Genome-Wide Association Study in Two Cohorts from a Multi-generational Mouse Advanced Intercross Line Highlights the Difficulty of Replication Due to Study-Specific Heterogeneity

Xinzhu Zhou; Celine L St Pierre; Natalia M Gonzales; Jennifer Zou; Riyan Cheng; Apurva S Chitre; Greta Sokoloff; Abraham A Palmer

doi:10.1534/g3.119.400763

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Genome-Wide Association Study in Two Cohorts from a Multi-generational Mouse Advanced Intercross Line Highlights the Difficulty of Replication Due to Study-Specific Heterogeneity

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Genome-Wide Association Study in Two Cohorts from a Multi-generational Mouse Advanced Intercross Line Highlights the Difficulty of Replication Due to Study-Specific Heterogeneity

Xinzhu Zhou, Celine L St Pierre, Natalia M Gonzales, Jennifer Zou, Riyan Cheng, Apurva S Chitre, Greta Sokoloff and Abraham A Palmer

G3 (Bethesda, Md.), Vol.10(3), pp.951-965

03/05/2020

DOI: 10.1534/g3.119.400763

PMCID: PMC7056977

PMID: 31974095

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Abstract

There has been extensive discussion of the "Replication Crisis" in many fields, including genome-wide association studies ( ). We explored replication in a mouse model using an advanced intercross line ( ), which is a multigenerational intercross between two inbred strains. We re-genotyped a previously published cohort of LG/J x SM/J AIL mice (F ; n = 428) using a denser marker set and genotyped a new cohort of AIL mice (F ; n = 600) for the first time. We identified 36 novel genome-wide significant loci in the F and 25 novel loci in the F cohort. The subset of traits that were measured in both cohorts (locomotor activity, body weight, and coat color) showed high genetic correlations, although the SNP heritabilities were slightly lower in the F cohort. For this subset of traits, we attempted to replicate loci identified in either F or F in the other cohort. Coat color was robustly replicated; locomotor activity and body weight were only partially replicated, which was inconsistent with our power simulations. We used a random effects model to show that the partial replications could not be explained by Winner's Curse but could be explained by study-specific heterogeneity. Despite this heterogeneity, we performed a mega-analysis by combining F and F cohorts (n = 1,028), which identified four novel loci associated with locomotor activity and body weight. These results illustrate that even with the high degree of genetic and environmental control possible in our experimental system, replication was hindered by study-specific heterogeneity, which has broad implications for ongoing concerns about reproducibility.

Animal Fur

Animals

Body Weight

Color

Crosses, Genetic

Female

Genome-Wide Association Study

Genotype

Locomotion - drug effects

Male

Methamphetamine - pharmacology

Mice, Inbred Strains

Phenotype

Polymorphism, Single Nucleotide

Reproducibility of Results

Details

Title: Subtitle: Genome-Wide Association Study in Two Cohorts from a Multi-generational Mouse Advanced Intercross Line Highlights the Difficulty of Replication Due to Study-Specific Heterogeneity
Creators: Xinzhu Zhou - University of California San Diego
Celine L St Pierre - Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110
Natalia M Gonzales - University of Chicago
Jennifer Zou - University of California, Los Angeles
Riyan Cheng - Department of Psychiatry,
Apurva S Chitre - Department of Psychiatry,
Greta Sokoloff - University of Iowa
Abraham A Palmer - University of California San Diego
Resource Type: Journal article
Publication Details: G3 (Bethesda, Md.), Vol.10(3), pp.951-965
DOI: 10.1534/g3.119.400763
PMID: 31974095
PMCID: PMC7056977
NLM abbreviation: G3 (Bethesda)
ISSN: 2160-1836
eISSN: 2160-1836
Language: English
Date published: 03/05/2020
Academic Unit: Psychological and Brain Sciences
Record Identifier: 9984256841802771

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