Genome-wide association studies and the problem of relatedness among advanced intercross lines and other highly recombinant populations
Date
2010
Authors
Cheng, Riyan
Lim, Jackie E
Samocha, Kaitlin E.
Sokoloff, Greta
Abney, Mark
Skol, Andrew D
Palmer, Abraham A
Journal Title
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Volume Title
Publisher
Genetics Society of America
Abstract
Model organisms offer many advantages for the genetic analysis of complex traits. However, identification of specific genes is often hampered by a lack of recombination between the genomes of inbred progenitors. Recently, genome-wide association studies (GWAS) in humans have offered gene-level mapping resolution that is possible because of the large number of accumulated recombinations among unrelated human subjects. To obtain analogous improvements in mapping resolution in mice, we used a 34th generation advanced intercross line (AIL) derived from two inbred strains (SM/J and LG/J). We used simulations to show that familial relationships among subjects must be accounted for when analyzing these data; we then used a mixed model that included polygenic effects to address this problem in our own analysis. Using a combination of F2 and AIL mice derived from the same inbred progenitors, we identified genome-wide significant, subcentimorgan loci that were associated with methamphetamine sensitivity, (e.g., chromosome 18; LOD = 10.5) and non-drug-induced locomotor activity (e.g., chromosome 8; LOD = 18.9). The 2-LOD support interval for the former locus contains no known genes while the latter contains only one gene (Csmd1). This approach is broadly applicable in terms of phenotypes and model organisms and allows GWAS to be performed in multigenerational crosses between and among inbred strains where familial relatedness is often unavoidable.
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Keywords
Keywords: methamphetamine; advanced intercross line; animal experiment; article; chromosome 18; controlled study; gene frequency; gene identification; gene locus; gene mapping; genetic analysis; genetic association; genetic recombination; genetic trait; genotype; h
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Genetics (Print) ceased Dec 2009 - don't use
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Journal article
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DOI
10.1534/genetics.110.116863
Restricted until
2037-12-31