Distinct impact modes of polygenic disposition to dyslexia in the adult brain

Dyslexia is a common condition that impacts reading ability. Identifying affected brain networks has been hampered by limited sample sizes of imaging case-control studies. We focused instead on brain structural correlates of genetic disposition to dyslexia in large-scale population data. In over 30,000 adults (UK Biobank), higher polygenic disposition to dyslexia was associated with lower head and brain size, and especially reduced volume and/or altered fiber density in networks involved in motor control, language and vision. However, individual genetic variants disposing to dyslexia often had quite distinct patterns of association with brain structural features. Independent component analysis applied to brain-wide association maps for thousands of dyslexia-disposing genetic variants revealed multiple impact modes on the brain, that corresponded to anatomically distinct areas with their own genomic profiles of association. Polygenic scores for dyslexia-related cognitive and educational measures, as well as attention-deficit/hyperactivity disorder, showed similarities to dyslexia polygenic disposition in terms of brain-wide associations, with microstructure of the internal capsule consistently implicated. In contrast, lower volume of the primary motor cortex was only associated with higher dyslexia polygenic disposition among all traits. These findings robustly reveal heterogeneous neurobiological aspects of dyslexia genetic disposition, and whether they are shared or unique with respect to other genetically correlated traits. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded by the Max Planck Society (Germany) and the Netherlands Organization for Scientific Research (Language in Interaction consortium: Gravitation grant number 024.001.006). The Wellcome Centre for Integrative Neuroimaging (RM) is supported by core funding from the Wellcome Trust [201319/Z/16/Z]. The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript. The study was conducted using the UK Biobank resource under application no. 16066 with C.F. as the principal applicant. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) approval. This approval means that researchers do not require separate ethical clearance and can operate under the RTB approval (there are certain exceptions to this which are set out in the Access Procedures, such as re-contact applications). This RTB approval was granted initially in 2011 and it is renewal on a 5-yearly cycle: hence UK Biobank successfully applied to renew it in 2016 and 2021. UK Biobank will in due course apply for renewal effective in 2026. These renewal applications and approvals are shown on the website. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes