Analysis of independent cohorts of outbred CFW mice reveals novel loci forbehavioral and physiological traits and identifies factors determiningreproducibility

Published: 01-01-2016 In Publication

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Combining samples for genetic association is standard practice in human genetic analysisofcomplextraits, but is rarely undertakeninrodentgenetics.Here,using23phenotypesandgenotypesfromtwo independent laboratories, we obtained a sample size of 3,076 commercially available outbred miceand 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 medianreduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6 andGM11545 with bone mineral density, and Psmb9 with weight. However replication at a nominalthreshold of 0.05 between the two component studies was surprisingly low, with less than a third ofloci identified in one study replicated in the second. In addition to overestimates in the effectsizein the discovery sample (Winner’s Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factorsvariedamongtraits.Availablemethods to control Winner’s Curse were contingent on the power of the discovery sample, and depending on the method used, both overestimated and underestimated the true effect. Leveraging these observations we integrated information about replication rates, confounding, and Winner’s Cursecorrected estimates of power to assign variants to one of four confidence levels. Our approachaddresses concerns about reproducibility, and demonstrates how to obtain robust results frommapping complex traits in any genome-wide association study.


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