General cognitive ability (""""""""g"""""""") is one of the most heritable behavioral traits. The present application requests renewal (Years 07-09) of the first study (HD27694) attempting to identify some of the specific genes (quantitative trait loci, QTLs) responsible for this heritability. The study uses an allelic association strategy with extreme selected groups in order to achieve the statistical power needed to identify QTLs of small effect size. The first grant (Years 01-03) established samples of 51 high """"""""g"""""""" subjects (2SD) at least two standard deviations above the mean (e.g., IQ scores greater than 130) and 51 average """"""""g"""""""" control subjects. The current grant (Years 04-06) adds samples of 50 super-high """"""""g"""""""" subjects (4SD), 50 very high """"""""g"""""""" subjects especially high in verbal ability (3SD- verbal), 50 very high """"""""g"""""""" subjects especially high in math (3SD-math), and 50 additional average """"""""g"""""""" control subjects. Permanent cell lines are established for all 300 subjects in order to create a permanent resource for molecular genetic analyses of cognitive ability. The proposed three-year project will capitalize on this NICHD investment. We will conduct the first systematic genome scan for allelic association using an exciting new DNA pooling technique developed as part of the current grant. Specifically, the efficiency of DNA pooling will make it possible to genotype 3500 DNA markers at roughly 1 cM intervals throughout the genome for the combined samples of 200 high """"""""g"""""""" subjects and 100 control subjects. Most QTL associations that account for as little as 2 percent of the variation in """"""""g"""""""" in the population can be detected while guarding against false positives (p lesser then .0001). The largest associations will be individually genotyped and tested in the four subgroups for a linear relationship predicted by our QTL model for """"""""g"""""""": 4SD more then 3SD-verbal =3SD-math more then 2SD. Identifying QTLs will carve out handholds in the climb towards understanding neurophysiological pathways between genes and cognitive development.
