Evidence map›Paper›PMID 34791208›Full record

ArticleG3 (Bethesda, Md.)2022

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, Jerome Nicod, Richard Mott, Na Cai, Arimantas Lionikas, Robert W Davies, Abraham A Palmer, Jonathan Flint

Abstract read
In one paragraph

Article in G3 (Bethesda, Md.), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Low-coverage whole-genome sequencing facilitates accurate and cost-effective haplotype reconstruction in complex mouse crosses.Mammalian genome : official journal of the International Mammalian Genome Society · 2025
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Jennifer ZouDepartment of Computer Science, University of California, Los Angeles, CA 90024, USA.
Shyam GopalakrishnanFaculty of Health and Medical Sciences, GLOBE Institute, University of Copenhagen, Copenhagen DK-1353, Denmark.
Clarissa C ParkerDepartment of Psychology and Program in Neuroscience, Middlebury College, Middlebury, VT 05753, USA.
Jerome NicodThe Francis Crick Institute, London NW1 1AT, UK.
Richard MottUCL Department of Genetics, Evolution & Environment, UCL Genetics Institute, London WC1E 6BT, UK.ORCID 0000-0002-1022-9330
Na CaiHelmholtz Zentrum Muenchen, Helmoltz Pioneer Campus, Neuherberg 85764, Germany.ORCID 0000-0001-7496-2075
Arimantas LionikasSchool of Medicine, Medical Sciences and Nutrition, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen AB24 3FX, UK.ORCID 0000-0002-0052-6171
Robert W DaviesDepartment of Statistics, University of Oxford, Oxford OX1 2JD, UK.
Abraham A PalmerDepartment of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.ORCID 0000-0003-3634-0747
Jonathan FlintDepartment of Biobehavioral Sciences, University of California, Los Angeles, CA 90024, USA.ORCID 0000-0002-9427-4429

Funding

Sequencing CoreP50DA037844 · NIDA · UNIVERSITY OF CHICAGO · PI PALMER, ABRAHAM A · 2014 to 2023
$27.4M
Developing a Pathway from Genetic Locus to Gene for Complex Traits in RodentsR01MH115979 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI FLINT, JONATHAN · 2018 to 2022
$3.5M
Genome-wide association studies in outbred miceR01GM097737 · NIGMS · UNIVERSITY OF CHICAGO · PI PALMER, ABRAHAM A · 2011 to 2014
$1.9M
NIDA NIH HHS P50 DA037844NIGMS NIH HHS R01 GM097737NIMH NIH HHS R01 MH115979
6 · The paper itself

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 3076 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 one-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.

Indexed as

Genome-Wide Association StudyPolymorphism, Single NucleotideAnimalsGenetic Predisposition to DiseaseMiceMultifactorial InheritancePeptide SynthasesPhenotypeReproducibility of ResultsPeptide SynthasesTTLL6 protein, mouseCFWGWASmega-analysispowerreplicationWinner’s Curse

Identifiers

PMID34791208
PMCPMC8728023

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.