$5 million grant funds dyslexia study

Jeffrey R. Gruen, M.D., a School of Medicine scientist whose discovery of a gene involved in dyslexia was named one of the top 10 scientific breakthroughs of 2005 by the journal Science, has received a $5.2 million grant from the New York-based Manton Foundation to further his research on the genetics of dyslexia.

The Manton Foundation was established in 1991 by Sir Edwin Manton and his wife, Lady Manton, the former Florence V. Brewer. Born in England in 1909, Edwin Manton, known to friends and colleagues as “Jimmy,” was successively director, executive vice president and senior advisor at American International Group. For his role as a major benefactor of Tate Gallery in London, Manton was knighted in 1994 by Queen Elizabeth II of England. The foundation supports education, health care and medical research.

Gruen, associate professor of pediatrics and of genetics, will use the grant monies to launch a new study that will compare the complete genomes of 1,000 dyslexic children with those of 1,000 fluent readers to obtain a fine-grained view of genes that are known to play a role in reading disabilities, and possibly to identify new genes that confer a risk of developing dyslexia. The ultimate goal of Gruen’s work is to devise a practical genetic test for dyslexia, making it possible for parents and teachers of children with dyslexia to begin educational interventions early in life, the time when researchers have shown those interventions to have the most significant and lasting impact on reading ability. In addition, the new study will enroll children of non-European ancestry, who have been underrepresented in research on the genetics of dyslexia, Gruen says.

“I have a folder full of e-mails from desperate parents who’ve read about our work and hope that I can provide some sage advice to help the third grader who comes home crying in frustration or the bright high school student whose horrible standardized test scores make college seem out of reach,” says Gruen. “These families could be helped through the creation of a simple, inexpensive dyslexia screening test that would apply to the general American population, including groups who have been excluded from dyslexia research up to now. We have the knowledge and the capability to develop such a test.”

Over the past decade, scientists have identified four genes in the “human lexinome” a term Gruen coined for the suite of genes that underlies our species’ unique ability to transmit and extract meaning via speech, writing and reading in which mutations appear to play a significant role in dyslexia, including DCDC2, the gene discovered in Gruen’s lab in 2005.

According to Gruen, there is good reason to believe that these four genes tell much of the genetic story of reading disorders, which affect between 7.5 and 20 percent of the population. “Studies have shown that the number of loci—areas in chromosomes where there is an effect—is very limited,” Gruen says. “So we’re not talking about hypertension, cancer or schizophrenia where there may be 100 genes at work. We’re talking about, maybe, 10. I think it’s likely that these four genes, or even two of the four, will be found to have very large effects.”

Accordingly, with a grant from the National Institute of Neurological Disorders and Stroke, Gruen has launched a study of these four genes using DNA taken from 10,000 English children whose educational performance has been tracked from birth through high school.

By documenting the range of mutations in the four “dyslexia genes” in these children and correlating these variants with reading ability and academic accomplishment, Gruen says, we can begin to assign the relative risk each gene and variant contribute to the development of dyslexia, a necessary component for any future genetic test to be of value.

In another effort to establish how gene variants change the way in which the brain decodes and interprets written language, Gruen has begun a series of “imaging-genetics” studies. Using functional magnetic resonance imaging (fMRI) to record brain activation in specific reading centers of the brain in awake, alert subjects, his group is linking individual differences in brain activity during specific reading tasks to particular genetic variations.

Unlike the study of the English children, which specifically targets four genes, the project underwritten by the new Manton Foundation grant will be a genome-wide association study, or GWAS (“gee-wahs”), exploring the entire genomes of the 2,000 study subjects at a fine level of detail.

In addition to finding new variants in the four previously discovered genes, some of which may not yet have been uncovered in European-American populations, Gruen says that the wide net cast by the GWAS method may unveil entirely new genes that confer a risk of developing reading disabilities.

The new grant will also fund fMRI research on a subgroup of 200 subjects, which Gruen says will be the largest imaging-genetics study of dyslexia to date.

While juggling these multiple scientific endeavors, Gruen keeps his eye on the prize of an eventual genetic test for dyslexia. “Unfortunately a lot of kids, possibly as many as a third, are missed—either misdiagnosed or not diagnosed at all. Now you’ve got a kid who hits fourth or fifth grade and they’re struggling; their self-esteem begins to diminish, and it almost becomes a self-fulfilling prophecy,” Gruen says.

“If you can identify these kids early, by third grade, and get them into an intervention program, you can frequently get them reading up to grade-level, and that effect is long-lasting. That’s a wonderful thing.”

Gruen says that the School of Medicine, which combines scientific prowess with an interdisciplinary, collegial spirit, has been an ideal incubator for his ideas.

“It’s all here,” he says. “It’s a unique confluence of strength in genetics, dyslexia, imaging and neurobiology. I don’t think there’s another place where I could have been where this work would have come together like it has.”