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Convergent functional genomics in addiction research - a translational approach to study candidate genes and gene networks.

Spanagel R - In Silico Pharmacol (2013)

Bottom Line: Convergent functional genomics (CFG) is a translational methodology that integrates in a Bayesian fashion multiple lines of evidence from studies in human and animal models to get a better understanding of the genetics of a disease or pathological behavior.Most powerful in terms of forward genetics is combined quantitative trait loci (QTL) analysis and gene expression profiling in recombinant inbreed rodent lines or genetically selected animals for a specific phenotype, e.g. high vs. low drug consumption.By Bayesian scoring genomic information from forward genetics in animals is then combined with human GWAS data on a similar addiction-relevant phenotype.

View Article: PubMed Central - PubMed

Affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany.

ABSTRACT
Convergent functional genomics (CFG) is a translational methodology that integrates in a Bayesian fashion multiple lines of evidence from studies in human and animal models to get a better understanding of the genetics of a disease or pathological behavior. Here the integration of data sets that derive from forward genetics in animals and genetic association studies including genome wide association studies (GWAS) in humans is described for addictive behavior. The aim of forward genetics in animals and association studies in humans is to identify mutations (e.g. SNPs) that produce a certain phenotype; i.e. "from phenotype to genotype". Most powerful in terms of forward genetics is combined quantitative trait loci (QTL) analysis and gene expression profiling in recombinant inbreed rodent lines or genetically selected animals for a specific phenotype, e.g. high vs. low drug consumption. By Bayesian scoring genomic information from forward genetics in animals is then combined with human GWAS data on a similar addiction-relevant phenotype. This integrative approach generates a robust candidate gene list that has to be functionally validated by means of reverse genetics in animals; i.e. "from genotype to phenotype". It is proposed that studying addiction relevant phenotypes and endophenotypes by this CFG approach will allow a better determination of the genetics of addictive behavior.

No MeSH data available.


Related in: MedlinePlus

Genome wide significant findings for alcohol consumption and alcohol addiction. Alcohol metabolizing genes, especially in the ADH cluster, are consistently found to be associated with alcohol addiction. Meta-analysis on large population based samples with almost 50,000 individuals demonstrated that a single nucleotide polymorphism (SNP) (rs6943555) in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (Schumann et al. 2011). This finding was supported by multiple lines of evidence from mouse and drosophila studies. Convergent evidence was also obtained for association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene with alcohol consumption (Stacey et al. 2012). This finding was functionally validated in Rasgrf2 knockout mice – this is shown in the lower panel where alcohol consumption in knockout and control littermate mice was measured in a drinkometer system (Vengeliene et al. 2013) throughout day and night time. Rasgrf2 knockouts show completely blunted alcohol consumption confirming the human findings that RASGRF2 is critically involved in regulating alcohol consumption (drinking data were kindly provided by Ainhoa Bilbao).
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Fig1: Genome wide significant findings for alcohol consumption and alcohol addiction. Alcohol metabolizing genes, especially in the ADH cluster, are consistently found to be associated with alcohol addiction. Meta-analysis on large population based samples with almost 50,000 individuals demonstrated that a single nucleotide polymorphism (SNP) (rs6943555) in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (Schumann et al. 2011). This finding was supported by multiple lines of evidence from mouse and drosophila studies. Convergent evidence was also obtained for association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene with alcohol consumption (Stacey et al. 2012). This finding was functionally validated in Rasgrf2 knockout mice – this is shown in the lower panel where alcohol consumption in knockout and control littermate mice was measured in a drinkometer system (Vengeliene et al. 2013) throughout day and night time. Rasgrf2 knockouts show completely blunted alcohol consumption confirming the human findings that RASGRF2 is critically involved in regulating alcohol consumption (drinking data were kindly provided by Ainhoa Bilbao).

Mentions: Fifteen GWASs of alcohol dependence and symptoms of alcohol dependence, and nine studies of alcohol consumption and other alcohol dependence related traits have to date been published (Rietschel and Treutlein 2012). The first GWAS on alcohol addiction (Treutlein et al. 2009) and alcohol consumption (Schumann et al. 2011; Stacey et al. 2012) yielded several genome-wide findings, especially in the alcohol dehydrogenease (ADH) cluster (Frank et al. 2012) and AUTS2 (Schumann et al. 2011) and were replicated in independent studies (Biernacka et al. 2013 (ADH, Kapoor et al. 2013 (AUTS2)) (Figure 1).Figure 1


Convergent functional genomics in addiction research - a translational approach to study candidate genes and gene networks.

Spanagel R - In Silico Pharmacol (2013)

Genome wide significant findings for alcohol consumption and alcohol addiction. Alcohol metabolizing genes, especially in the ADH cluster, are consistently found to be associated with alcohol addiction. Meta-analysis on large population based samples with almost 50,000 individuals demonstrated that a single nucleotide polymorphism (SNP) (rs6943555) in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (Schumann et al. 2011). This finding was supported by multiple lines of evidence from mouse and drosophila studies. Convergent evidence was also obtained for association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene with alcohol consumption (Stacey et al. 2012). This finding was functionally validated in Rasgrf2 knockout mice – this is shown in the lower panel where alcohol consumption in knockout and control littermate mice was measured in a drinkometer system (Vengeliene et al. 2013) throughout day and night time. Rasgrf2 knockouts show completely blunted alcohol consumption confirming the human findings that RASGRF2 is critically involved in regulating alcohol consumption (drinking data were kindly provided by Ainhoa Bilbao).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230431&req=5

Fig1: Genome wide significant findings for alcohol consumption and alcohol addiction. Alcohol metabolizing genes, especially in the ADH cluster, are consistently found to be associated with alcohol addiction. Meta-analysis on large population based samples with almost 50,000 individuals demonstrated that a single nucleotide polymorphism (SNP) (rs6943555) in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (Schumann et al. 2011). This finding was supported by multiple lines of evidence from mouse and drosophila studies. Convergent evidence was also obtained for association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene with alcohol consumption (Stacey et al. 2012). This finding was functionally validated in Rasgrf2 knockout mice – this is shown in the lower panel where alcohol consumption in knockout and control littermate mice was measured in a drinkometer system (Vengeliene et al. 2013) throughout day and night time. Rasgrf2 knockouts show completely blunted alcohol consumption confirming the human findings that RASGRF2 is critically involved in regulating alcohol consumption (drinking data were kindly provided by Ainhoa Bilbao).
Mentions: Fifteen GWASs of alcohol dependence and symptoms of alcohol dependence, and nine studies of alcohol consumption and other alcohol dependence related traits have to date been published (Rietschel and Treutlein 2012). The first GWAS on alcohol addiction (Treutlein et al. 2009) and alcohol consumption (Schumann et al. 2011; Stacey et al. 2012) yielded several genome-wide findings, especially in the alcohol dehydrogenease (ADH) cluster (Frank et al. 2012) and AUTS2 (Schumann et al. 2011) and were replicated in independent studies (Biernacka et al. 2013 (ADH, Kapoor et al. 2013 (AUTS2)) (Figure 1).Figure 1

Bottom Line: Convergent functional genomics (CFG) is a translational methodology that integrates in a Bayesian fashion multiple lines of evidence from studies in human and animal models to get a better understanding of the genetics of a disease or pathological behavior.Most powerful in terms of forward genetics is combined quantitative trait loci (QTL) analysis and gene expression profiling in recombinant inbreed rodent lines or genetically selected animals for a specific phenotype, e.g. high vs. low drug consumption.By Bayesian scoring genomic information from forward genetics in animals is then combined with human GWAS data on a similar addiction-relevant phenotype.

View Article: PubMed Central - PubMed

Affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany.

ABSTRACT
Convergent functional genomics (CFG) is a translational methodology that integrates in a Bayesian fashion multiple lines of evidence from studies in human and animal models to get a better understanding of the genetics of a disease or pathological behavior. Here the integration of data sets that derive from forward genetics in animals and genetic association studies including genome wide association studies (GWAS) in humans is described for addictive behavior. The aim of forward genetics in animals and association studies in humans is to identify mutations (e.g. SNPs) that produce a certain phenotype; i.e. "from phenotype to genotype". Most powerful in terms of forward genetics is combined quantitative trait loci (QTL) analysis and gene expression profiling in recombinant inbreed rodent lines or genetically selected animals for a specific phenotype, e.g. high vs. low drug consumption. By Bayesian scoring genomic information from forward genetics in animals is then combined with human GWAS data on a similar addiction-relevant phenotype. This integrative approach generates a robust candidate gene list that has to be functionally validated by means of reverse genetics in animals; i.e. "from genotype to phenotype". It is proposed that studying addiction relevant phenotypes and endophenotypes by this CFG approach will allow a better determination of the genetics of addictive behavior.

No MeSH data available.


Related in: MedlinePlus