P0651 Candidate Gene Evaluation of Equine Neuroaxonal Dystrophy Based on Genome-Wide Association Analysis

Carrie J. Finno , University of California, Davis, CA
Robert J. Higgins , University of California, Davis, CA
Monica Aleman , University of California, Davis, CA
John E. Madigan , University of California, Davis, CA
Danika Bannasch , University of California, Davis, CA
During the first year of life, genetically-predisposed foals may develop the neurodegenerative disorder, neuroaxonal dystrophy (NAD).  Currently, a definitive diagnosis of NAD requires post-mortem examination of the spinal cord and brainstem.   NAD resembles ataxia with vitamin E deficiency in humans, an inherited disease caused by mutations in the α-tocopherol transfer protein (α-TTP) gene.  Sequencing of α-TTP in affected and unaffected Quarter horses with NAD revealed no putative mutations.  A genome-wide association analysis was performed with phenotyping based on clinical examination and exclusion of other neurologic disorders.  36 NAD affected and 58 unaffected Quarter Horses were genotyped using the Illumina 54KSNP platform.   After 50,000 permutations, 21 significantly associated regions were identified (p<0.05).   A large degree of population stratification was present (λ=2.69).  A subset of the clinically phenotyped cases (n=23) and controls (n=63) were selected based on achieving minimal population stratification (λ=1.15) and genotyped on the Illumina 75K platform.  Following permutations, there were no significantly associated regions identified (p<0.05).  Therefore, after accounting for population dynamics, either enough power was not obtained to accurately map NAD or cases were potentially misphenotyped.  To establish the most accurate phenotyping criteria possible, a final analysis was performed using 9 post-mortem confirmed cases of NAD and 65 controls.  Following permutations, two regions of genome wide significance were identified (ECA8:62130705-62134644, p=0.029 and ECA21:2859633, p=0.048).  In the region on ECA8, two candidate genes were present (RIT2 and PIK3C3) that are both involved in synaptic transmission.  Sequencing of RIT2 revealed no putative mutations and sequencing of PIK3C3 is currently underway.