Update on genetics research

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Update on genetics research

• Dennis Drayna, PhD
• NIDCD/National Institutes of Health
• US Public Health Service, DHHS

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Who are we?

• National Institute on Deafness and Other
  Communication Disorders
• National Institutes of Health
• U.S. Public Health Services
• U.S. Department of Health and Human Services
• Your tax dollars at work

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Difficulties in stuttering research

• Disorder presents only in humans
• Cannot be studied in model organisms
• Cannot be studied in cells in a dish
• Disorder has its origins in the brain
• Inaccessible for research

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Fact 1- Not all stuttering is genetic

• Of the people who come to stuttering therapy,
  about half report a family history and half have
  no family history
• So, perhaps half of stuttering is due to genetic
  factors
• The other half is due to unknown causes
• Low birth weight, perinatal hypoxia

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Fact 2 - Genes do not entirely control
stuttering in anyone

• Severity varies from day to day, and in children,
  from month to month
• Stuttering therapy can largely eliminate
  stuttering
• Their genes have not changed

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The power of genetics

• If a disorder is genetic in origin, we can find
  the gene that causes the disorder
• Once we have the gene, we can see what the gene
  codes for, and what the gene product does, both
  normally and in individuals who stutter
• Can lead us to the cells and molecules involved
  in the disorder

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Evidence for genetic factors in stuttering

• Twin studies
• Adoption studies
• Family clusters of stuttering
• Segregation analysis

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NIH genetics research

• Genetic linkage studies
• Performed in families
• Applicable to any inherited disorder
• Identify the location of the gene or genes that
  cause the disorder

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NIH linkage studies

• North American families
• Pakistani families
• West African families

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North American linkage study

• Found weak evidence of a location on chromosome
  18
• Most of the evidence came from a single family
• Conclusion - there is no single common gene that
  causes stuttering in the general population

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Pakistan linkage study

• 70 of all marriages are between either 1st or
  2nd cousins
• This marriage pattern has persisted for over 1000
  years
• Sought stuttering families through the school
  system
• Identified 100 families, chose 44 for our linkage
  study

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NIH genetic linkage studies Pakistani families
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Can we find the gene?

• Focus on the region on chromosome 12 in Pakistani
  families
• Additional analysis of the region in a group of
  unrelated Pakistani individuals who stutter

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West African linkage study

• Identified a large family cluster via the Online
  Symposium sponsored by the Stuttering Home Page
• Family resides in Cameroon
• English speaking, highly educated
• Ultimately found other large families with many
  cases of stuttering

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Cameroon Family 1
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Can we find the gene?

• Focus on the region on chromosome 1 in African
  families
• Also gather a group of unrelated Cameroonian
  individuals who stutter

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Beyond linkage studies

• Association studies
• Study unrelated individuals rather than families
• Rely on variant genes that are relatively common
  in the population

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NIH Genetic Association Study

• Enroll subjects nationwide
• Must have a family history of stuttering
• Must stutter beyond childhood
• Total of 476 subjects enrolled to date
• Goal is to test 1 million genetic markers in each
  individual

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Future

• Detailed evaluation of candidate genes on
  chromosomes 1 and 12
• Large-scale association studies
• Pharmacogenetics
• Pagoclone efficacy

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Acknowledgments

• NIDCD
• Bailey Levis
• Naveeda Riaz
• Changsoo Kang
• NISC/NHGRI
• Alice Young
• Jim Mullikan
• Hollins Communications Research Institute
• Jennifer Mundorff
• University of Chicago
• Stacy Steinberg
• Anna Pluzhnikov
• Nancy Cox

• CEMB/University of the Punjab
• Jamil Ahmad
• Hashim Raza
• S. Riazuddin
• SCAC Cameroon
• Joseph Lukong
• Stuttering Research Subjects worldwide