Genetics of stuttering: Largest study ever identifies 57 DNA regions linked to speech disorder

The largest genetic analysis of stuttering has revealed its clear genetic basis and pinpointed neural risk pathways. The study, published July 28 in the journal Nature Genetics, used data from more than 1 million people who underwent genetic testing at 23andMe Inc.

The results point to 57 different genomic loci associated with stuttering and suggest a common genetic architecture for stuttering, autism, depression, and musicality. These findings provide a foundation for further research that could lead to earlier identification or therapeutic advances in the treatment of stuttering. A better understanding of the causes of stuttering may also help replace outdated, stigmatizing views that often exist in society.

Stuttering—characterized by repetition of syllables and words, prolongation of sounds, and gaps between words—is the most common speech disorder, affecting more than 400 million people worldwide, says Jennifer (Piper) Bilow, Ph.D., director of the Vanderbilt Genetics Institute and professor of medicine at Vanderbilt University Medical Center. Yet the causes of this common speech disorder remain unclear.

“Nobody really understood why someone would stutter; it was a complete mystery. And the same is true for most speech and language disorders. They are deeply understudied because they don’t usually result in hospitalization, but they can have huge consequences for people’s quality of life,” says Bilow, who holds the Robert A. Goodwin Jr., MD, Chair in Medicine.

"We need to understand the risk factors associated with speech and language traits so we can identify children early and provide them with appropriate help if they want it."

Young people who stutter report increased levels of bullying, decreased classroom participation, and more negative educational experiences. Stuttering can also negatively impact employment opportunities and perceptions of work, as well as mental and social well-being, Bilow adds.

“There have been hundreds of years of misconceptions about what causes stuttering, from left-handedness to childhood trauma to overprotective mothers,” says Bilow. “Our research shows that stuttering is determined by genes, not by personal or family weaknesses or intelligence.”

Bylow and her longtime collaborator Shelly Jo Kraft, Ph.D., an assistant professor of speech-language pathology and audiology at Wayne State University and a co-author of the paper, began studying the genetics of stuttering more than two decades ago. Working with colleagues around the world, Kraft collected blood and saliva samples from more than 1,800 people who stutter as part of the International Stuttering Project. But the project didn’t have enough participants to conduct a large-scale genomic study (GWAS). That’s where 23andMe came in.

“A friend sent me a picture of a 23andMe survey, and one of the questions was, ‘Have you ever stuttered?’ I thought, ‘Oh my god, if we could get access to this information, it would be a game changer,’” Bilow says. The researchers applied and were selected to collaborate with 23andMe. They analyzed data from 99,776 cases — people who answered “yes” to the stuttering question — and 1,023,243 controls — people who answered “no.”

Stuttering typically begins between the ages of 2 and 5, and about 80% of children will recover on their own, with or without therapy. Boys and girls stutter at about the same rate at onset, but boys tend to stutter more often in adolescence and adulthood (ratio about 4:1), due to differences in spontaneous recovery rates between the sexes. Because of this sex difference, the researchers conducted a GWAS analysis on eight groups divided by sex and ethnicity, then pooled the results in a meta-analysis.

They identified 57 unique genomic loci that corresponded to 48 genes associated with risk of stuttering. The genetic signatures differed between men and women, which may be related to persistent versus recovered stuttering, Bilow explains. Answering “yes” to the question about stuttering in adults likely reflects current stuttering in men and memories of stuttering in women, she adds.

The researchers also constructed a polygenic risk score for stuttering based on the GWAS results and applied it to participants in the International Stuttering Project clinical cohort and another self-reported stuttering cohort (Add Health). They found that the risk score calculated based on genetic signals in males, but not in females, predicted stuttering in both males and females in two independent data sets.

“It’s possible that what we’re measuring in women in the 23andMe data is distorted by memory differently than what we’re measuring in men, but we can’t tell with the data we have,” Bilow says. “We hope these results will prompt more sophisticated and detailed studies of stuttering recovery and the impact of gender.”

The scientists also studied other traits previously associated with the identified stuttering genes and found links to neurological traits, metabolic disorders (obesity, endocrine and metabolic traits), cardiovascular traits, and others.

The most significant genomic signal associated with stuttering in men was the VRK2 gene, which was also found to be most significant in a GWAS of rhythm synchronization (self-reported ability to clap to the beat) and in a study of language decline in people with Alzheimer's disease, Bilow says.

"Historically, we've thought of musicality, speech and language as three separate entities, but these studies suggest that there may be a common genetic basis - the brain architecture that controls musicality, speech and language may be part of a single pathway," she says.

“Beginning to understand at the biochemical, molecular and cellular level what makes us as a species – our ability to communicate – is incredibly exciting, and we hope it will stimulate new research into this gene and its function in the brain.”

Dr. Dillon Pruitt, Ph.D., a postdoc and co-author of the study, stutters himself.

“There are still a lot of questions about stuttering, and as someone who has it, I wanted to contribute to this body of research,” he says. “Our research has shown that many genes ultimately influence the risk of stuttering, and we hope to use this knowledge to help remove the stigma associated with stuttering and perhaps develop new treatment approaches in the future.”