title: An Allometric Analysis of Sex and Sex Chromosome Dosage Effects on Subcortical Anatomy in Humans.
abstract: Structural neuroimaging of humans with typical and atypical sex-chromosome complements has established the marked influence of both Yand X-/Y-chromosome dosage on total brain volume (TBV) and identified potential cortical substrates for the psychiatric phenotypes associated with sex-chromosome aneuploidy (SCA). Here, in a cohort of 354 humans with varying karyotypes (XX, XY, XXX, XXY, XYY, XXYY, XXXXY), we investigate sex and SCA effects on subcortical size and shape; focusing on the striatum, pallidum and thalamus. We find large effect-size differences in the volume and shape of all three structures as a function of sex and SCA. We correct for TBV effects with a novel allometric method harnessing normative scaling rules for subcortical size and shape in humans, which we derive here for the first time. We show that all three subcortical volumes scale sublinearly with TBV among healthy humans, mirroring known relationships between subcortical volume and TBV among species. Traditional TBV correction methods assume linear scaling and can therefore invert or exaggerate sex and SCA effects on subcortical anatomy. Allometric analysis restricts sex-differences to: (1) greater pallidal volume (PV) in males, and (2) relative caudate head expansion and ventral striatum contraction in females. Allometric analysis of SCA reveals that supernumerary X- and Y-chromosomes both cause disproportionate reductions in PV, and coordinated deformations of striatopallidal shape. Our study provides a novel understanding of sex and sex-chromosome dosage effects on subcortical organization, using an allometric approach that can be generalized to other basic and clinical structural neuroimaging settings.
authors.affiliation: Developmental Neurogenomics Unit, Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, kirk.reardon@nih.gov.
authors.forename: Paul Kirkpatrick
authors.initials: PK
authors.lastname: Reardon
authors.affiliation: Developmental Neurogenomics Unit, Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Liv
authors.initials: L
authors.lastname: Clasen
authors.affiliation: Department of Psychiatry, University of California San Diego, San Diego, California 92093.
authors.forename: Jay N
authors.identifier: http://orcid.org/0000-0003-2002-8978
authors.initials: JN
authors.lastname: Giedd
authors.affiliation: Developmental Neurogenomics Unit, Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Blumenthal
authors.affiliation: Department of Psychiatry and Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5T 1R8, Canada.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Lerch
authors.affiliation: Computational Brain Anatomy Laboratory, Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, Quebec H4H 1R3, Canada, and Departments of Psychiatry and Biomedical Engineering, McGill University, Montreal, Quebec H3A 1A1, Canada.
authors.forename: M Mallar
authors.initials: MM
authors.lastname: Chakravarty
authors.affiliation: Developmental Neurogenomics Unit, Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Armin
authors.identifier: http://orcid.org/0000-0002-5622-1190
authors.initials: A
authors.lastname: Raznahan
mesh_terms: D000293:Adolescent; D000328:Adult; D000782:Aneuploidy; D001921:Brain / Q000033:anatomy & histology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003342:Corpus Striatum / Q000033:anatomy & histology*; D003430:Cross-Sectional Studies; D005260:Female; D018628:Gene Dosage / Q000502:physiology*; D005917:Globus Pallidus / Q000033:anatomy & histology*; D006801:Humans; D008297:Male; D012727:Sex Characteristics; D012730:Sex Chromosomes / Q000502:physiology*; D013788:Thalamus / Q000033:anatomy & histology*; D055815:Young Adult
keywords: allometry; aneuploidy; morphometry; sex; subcortex