In Silico Mapping of Complex Disease-Related Traits in Mice

Grupe, Andrew; Germer, Søren; Usuka, Jonathan; Aud, Dee; Belknap, John K.; Klein, Robert F.; Ahluwalia, Mandeep K.; Higuchi, Russell; Peltz, Gary

doi:10.1126/science.1058889

Cited by 272 publications

(234 citation statements)

References 18 publications

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“…Large strain panels have not often been used in psychostimulant drug research, although the work of Janowsky et al (2001) which examined DAT density in a panel of recombinant inbred strains and correlated this with multiple behavioral traits serves as one example. As genome-wide sequence information for multiple inbred strains has increased, more direct genotype-phenotype, in silico mapping approaches (e.g., Grupe et al, 2001) are becoming feasible. Direct gene and gene expression co-mapping in selected lines (e.g., Palmer et al, 2005) also represents a more direct path to gene finding for complex, drug-related traits.…”

Section: Discussionmentioning

confidence: 99%

Behavioral genetic contributions to the study of addiction-related amphetamine effects

Phillips

Kamens

Wheeler

2008

Neuroscience & Biobehavioral Reviews

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Amphetamines, including methamphetamine, pose a significant cost to society due to significant numbers of amphetamine-abusing individuals who suffer major health-related consequences. In addition, methamphetamine use is associated with heightened rates of violent and property-related crimes. The current paper reviews the existing literature addressing genetic differences in mice that impact behavioral responses thought to be relevant to the abuse of amphetamine and amphetaminelike drugs. Summarized are studies that used inbred strains, selected lines, single gene knockouts and transgenics, and quantitative trait locus (QTL) mapping populations. Acute sensitivity, neuroadaptive responses, rewarding and conditioned effects are among those reviewed. Some gene mapping work has been accomplished, and although no amphetamine-related complex trait genes have been definitively identified, translational work leading from results in the mouse to studies performed in humans is beginning to emerge. The majority of genetic investigations has utilized single-gene knockout mice and has concentrated on dopamine-and glutamate-related genes. Genes that code for cell support and signaling molecules are also well-represented. There is a large behavioral genetic literature on responsiveness to amphetamines, but a considerably smaller literature focused on genes that influence the development and acceleration of amphetamine use, withdrawal, relapse, and behavioral toxicity. Also missing are genetic investigations into the effects of amphetamines on social behaviors. This information might help to identify at-risk individuals and in the future to develop treatments that take advantage of individualized genetic information.

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Section: Discussionmentioning

confidence: 99%

Behavioral genetic contributions to the study of addiction-related amphetamine effects

Phillips

Kamens

Wheeler

2008

Neuroscience & Biobehavioral Reviews

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“…20 Experimental sources of error, primarily allele frequency measurement error, degrade the test power. 21 Recent applications 22,23 suggest that typical absolute measurement errors are 1 -4%.…”

Section: Introductionmentioning

confidence: 99%

Family-based association tests for quantitative traits using pooled DNA

Bader

Sham

2002

Eur J Hum Genet

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Interest in whole-genome QTL mapping has spurred efforts to reduce the cost of studies now based primarily on individual genotyping. Pooled DNA tests are a possible solution, and understanding how measurement error affects test power could assist in study design. Here we describe pooled tests explicitly optimised for measurement error, including family-based tests robust to population stratification. Our results suggest that pooled DNA whole-genome screens may be feasible with current instruments.

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“…where b 0 is the regression intercept and b is the regression slope (Grupe et al, 2001). Provided that each marker locus on the entire genome can be linked to putative QTL, the model (1) can be extended to the MLISM:…”

Section: Genetic Modelmentioning

confidence: 99%

“…Therefore it is relevant to ask whether it is also possible to map a quantitative trait locus (QTL) within the crop cultivars or animal inbred strains. Grupe et al (2001) proposed the use of the mean phenotypic values of inbred strains to map the likely genomic locations of QTL 'in silico,' which theoretically would represent a major advance. Chesler et al (2001) and Darvasi (2001) have questioned the validity of this so-called in silico mapping (ISM) on the basis that it is associated with a relatively high false-positive rate (FPR).…”

Section: Introductionmentioning

confidence: 99%

Multiple loci in silico mapping in inbred lines

Lü

et al. 2009

Heredity

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The in silico mapping (ISM) technique and its extension represent major advances for novel gene discovery in germplasm resources of inbred lines. However, the techniques suffer from a relatively high false-positive rate (FPR) and they do not consider the effect of linkage disequilibrium (LD) markers around the identified quantitative trait locus (QTL). In addition, it has not yet been established whether it is optimal to use absolute trait differences as the response variable. To address these problems, this article presents the multiple loci ISM (MLISM) approach, which uses all markers on the entire genome, along with a penalized maximum likelihood. The method proposed here was verified by a series of simulation experiments with a maize pedigree population of inbred lines of known ancestry. Results from the simulated studies show that the best response variable is the trait product. The MLISM FPR is substantially decreased and the proportion of the number of false QTL to the number of LD markers around the identified QTL is adequately reduced. The MLISM method, with the trait product as the response variable, is an improvement on the existing methods for novel QTL mapping in germplasm resources of inbred lines.

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In Silico Mapping of Complex Disease-Related Traits in Mice

Cited by 272 publications

References 18 publications

Behavioral genetic contributions to the study of addiction-related amphetamine effects

Behavioral genetic contributions to the study of addiction-related amphetamine effects

Family-based association tests for quantitative traits using pooled DNA

Multiple loci in silico mapping in inbred lines

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