Fine Mapping of Polymorphic Alcohol-Related Quantitative Trait Loci Candidate Genes Using Interval-Specific Congenic Recombinant Mice

Ehringer, Marissa A.; Thompson, Jessica; Conroy, Otakuye; Yang, Fan; Hink, Raquel; Bennett, Beth; Johnson, Thomas E.; Sikela, James M.

doi:10.1097/00000374-200211000-00001

Cited by 3 publications

(3 citation statements)

References 21 publications

(21 reference statements)

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“…ISCL lines have been used extensively to refine the location of a QTL for identification and confirmation of candidate genes in a variety of other species (Bennett et al. , 2002; Ehringer et al. , 2002; Fehr et al.…”

Section: Discussionmentioning

confidence: 99%

A quantitative trait locus on chromosome 18 is a critical determinant of excitotoxic cell death susceptibility

Lorenzana

Chancer

Schauwecker

2007

Eur J of Neuroscience

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C57BL/6J (B6) and FVB/NJ (FVB) mice are phenotypically distinct in their susceptibility to seizure-induced cell death after kainate administration. Previous studies using quantitative trait loci (QTLs) mapping established that the distal region of mouse chromosome 18 contains a gene(s) that is probably responsible for the difference in seizure-induced cell death susceptibility between two inbred strains, B6 and FVB, that are relatively resistant and susceptible, respectively, to seizure-induced cell death. The genetic locus has been mapped to a approximately 12-centimorgan region of chromosome 18, designated as seizure-induced cell death 1 (Sicd1). In order to confirm the Sicd1 QTL, we have developed congenic mouse strains containing the relevant donor segment from the resistant B6 strain on the susceptible FVB background, also referred to as the FVB.B6-Sicd1 congenic strain. Congenic and FVB littermate controls were tested in a seizure-induced cell death paradigm. The presence of B6 chromosome 18 alleles on an FVB genetic background conferred protection against seizure-induced cell death, as compared with FVB littermate controls. To further localize the Sicd1 QTL, new congenic lines carrying overlapping intervals of the B6 segment were created [interval-specific congenic lines (ISCLs)-1-4] and assessed for seizure-induced cell death phenotype. All of the ISCLs exhibited reduced cell death associated with the B6 phenotype, as compared with the parental FVB strain. The most dramatic of these, ISCL-4, showed a nearly four-fold reduction in the extent of seizure-induced cell death. This suggests that ISCL-4 contains the putative gene(s) of the Sicd1 QTL.

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Section: Discussionmentioning

confidence: 99%

A quantitative trait locus on chromosome 18 is a critical determinant of excitotoxic cell death susceptibility

Lorenzana

Chancer

Schauwecker

2007

Eur J of Neuroscience

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“…Zinc-finger gene ZNF699 (chromosome 19p13.2) is related to Drosophila gene “hang”, which is associated with increased alcohol tolerance (Scholz et al, 2005) and to QTLs involved in alcohol sedation in mice (e.g., Bennett and Johnson, 1998; Ehringer et al, 2002; Markel et al, 1997; Riley et al, 2006). In humans, several gene variants (e.g., rs7254880) might relate to alcohol dependence (Riley et al, 2006).…”

Section: The Search For Gene Variants Related To Alcohol Sensitivity mentioning

confidence: 99%

A Critical Review of Methods and Results in the Search for Genetic Contributors to Alcohol Sensitivity

Schuckit

2018

Alcoholism Clin & Exp Res

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Attributes of alcohol sensitivity are present before alcohol use disorders (AUDs) develop, they predict those adverse alcohol outcomes, are familial in nature, and many are heritable. Whether measured by alcohol challenges or retrospective reports of numbers of drinks required for effects, alcohol sensitivity reflects multiple phenotypes, including low levels of alcohol response and alcohol-related stimulation. Identification of genes that contribute to alcohol sensitivity could help identify individuals carrying risks for AUDs through their alcohol responses for whom early intervention might mitigate their vulnerability. Such genes could also improve understanding of biological underpinnings of AUDs, which could lead to new treatment approaches. However, the existing literature points to a wide range of genetic mechanisms that might contribute to alcohol responses, and few such genetic findings have been widely replicated. This critical review describes the potential impact of the diverse methods used to study sensitivity on the diversity of genetic findings that have been reported, places the genetic variants mentioned in the literature into broader categories rather than isolated results, and offers suggestions regarding how to advance the field by interpreting findings in light of the methods used to select research subjects and to measure alcohol sensitivity. To date, the most promising results have been for GABA, glutamate, opioid, dopamine, serotonin, and cholinergic system genes. The more gene variants that can be identified as contributors to sensitivity the better future gene screening platforms or polygenic scores are likely to be.

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“…Genetic differences underlying the QTLs can fall into one of two broad categories: coding region polymorphisms that affect the amino acid sequence of the translated protein or regulatory region polymorphisms that affect the level or pattern of expression of a gene. The coding regions of many candidate genes mapping to the Lore QTL regions have been sequenced to address the first possibility ( Ehringer et al 2001 , 2002 ). This study is intended to address the second possibility by examining the transcript levels of Lore genes in these mouse strains to determine which are differentially expressed (DE).…”

Section: Introductionmentioning

confidence: 99%

Expression profiling identifies novel candidate genes for ethanol sensitivity QTLs

et al. 2006

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The Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) mouse strains have a 16-fold difference in duration of loss of the righting response (LORR) following administration of a sedative dose of ethanol. Four quantitative trait loci (QTLs) have been mapped in these strains for this trait. Underlying each of these QTLs must be one or more genetic differences (polymorphisms in either gene coding or regulatory regions) influencing ethanol sensitivity. Because prior studies have tended to focus on differences in coding regions, genomewide expression profiling in cerebellum was used here to identify candidate genes for regulatory region differences in these two strains. Fifteen differentially expressed genes were found that map to the QTL regions and polymorphisms were identified in the promoter regions of four of these genes by direct sequencing of ILS and ISS genomic DNA. Polymorphisms in the promoters of three of these genes, Slc22a4, Rassf2, and Tax1bp3, disrupt putative transcription factor binding sites. Slc22a4 and another candidate, Xrcc5, have human orthologs that map to genomic regions associated with human ethanol sensitivity in genetic linkage studies. These genes represent novel candidates for the LORR phenotype and provide new targets for future studies into the neuronal processes underlying ethanol sensitivity.

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Fine Mapping of Polymorphic Alcohol-Related Quantitative Trait Loci Candidate Genes Using Interval-Specific Congenic Recombinant Mice

Cited by 3 publications

References 21 publications

A quantitative trait locus on chromosome 18 is a critical determinant of excitotoxic cell death susceptibility

A quantitative trait locus on chromosome 18 is a critical determinant of excitotoxic cell death susceptibility

A Critical Review of Methods and Results in the Search for Genetic Contributors to Alcohol Sensitivity

Expression profiling identifies novel candidate genes for ethanol sensitivity QTLs

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