Analysis of independent cohorts of outbred CFW mice reveals novel loci for behavioral and physiological traits and identifies factors determining reproducibility

Jennifer Zou, Shyam Gopalakrishnan, Clarissa C. Parker, Jérôme Nicod, Richard Mott, Na Cai, Arimantas Lionikas, Robert W. Davies, Abraham Palmer* (Corresponding Author), Jonathan Flint* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3,076 commercially available outbred mice
and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6 and GM11545 with bone mineral density, and Psmb9 with weight. However replication at a nominal
threshold of 0.05 between the two component studies was low, with less than a third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winner’s Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Leveraging these
observations we integrated information about replication rates, study-specific heterogeneity, and Winner’s Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility, and demonstrates how to obtain robust results
from mapping complex traits in any genome-wide association study.
Original languageEnglish
Article numberjkab394
JournalG3: Genes, Genomes, Genetics Mission
Early online date13 Nov 2021
DOIs
Publication statusE-pub ahead of print - 13 Nov 2021

Keywords

  • GWAS
  • CFW
  • replication
  • Winner's curse
  • power
  • mega-analysis

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