A study of more than a million people reveals the genetic basis of stuttering.

The largest genetic analysis of stuttering has demonstrated a clear genetic basis for this speech disorder. The study, published in the journal Nature Genetics , used data from more than one million people whose DNA was analyzed.

The findings point to 57 distinct genomic loci associated with stuttering and suggest a shared genetic architecture between stuttering, autism, depression, and musicality.

The results lay the groundwork for future research that could lead to earlier identification or therapeutic advances in stuttering.

More broadly, researchers at the Vanderbilt Genetics Institute (USA) acknowledge, a better understanding of the causes of stuttering could replace outdated ideas about stuttering, often held by the general public and which contribute to stigma .

Stuttering, characterized by repetitions of syllables and words, prolonged sounds, and pauses between words, is the most common fluency disorder, affecting more than 400 million people worldwide, according to Jennifer Below, the study's leader. However, the causes of this common speech disorder are unclear.

" No one really understands why someone stutters; it's been a complete mystery . And this applies to most speech-language pathologies. They've been very little studied because they don't require hospitalization, but they can have enormous consequences for people's quality of life," Below notes.

"We need to understand the risk factors for speech and language disorders so we can identify children early and provide appropriate care to those who need it."

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

"There have been hundreds of years of misconceptions about the causes of stuttering, from ideas about being left-handed to childhood trauma and overbearing mothers," Below says. "Rather than it being caused by personal or family defects or intelligence, our study shows that stuttering is influenced by our genes."

Below's team began exploring the genetics of stuttering more than two decades ago. Working with colleagues around the world, they collected blood and saliva samples for genetic studies from more than 1,800 people who stutter as part of the International Stuttering Project . However, the project did not have enough participants to support a large-scale genome-wide association study (GWAS).

That's where 23andMe Inc. came in. They were able to analyze data from 99,776 cases (people who answered "yes" to the question about stuttering) and 1,023,243 controls (who answered "no") who participated in a survey conducted by the company.

Developmental stuttering typically appears in children between the ages of 2 and 5, and approximately 80% of these children recover spontaneously , with or without speech therapy. Initially, stuttering affects nearly equal numbers of males and females, but it is more common in adolescent and adult males (a 4:1 male-female ratio) due to sex differences in the rate of spontaneous recovery. Because of this difference in prevalence between males and females, researchers conducted GWAS studies in eight sex- and ancestry-specific groups, followed by meta-analyses that combined the findings.

They identified 57 distinct genomic loci, which were mapped to 48 genes, associated with stuttering risk. The genetic signatures differed between men and women, which could be related to persistent stuttering versus recovered stuttering, Below notes. A yes response to the 23andMe stuttering question in adults would likely reflect current stuttering in a man and memory of stuttering in a woman, she explains.

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

They also identified other traits that had 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 “biggest hit” for genes associated with stuttering in males was the VRK2 gene, which was also the biggest hit in a GWAS of rhythm entrainment (i.e., the self-reported ability to clap to a beat) and in a study of language impairment 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 may be a shared genetic basis—that the brain architecture that controls our musicality, speech, and language may be part of a common pathway,” he says. “Beginning to understand at the biochemical, molecular, and cellular levels what defines us as a species—our ability to communicate—is fascinating, and we hope this will spur further studies of this gene and its function in the brain,” explains Dillon Pruett, co-author of the study.

"There are many unanswered questions about stuttering, and as someone personally affected by it, I wanted to contribute to this research," Pruett says. "Our study revealed that there are many genes that ultimately contribute to the risk of stuttering, and we hope to use this knowledge to dispel the stigma associated with stuttering and, hopefully, develop new therapeutic approaches in the future."