Discovery of 36 loci significantly associated with stuttering

Abstract Developmental stuttering is a common speech disorder (studies estimate at least a 5% lifetime prevalence) characterized by prolongations, blocks, and repetitions of speech sounds. In approximately 75–80% of cases in early childhood, stuttering will resolve within a few years (referred to as ‘recovery’); the remaining cases will often experience stuttering into school-age years and adulthood (referred to as ‘persistence’). In adults, the prevalence of stuttering is substantially higher in men compared to women, at a ratio of 4:1 or greater (compared to between 1:1 and 2:1 in young children); this has typically been explained by differences in likelihood of recovery by sex. Heritability studies have established that a genetic component for stuttering exists, with heritability estimates as high as 84%. However, genetic factors impacting stuttering risk remain largely uncharacterized. To date, only two prior genome-wide association studies (GWAS) of developmental stuttering have been published, both of which included less than 10,000 cases. Here, we performed eight self-reported stuttering GWAS that were stratified by sex and ancestries. These analyses included more than 1 million individuals (99,776 cases and 1,023,243 controls) and identified 36 unique genome-wide significant loci. We validated the self-reported stuttering phenotype using polygenic risk scores from two independent stuttering datasets. We examined genetic correlation of our GWAS results with published GWAS for other previously identified comorbid traits and found strong evidence of correlation with hearing loss, daytime sleepiness, depression, and poorer beat synchronization. We also performed Mendelian randomization analyses which revealed distinct causal relationships in males and females for genetically associated traits. These distinct causal relationships motivate continued research into sex-specific phenotypic differences, with emphasis on recovery status. Additionally, a high proportion of genes impacting stuttering risk were found to be associated with neurological traits from the GWAS catalog, supporting a neurological basis for stuttering. Our findings provide the first well-powered insight into genetic factors underlying stuttering, representing a major step forward in our understanding of this condition.