Challenges and Opportunities in Characterizing the Genetics of Stuttering: From Sample Acquisition to Functional Interpretation of the Genome.

Purpose: Converging etiological evidence supports a genetic risk for developmental stuttering; however, major gaps detailing the genetic architecture remain. Technological advances in genetics have allowed us to explore novel approaches to analyzing this complex trait, but conducting robust and replicable genetic studies requires large, well-phenotyped cohorts of subjects. This article reviews previous research strategies employed to overcome these challenges in identifying genetic variants associated with stuttering and translating stuttering-associated variants into molecular and cellular mechanisms.

Method: We present an overview of data sources and strategies research teams have utilized for the genetic study of stuttering, highlighting the advantages and limitations of each approach. Primary data sources include (a) the International Stuttering Project, (b) the National Longitudinal Study of Adolescent to Adult Health, (c) BioVU, and (d) 23andMe, Inc. In addition to genome-wide association studies (GWASs), we review multiple post-GWAS follow-up analyses to probe the functional impact of stuttering-associated genetic variants and offer new transcriptome-wide analyses.

Results: To date, a diverse array of approaches has resulted in the identification of over 50 stuttering-associated genes. Many genetic associations were near or within genes previously linked to known neurological traits, highlighting a neurological role in stuttering. Additionally, validation studies using polygenic risk scores suggested a high level of genetic concordance between our samples. Functional follow-up studies suggest stuttering-associated variants may affect gene expression in tissues relevant to speech-related structures and neural correlates.

Conclusions: While understanding how specific regions of the genome contribute to stuttering risk remains complex, research from our team and others has utilized a variety of data sources in an attempt to overcome previous limitations in the identification of genetic variation associated with stuttering. As the field of genetics evolves toward large-scale biobanks for research and discovery, prioritizing inclusion of traits such as stuttering will be key.

Supplemental material: https://doi.org/10.23641/asha.30299764.