Poster abstracts

Poster number 37 submitted by Tabatha Simmons

Multivariate and multilocus genetic analysis of specific language

Tabatha R. Simmons (Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Childrens Hospital, Columbus, Ohio), J. F. Flax (Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ, and Department of Genetics, Rutgers University, Piscataway, NJ), A. S. Bassett (Department of Psychiatry, University of Toronto, and Schizophrenia Research Program, Queen Street Division, Centre for Addiction and Mental Health, Toronto), P. Tallal (Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ), L. M. Brzustowicz (Department of Genetics, Rutgers University, Piscataway, NJ), C. W. Bartlett (Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Childrens Hospital, Columbus, Ohio)

Abstract:
SLI is a heritable developmental language disorder occurring in absence explanatory factors and is characterized by significant problems of comprehension and/or expression of spoken language. We have previously found compelling evidence for an SLI susceptibility locus using a reading impairment (RI) variable on 13q21-22 with a PPL of 53% (LOD=3.92) and a replication PPL of 17% (LOD=2.62). Joint analysis resulted in a PPL of 96.9% (LOD=7.86), further showing strong evidence of linkage to 13q21. Despite the overwhelming evidence for a susceptibility allele in 13q21, prima fascia, it is unclear how “reading impairment” relates to either SLI or quantitative measures of language at this locus. We therefore performed a joint analysis with a model implicitly assuming RI is at the low end of the language score distribution. We also performed the complimentary linkage analysis where language impairment (LI) was analyzed with several quantitative reading measures. Results show a clear dissociation that is consistent with our hypothesis – (in our sample) RI is due to either an underlying LI or both reading and language deficits are caused by the same (similar) underlying factors.

We additionally tested for epistasis with a coding variant in the brain-derived neurotrophic factor (BDNF) gene, shown to be involved in working memory in mice and humans. The inclusion of this gene into an interaction model greatly increases our evidence for an SLI susceptibility allele within 13q21, indicating an interaction between this BDNF SNP and the uncloned 13q21 variant. Our results show an overwhelming linkage signal to 13q21 allowing for us to further narrow our region down to clone the susceptibility allele. Additionally, the BDNF finding will aid us in proposing a possible pathway by which BDNF is contributing to SLI.

References:
Bartlett CW, Flax JF, Logue MW, Smith BJ, Vieland VJ, Tallal P, Brzustowicz LM (2004) Examination of potential overlap in autism and language loci on chromosomes 2, 7, and 13 in two independent samples ascertained for specific language impairment. Hum Hered 57:10-20.
Bartlett CW, Flax JF, Logue MW, Vieland VJ, Bassett AS, Tallal P, Brzustowicz LM (2002) A major susceptibility locus for specific language impairment is located on 13q21. Am J Hum Genet 71:45-55
Bartlett CW, Vieland VJ (2007) Accumulating quantitative trait linkage evidence across multiple datasets using the posterior probability of linkage. Genet Epidemiol 31:91-102

Keywords: Genetics, Language, BDNF