On the Integration of Alcohol‐Related Quantitative Trait Loci and Gene Expression Analyses

Hitzemann, Robert; Reed, Cheryl; Malmanger, Barry; Lawler, Maureen; Hitzemann, Barbara; Cunningham, Brendan; McWeeney, Shannon K.; Belknap, John K.; Harrington, Christina A.; Buck, Kari J.; Phillips, Tamara J.; Crabbe, John C.

doi:10.1097/01.alc.0000139827.86749.da

Cited by 49 publications

(55 citation statements)

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“…Likewise, most of the differences in expression levels in the hippocampi of iP and iNP alcohol-naïve rats were less than 50% . In another study, brain gene expression differences between the C57BL/6 and DBA/2 mice within QTL were compared; again, most of the differences were small (Hitzemann et al, 2004). In summary, very interesting candidate genes and possible pathways have been identified by expression profiling of the congenic NP.P strain.…”

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confidence: 99%

“…However, finding the specific genes within such regions is difficult. A strategy of making congenic animal models carrying a single QTL, and then using microarray analysis to determine which genes are altered in expression, should provide a powerful approach toward gene identification (Hitzemann et al, 2004;Hoffman and Tabakoff, 2005;Spence et al, 2005). Using this combined approach dramatically decreases the number of genes that are expected to be differentially expressed because the 2 strains are identical except for the QTL sequences, thereby increasing the probability to identify differentially expressed genes contributing to a specific phenotype such as alcohol preference.…”

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Identification of Candidate Genes for Alcohol Preference by Expression Profiling of Congenic Rat Strains

Carr

Kimpel

Liang

et al. 2007

Alcoholism Clin & Exp Res

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Background-A highly significant quantitative trait locus (QTL) on chromosome 4 that influenced alcohol preference was identified by analyzing crosses between the iP and iNP rats. Congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP (NP.P) exhibited the expected increase in alcohol consumption compared with the iNP background strain. This study was undertaken to identify genes in the chromosome 4 QTL interval that might contribute to the differences in alcohol consumption between the alcohol-naïve congenic and background strains.

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Identification of Candidate Genes for Alcohol Preference by Expression Profiling of Congenic Rat Strains

Carr

Kimpel

Liang

et al. 2007

Alcoholism Clin & Exp Res

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“…Such Musunuru et al 2010). A few eQTL studies have also recently been carried out to identify candidate genes for behavioral QTL (Hitzemann et al 2004;De Jong et al 2011;Saba et al 2011;Kelly et al 2012).Here, we studied two lines of rats (Rattus norvegicus) that, starting from one wild population, have been selected for increased tameness and increased aggression toward humans, respectively. These experimental populations derive from the work of Dmitry K. Belyaev who, along with his famous related work in foxes (Belyaev 1979;Trut 1999), initiated the rat lines to study the evolution and underlying biological mechanisms of tameness as a crucial first step in animal domestication (Diamond 1999;Trut 1999;Wiener and Wilkinson 2011).…”

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confidence: 99%

“…This approach has been successfully applied to quantitative traits in different species, e.g., yeast (Perlstein et al 2007), rats (Hubner et al 2005;Heinig et al 2010), mice (Mehrabian et al 2005;Schadt et al 2005), and humans (Moffatt et al 2007;Musunuru et al 2010). A few eQTL studies have also recently been carried out to identify candidate genes for behavioral QTL (Hitzemann et al 2004;De Jong et al 2011;Saba et al 2011;Kelly et al 2012).…”

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Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Heyne

Lautenschlaeger²,

Nelson

et al. 2014

Preprint

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Interindividual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F 2 intercross of two outbred lines of rats selected for tame and aggressive behavior toward humans for .64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F 2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F 2 animals, we identify the genes Gltscr2, Lgi4, Zfp40, and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals. B EHAVIORAL differences among members of a species are in part due to genetic variation. The identification of the genes and variants that influence behavior remains challenging. In human genome-wide association studies of psychiatric and cognitive traits, the identified loci typically explain only a small fraction of the heritability, i.e., the additive genetic contribution to the trait (Watanabe et al. 2007;Hovatta and Barlow 2008;Deary et al. 2009;Otowa et al. 2009;Calboli et al. 2010;Terracciano et al. 2010;Flint and Munafo 2013;Rietveld et al. 2013;Sokolowska and Hovatta 2013). In experimental crosses in model species, especially between inbred lines, the identified loci (termed quantitative trait loci, QTL), often explain much more of the heritability (Lynch and Walsh 1998). However, in this design the spatial resolution is limited-the QTL are wide and contain many, sometimes hundreds of genes. With the exception of a handful of identified genes with quantitative effects on behavioral traits (Yalcin et al. 2004;Watanabe et al. 2007;McGrath et al. 2009;Bendesky et al. 2012;Goodson et al. 2012), gene identification is particularly difficult for behavioral QTL that often have modest effect sizes (Flint 2003;Willis-Owen and Flint 2006;Wright et al. 2006;Hovatta and Barlow 2008).The causal variants within a QTL can alter the protein sequence encoded by a gene or affect gene expression. Such Musunuru et al. 2010). A few eQTL studies have also recently been carried out to identify candidate genes for behavioral QTL (Hitzemann et al. 2004;De Jong et al. 2011;Saba et al. 2011;Kelly et al. 2012).Here, we studied two lines of rats (Rattus norvegicus) that, starting from one wild population, have been selected for increased tameness and increased aggression toward humans, respectively. These experimental...

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Genetic analysis reveals polygenic influences on iron, copper, and zinc in mouse hippocampus with neurobiological implications

2008

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Fe, Cu, and Zn are of widespread neurobiological importance, but must be regulated closely as too much or too little of these metals can have adverse effects on brain function. Recent evidence from nutritional models notes that the hippocampus is particularly vulnerable to Fe and Zn deficiencies. We recently performed a quantitative trait loci (QTL) analysis as a preliminary step in identifying genes that contribute to natural variation in hippocampal Fe, Cu, and Zn content. We used ICP-MS to measure the concentrations of these metals in 120-day-old mice from 30 strains of the BXD/TY panel. The BXD/Ty recombinant inbred strain panel is well-suited for complex trait analysis, as all strains are genotyped with a dense marker set and have been phenotyped extensively for neurobehavioral traits and hippocampal gene expression. We observed a wide-range of hippocampal Fe, Cu, and Zn concentrations across the BXD strains. These concentrations were related to systemic Fe status, but not to Fe, Cu, and Zn elsewhere in the brain. The three metals also showed strong covariance, suggestive of overlap in their regulatory pathways. We identified two QTL, on chromosomes 14 and 9, most strongly associated with Cu but also suggestively associated with Fe (chr. 14) and Zn (chr. 9). We also performed genetic correlational analyses with existing data on these strains and revealed associations with cognitive, anxiety-related, and alcohol-related phenotypes. Covariance of these metals with gene expression is also discussed. This work shows that hippocampal Fe, Cu, and Zn are under polygenic influence and that trace metal regulation is associated with hippocampus-related behaviors. Future work will elucidate the genes underlying the two QTL identified, to aid in identifying homologous genetic variants in human populations, which may underlie altered trace metal homeostasis and related neurological disease.

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On the Integration of Alcohol‐Related Quantitative Trait Loci and Gene Expression Analyses

Abstract: Although improvements are needed in the expression databases, the integration of QTL and gene expression analyses seems to have potential as a high-throughput strategy for moving from QTL to QTG.

Cited by 49 publications

References 49 publications

Identification of Candidate Genes for Alcohol Preference by Expression Profiling of Congenic Rat Strains

Identification of Candidate Genes for Alcohol Preference by Expression Profiling of Congenic Rat Strains

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Genetic analysis reveals polygenic influences on iron, copper, and zinc in mouse hippocampus with neurobiological implications

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