Largest genetic study confirms biological basis of stuttering

The largest genetic analysis of stuttering has demonstrated a clear genetic basis for the speech disorder, highlighting neurological pathways of risk. The study, published July 28 in the journal Nature Genetics, used data representing more than 1 million individuals who had their DNA analyzed by the company 23andMe Inc. 

The findings point to 57 distinct genomic loci associated with stuttering and suggest a shared genetic architecture of stuttering with autism, depression and musicality. The results provide a foundation for additional research that could lead to earlier identification or therapeutic advances in stuttering. More broadly, improving understanding of the causes of stuttering may replace outdated views of stuttering often held by the general public that contribute to stigma. 

Stuttering - characterized by syllable and word repetitions, sound prolongations, and breaks between words - is the most common fluency disorder, with more than 400 million people affected worldwide, said Jennifer (Piper) Below, PhD, director of the Vanderbilt Genetics Institute and professor of Medicine at Vanderbilt University Medical Center. And yet, the causes of this common speech disorder are unclear. 

"No one really understands why someone stutters; it has been a complete mystery. And that's true for most speech and language pathologies. They are profoundly understudied because they don't put people in the hospital, but they can have enormous consequences on people's quality of life," said Below, who holds the Robert A. Goodwin Jr., MD Directorship in Medicine. "We need to understand risk factors for speech and language traits so that we can identify kids early and get appropriate care for those that want it." 

Young people who stutter report increased bullying, decreased classroom participation, and a more negative educational experience. Stuttering can also negatively impact employment opportunities and perceived job performance, and mental and social well-being, Below noted. 

There have been hundreds of years of misconceptions about what causes stuttering - from ideas about left-handedness to childhood trauma to overbearing mothers. Rather than being caused by personal or familial failings or intelligence, our study shows that stuttering is influenced by our genes." 

Jennifer (Piper) Below, PhD, director of the Vanderbilt Genetics Institute and professor of Medicine at Vanderbilt University Medical Center

Below and her longtime collaborator Shelly Jo Kraft, PhD, associate professor of Speech Language Pathology & Audiology at Wayne State University and a co-author of the Nature Genetics paper, first began exploring the genetics of stuttering more than two decades ago. Working with colleagues around the world, Kraft collected blood and saliva samples for genetic studies from more than 1,800 people who stutter as part of the International Stuttering Project. But the project didn't have enough participants to support a large-scale genome-wide association study (GWAS). That's where 23andMe Inc. came in. 

"A friend sent me a picture of the 23andMe survey questions, and one was 'Have you ever had a stutter or stammer?' I thought, oh my gosh, if we can get access to this case-control information, it will be game-changing," Below said. The researchers applied and were selected for a collaborative partnership with 23andMe Inc. They analyzed data for 99,776 cases - people who answered "yes" to the stutter or stammer question - and 1,023,243 controls who answered "no." 

Developmental stuttering onset typically occurs in children between ages 2 and 5, and about 80% of children will spontaneously recover, with or without speech therapy. At its onset, stuttering affects about even numbers of males and females, but it is more common in adolescent and adult males (4-1 ratio of males to females) because of differences in the rate of spontaneous recovery by sex. Because of this difference in male-to-female prevalence, the researchers conducted GWAS studies on eight sex- and ancestry-specific groups, followed by meta-analyses that combined the findings. 

They identified 57 distinct genomic loci, which mapped to 48 genes, associated with stuttering risk. The genetic signatures differed between males and females, which could relate to persistent stuttering versus recovered stuttering, Below said. A "yes" answer to the 23andMe stuttering question from adults would be more likely to reflect current stuttering in a male and recalled stuttering in a female, she explained. 

The researchers used their GWAS results to construct a polygenic risk score for stuttering and applied the score to participants in the clinically ascertained stuttering cohort (International Stuttering Project) and another cohort of self-reported stuttering (Add Health). They found that a polygenic risk score derived from the genetic signals in males, but not females, predicted stuttering for both males and females in the two independent datasets. 

"It may be that what we're measuring in females in the 23andMe data is differently confounded by recall compared to what we are measuring in men, but we can't determine that with the data we have," Below said. "We hope these results will motive intricate, detailed future studies of stuttering recovery versus sex." 

The researchers also determined other traits that have been previously associated with the genes they identified for stuttering and found associations with neurological traits, obesity/endocrine/metabolic traits, cardiac/circulatory traits, and others. 

The "top hit" for genes associated with stuttering in males was the gene VRK2, which was also the top hit in a GWAS of beat synchronization (i.e., self-reported ability to clap to a beat) and in a study of language decline in people with Alzheimer's disease, Below said. 

"Historically, we've thought of musicality, speech and language as three separate entities, but these studies suggest there might be a shared genetic underpinning - that the architecture of the brain that controls our musicality, our speech and our language might be all part of a shared pathway," she said. "To begin to understand at a biochemical, molecular, cellular level what makes us who we are as a species - our capacity for communication - is incredibly cool, and we hope this will spur additional studies of this gene and its function in the brain." 

Dillon Pruett, PhD, a postdoctoral fellow and co-author of the study, stutters. 

"There are a lot of unanswered questions about stuttering, and as someone personally affected, I wanted to contribute to this body of research," he said. "Our study found that there are many genes that ultimately contribute to stuttering risk, and we hope to use this knowledge to dispel stigma related to stuttering and also to hopefully develop new therapeutic approaches in the future." 

Co-first authors of the Nature Genetics paper are Hannah Polikowsky, PhD, Alyssa Scartozzi and Douglas Shaw, PhD, from the Vanderbilt Genetics Institute. The research was supported by the National Institutes of Health (grants R03DC015329, R01DC017175, R21DC016723, R01DC020311, TL1TR002244 and F31DC022482).