Genetic Background Limits Generalizability of Genotype-Phenotype Relationships.
Genome-wide association studies (GWASs) have identified numerous loci that influence risk for psychiatric diseases. Genetically engineered mice are often used to characterize genes implicated by GWASs. These studies are based on the assumption that observed genotype-phenotype relationships will generalize to humans, implying that the results would at least generalize to other inbred mouse strains. Given current concerns about reproducibility, we sought to directly test this assumption. We produced F1 crosses between male C57BL/6J mice heterozygous for null alleles of Cacna1c and Tcf7l2 and wild-type females from 30 inbred laboratory strains. We found extremely strong interactions with genetic background that sometimes supported diametrically opposing conclusions. These results do not negate the invaluable contributions of mouse genetics to biomedical science, but they do show that genotype-phenotype relationships cannot be reliably inferred by studying a single genetic background, and thus constitute a major challenge to the status quo. VIDEO ABSTRACT.
Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA; Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Laura J
LJ
Sittig
Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA.
Peter
P
Carbonetto
Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA.
Kyle A
KA
Engel
Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA.
Kathleen S
KS
Krauss
Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA.
Camila M
CM
Barrios-Camacho
Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA; Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: aap@ucsd.edu.
Abraham A
AA
Palmer
D000483:Alleles; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D000068617:Genetic Background; D005838:Genotype; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D010641:Phenotype; D015203:Reproducibility of Results; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics
C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein