RT Journal Article
SR Electronic
T1 Genome-wide association study, replication, and mega-analysis using a dense marker panel in a multi-generational mouse advanced intercross line
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 387613
DO 10.1101/387613
A1 Xinzhu Zhou
A1 Celine L. St. Pierre
A1 Natalia M. Gonzales
A1 Riyan Cheng
A1 Apurva Chitre
A1 Greta Sokoloff
A1 Abraham A. Palmer
YR 2019
UL http://biorxiv.org/content/early/2019/01/20/387613.abstract
AB Replication is critical for genome-wide association studies (GWAS) in humans. In contrast, replication is not routinely performed in model organism GWAS. Advanced intercross lines (AILs) are produced by crossing two inbred strains and then breeding unrelated offspring for additional generations. We re-genotype a previously reported cohort of sparsely genotyped LG/J × SM/J AIL mice (F34; n=428) using genotyping-by-sequencing (GBS). In addition, we genotyped a second novel cohort of LG/J × SM/J AIL mice (F39-43; n=600) also using GBS. The denser set of GBS markers in the F34 allowed us to identify 110 significant loci, 36 of which had not been identified in our previously published studies, for 79 behavioral and physiological traits. The genotypes in the F39-43 were then used to perform a GWAS which identified 27 significant loci for 21 behavioral and physiological traits. We then attempted to replicate loci identified in either F34 or F39-43 in the other cohort, focusing on the subset of traits that were measured in both cohorts (locomotor activity, body weight, and coat color). While coat color loci were robustly replicated, we observed only partial replication of associations for locomotor activity and body weight. Finally, to achieve better mapping power, we performed a mega-analysis of locomotor activity and body weight by combining F34 and F39-43 cohorts (n=1,028), which identified four novel loci. The present study provides empirical insights into replication, the utility of denser genotyping, and identifies new candidate loci for numerous behavioral and physiological traits.Author contributions XZ imputed genotypes, performed SNP and individual QC, and conducted GWAS in F34 and F39-43 AILs under supervision of AAP. AAP also provided computational resources for the analyses in this paper. CS prepared GBS libraries for sequencing, as well as organizing portions of the F39-43 phenotypes. NMG de-multiplexed GBS sequencing results and performed alignment and variant calling. RC helped with kinship relatedness matrix calculated from AIL pedigree. AC provided technical support for running programs and scripts. GS collected F39-43 phenotypes, respectively. XZ co-wrote the manuscript with AAP, who designed the study and oversaw data collection.