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Zou, J.* ; Gopalakrishnan, S.* ; Parker, C.C.* ; Nicod, J.* ; Mott, R.* ; Cai, N. ; Lionikas, A.* ; Davies, R.W.* ; Palmer, A.A.* ; Flint, J.*

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

Genes Genomes Genetics G3 12:jkab394 (2022)

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	Open Access Gold

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cfw ; Gwas ; Winner's Curse ; Mega-analysis ; Power ; Replication; Genome-wide Association; Prepulse Inhibition; Complex Traits; Metaanalysis; Replication; Permutation; Expression; Efficient; Genetics; Bone

ISSN (print) / ISBN 2160-1836

e-ISSN 2160-1836

Journal Genes Genomes Genetics G3

Quellenangaben Volume: 12, Issue: 1, Article Number: jkab394

Publisher Genetics Society of America

Publishing Place Pittsburgh, PA

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Helmholtz Pioneer Campus (HPC)

Grants 1R01MH115979
National Science Foundation Graduate Research Fellowship
National Institutes of Health