Understanding vulnerability through variability: A longitudinal twin study linking sex differences in neurodiversity, neurodevelopment and X-linked genetic mechanisms

Behavioural Brain Research, vol. 514, pp. 116350

Abstract

There are marked sex differences in the prevalence and expression of neurodiverse conditions, including autism and ADHD. Yet, it is unclear how sex-related mechanisms may affect differences in the expression of symptoms. In the present study, we examine whether previously reported greater male than female variability in neuroanatomy extends to brain development and if X-linked mechanisms are involved, using twin modeling. We further tested whether these observed patterns may be behavioral relevant and linked to symptoms of autism and ADHD. The present study included data from the L-CID study with up to three longitudinal imaging scans from 990 same-sex twin pairs (56% monozygotic, 7-14 yo, 49% females). We replicated greater male than female variability in both cross-sectional and longitudinal data, which was most pronounced for cortical surface area. In line with our hypothesis, twin modeling results support a significant role of X-chromosome expression related to sex differences in neuroanatomical variation. In addition, normative modeling analysis showed that, as predicted, deviations in brain anatomy at both upper and lower ends of the distribution were associated with symptoms of neurodiversity. These findings support a significant and understudied role of the X-chromosome in sex differences in the brain and the need to move beyond binary models to better understand sex-linked vulnerability and protective mechanisms in mental health.

Authors 8

1. M. Wierenga L. Aachen

   Leiden University

   Affiliation as printed

   Institute of Psychology, Leiden University, Leiden, the Netherlands; Leiden Institute for Brain and Cognition, Leiden University, Leiden, the Netherlands. Electronic address: l.m.wierenga@fsw.leidenuniv.nl

2. M. Zabihi

   Radboud University Nijmegen · MRC Unit for Lifelong Health and Ageing · Donders Institute for Brain, Cognition and Behaviour · University College London

   Affiliation as printed

   MRC Unit for Lifelong Health & Ageing, University College London (UCL), London, United Kingdom; Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, the Netherlands

3. Lina van Drunen Aachen

   Leiden University · Erasmus University Rotterdam

   Affiliation as printed

   Institute of Psychology, Leiden University, Leiden, the Netherlands; Leiden Institute for Brain and Cognition, Leiden University, Leiden, the Netherlands; Erasmus School of Social and Behavioral Sciences, Erasmus University, Rotterdam, the Netherlands

4. M. van der Meulen Aachen

   Leiden University

   Affiliation as printed

   Institute of Psychology, Leiden University, Leiden, the Netherlands; Leiden Institute for Brain and Cognition, Leiden University, Leiden, the Netherlands

5. Michelle Achterberg Aachen

   Leiden University · Erasmus University Rotterdam

   Affiliation as printed

   Institute of Psychology, Leiden University, Leiden, the Netherlands; Leiden Institute for Brain and Cognition, Leiden University, Leiden, the Netherlands; Erasmus School of Social and Behavioral Sciences, Erasmus University, Rotterdam, the Netherlands

6. S. Rutherford

   Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour

   Affiliation as printed

   Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, the Netherlands; Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands

7. A.F. Marquand

   Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour

   Affiliation as printed

   Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, the Netherlands; Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands

8. E.A. Crone Aachen

   Leiden University · Erasmus University Rotterdam

   Affiliation as printed

   Institute of Psychology, Leiden University, Leiden, the Netherlands; Leiden Institute for Brain and Cognition, Leiden University, Leiden, the Netherlands; Erasmus School of Social and Behavioral Sciences, Erasmus University, Rotterdam, the Netherlands