Talk 19
Presenter: Natalia Gonzales
Thursday, 2:40pm
Gonzales NM, Distler MG, Parker CC, Sokoloff G & Palmer AA. Department of Human Genetics, University of Chicago
Replication of genome-wide association studies (GWAS) is considered a necessary step in the field of human genetics. Replication is defined as observing the same significant association in at least two independent populations. In model organisms replication can be accomplished using the same standard or by directly manipulating the implicated gene and observing the effects on the relevant phenotype.
We have previously performed a GWAS using an advanced intercross line (AIL) that was produced by randomly mating the progeny from an F2 cross between LG/J × SM/J mice until the F34 generation. Because of additional recombinations that accumulated during the intervening generations, the F34 AILs provided much better QTL mapping resolution as compared to the corresponding F2 cross. Using an approach that accounted for relatedness in the F34 we mapped QTLs for various behavioral and physiological phenotypes to sub-centiMorgan intervals. In particular we identified a highly significant (P<10-10) QTL for locomotor activity in a novel environment that contained just one gene: Csmd1. However, we have not previously attempted to replicate that finding.
In an effort to fully exploit the advantages of our model system, we have now performed both possible replication studies: we have established that the same association is observed in mice from the F39-F43 AIL generations, and we have also obtained Csmd1 null mutant mice and demonstrated the null allele recapitulates the phenotype. Thus, we have replicated our previous GWAS finding using two complimentary approaches, which together reflect the power of a model system. Interestingly, since our original identification of Csmd1 in mice, it was identified as one of 5 genome-wide significant GWAS results for schizophrenia by the psychiatric genetics consortium, which reflects the translational potential of our system.