ratio between the observed proportion of total heritability assigned to the X-chromosome, and the expected proportion from X-chromosome size (XI ratio). Values greater than one reflect enriched XIs and values less than one reflect depleted XIs (Methods).

Extended Data Fig. 6 Comparison of the enrichment ratio for X-chromosome influences (XIs) on three morphological features of the cortex.

a, Ranked scatter plot of the regional XI enrichment ratio for cortical surface area, volume, and thickness, where the 358 cortical regions are ranked by their XI enrichment ratio for surface area. b,c,d, Scatter plots of the regional XI enrichment ratio for (b) surface area and volume, (c) thickness and volume, and (d) thickness and surface area.

Extended Data Fig. 7 Comparison of the enrichment Z statistic for X-chromosome influences (XIs) on three morphological features of the cortex.

a, Ranked scatter plot of the regional XI enrichment Z-statistic for cortical surface area, volume, and thickness, where the 358 cortical regions are ranked by their XI enrichment Z-statistic for surface area. b,c,d, Scatter plots of the regional XI enrichment Z-statistic for (b) surface area and volume, (c) thickness and volume, and (d) thickness and surface area.

Extended Data Fig. 8 Statistically-significant depletion and enrichment of X-chromosome influences (XIs) on three morphological features of the cortex.

a,b,c, Categorical maps showing the regions of statistically significant depletion or enrichment of XIs (after correction for multiple comparisons) on (a) cortical surface area, (b) cortical volume, and (c) cortical thickness.

Extended Data Fig. 9 Sensitivity analyses for observed X-chromosome influences (XIs) on cortical surface area (SA).

a, Cross-region of interest (ROI) correlation in the XI Z-statistic for SA between first and second releases of UKB neuroimaging data. b, Distribution of cross-ROI correlations in the XI Z-statistic for SA for 100 split-halves of the UKB dataset. c, Cross-ROI correlation in the XI Z-statistic for SA between UKB analyses differing in minor allele frequency (MAF) threshold. d, Continuous map of XI enrichment ratio for SA as computed in the 308-parcellation. e, Observed cross-ROI correlation (dashed line) in the 308-parcellation between XI Z-statistics computed in the 308-parcellation vs. those projected into the 308-parcellation from values computed in the primary HCP atlas. Density plot shows a null distribution of these correlations from 10,000 rotational permutations ‘spins’ of the 308 map. The observed correlation (two-sided Pearson’s r = .76) is significantly elevated relative to this null distribution (Pspin < 1e-4) (Methods).

Extended Data Fig. 10 X-linked SNPs associated with regional surface area phenotypes with enriched X-chromosome influences (XIs).

An X-chromosome-wide Manhattan plot of the minimum P-value for each SNP across all tested phenotypes. The x-axis refers to the chromosomal position, the y-axis refers to the significance of the SNP-based association test as a -log10 P-value, the horizontal dashed line denotes genome-wide significance (P = 5e-8), and the horizontal two-dashed line denotes a more conservative significance threshold accounting for all tested phenotypes (P = 8.93e-10).

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Mallard, T.T., Liu, S., Seidlitz, J. et al. X-chromosome influences on neuroanatomical variation in humans. Nat Neurosci 24, 1216–1224 (2021). https://doi.org/10.1038/s41593-021-00890-w

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