Stuttering Comorbidities and Genetic Associations Identified Using Electronic Health Records

Abstract

Developmental stuttering, a speech condition characterized by syllable repetitions and prolongations and involuntary pauses that disrupt the forward flow of speech, has a population prevalence of approximately 1%. Stuttering is considerably more common in males with a male-to-female ratio of 2:1 in children under 4 years of age and a ratio of nearly 5:1 in adolescents and adults. Emerging evidence suggests a high incidence of comorbid conditions for individuals who stutter. Additionally, studies of stuttering within families, twins, and population isolates provide evidence for a strong genetic influence on stuttering risk. Despite incurring significant personal, educational, and professional cost, the proximal cause of developmental stuttering remains obscure. The investigations described in Study 1 (Chapter II) and Study 2 (Chapter III) employ electronic health records (EHRs) and EHR-linked biobanks to study stuttering comorbidities and genetic variants associated with the condition to advance the understanding of biological mechanisms related to the condition. Specifically, Study 1 uses EHRs to explore stuttering comorbidities and builds a comorbidity-based stuttering prediction model. Study 2 builds on Study 1 and uses EHRs linked to a DNA biobank to identify sex-specific comorbidities and genetic variants associated with stuttering. Study 1 revealed a variety of expected and novel conditions associated with stuttering within EHRs. These associated comorbidities were then used in a machine learning model to predict stuttering within EHRs independent of traditional clinical notation. Study 2 demonstrated significant overlap in comorbidities between males and females, with a greater number of neurological, psychological, and cardiovascular conditions reaching suggestive significance in females. In the genome-wide association study, one locus on chromosome 7 reached the suggestive significance and implicated MAGI2, a membrane-associated guanylate kinase gene involved in the development and function of numerous tissues, including synaptic plasticity in the mammalian brain. Collectively, these findings continue to illuminate the biological underpinnings of stuttering. Genetics may provide a mechanistic framework for integrating findings across domains of stuttering research, with the ultimate goal of enhancing identification, assessment, and treatment approaches.