Pleiotropy between language impairment and broader behavioral disorders—an investigation of both common and rare genetic variants

Journal of Neurodevelopmental Disorders

Vivek Appadurai¹  Alfonso Buil¹  Ron Nudel²  Thomas Werge³  Merete Nordentoft⁴ 

[1] Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark;The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark;Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark;The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark;CORE - Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark;Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark;The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark;Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark;CORE - Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark;Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;

关键词: Specific language impairment;    Autism spectrum disorder;    Attention deficit/hyperactivity disorder;    Schizophrenia;    Polygenic risk score;    Exome sequencing;   

DOI  :  10.1186/s11689-021-09403-z

来源: Springer

【 摘 要 】

BackgroundLanguage plays a major role in human behavior. For this reason, neurodevelopmental and psychiatric disorders in which linguistic ability is impaired could have a big impact on the individual’s social interaction and general wellbeing. Such disorders tend to have a strong genetic component, but most past studies examined mostly the linguistic overlaps across these disorders; investigations into their genetic overlaps are limited. The aim of this study was to assess the potential genetic overlap between language impairment and broader behavioral disorders employing methods capturing both common and rare genetic variants.MethodsWe employ polygenic risk scores (PRS) trained on specific language impairment (SLI) to evaluate genetic overlap across several disorders in a large case-cohort sample comprising ~13,000 autism spectrum disorder (ASD) cases, including cases of childhood autism and Asperger’s syndrome, ~15,000 attention deficit/hyperactivity disorder (ADHD) cases, ~3000 schizophrenia cases, and ~21,000 population controls. We also examine rare variants in SLI/language-related genes in a subset of the sample that was exome-sequenced using the SKAT-O method.ResultsWe find that there is little evidence for genetic overlap between SLI and ADHD, schizophrenia, and ASD, the latter being in line with results of linguistic analyses in past studies. However, we observe a small, significant genetic overlap between SLI and childhood autism specifically, which we do not observe for SLI and Asperger’s syndrome. Moreover, we observe that childhood autism cases have significantly higher SLI-trained PRS compared to Asperger’s syndrome cases; these results correspond well to the linguistic profiles of both disorders. Our rare variant analyses provide suggestive evidence of association for specific genes with ASD, childhood autism, and schizophrenia.ConclusionsOur study provides, for the first time, to our knowledge, genetic evidence for ASD subtypes based on risk variants for language impairment.

【 授权许可】

CC BY