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Mapping the genetic architecture of gene expression in human liver.

Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum PY, Kasarskis A, Zhang B, Wang S, Suver C, Zhu J, Millstein J, Sieberts S, Lamb J, GuhaThakurta D, Derry J, Storey JD, Avila-Campillo I, Kruger MJ, Johnson JM, Rohl CA, van Nas A, Mehrabian M, Drake TA, Lusis AJ, Smith RC, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich R - PLoS Biol. (2008)

Bottom Line: Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits.By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study.We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.

View Article: PubMed Central - PubMed

Affiliation: Rosetta Inpharmatics, Seattle, Washington, United States of America. eric_schadt@merck.com

ABSTRACT
Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.

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Local Networks for Rps26 and Erbb3 Derived from Causal, Probabilistic Whole-Gene Networks Constructed from the Liver, Adipose, Muscle, and Brain Gene Expression Data Generated from the BXH/wt and BXC Mouse Crosses(A) The Rps26 subnetwork includes a number of known T1D associated genes (green nodes), and RPS26 in this subnetwork is directly linked to H2-Eb1, a mouse ortholog of HLA-DRB1, a previously identified T1D susceptibility gene that is also strongly associated with a cis eSNP in the HLC (Table 2). The known T1D genes annotated by the Gene Ontology are significantly enriched in this subnetwork (Table 3).(B) The Erbb3 subnetwork is not associated with any pathways known or predicted to be involved in T1D.
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pbio-0060107-g001: Local Networks for Rps26 and Erbb3 Derived from Causal, Probabilistic Whole-Gene Networks Constructed from the Liver, Adipose, Muscle, and Brain Gene Expression Data Generated from the BXH/wt and BXC Mouse Crosses(A) The Rps26 subnetwork includes a number of known T1D associated genes (green nodes), and RPS26 in this subnetwork is directly linked to H2-Eb1, a mouse ortholog of HLA-DRB1, a previously identified T1D susceptibility gene that is also strongly associated with a cis eSNP in the HLC (Table 2). The known T1D genes annotated by the Gene Ontology are significantly enriched in this subnetwork (Table 3).(B) The Erbb3 subnetwork is not associated with any pathways known or predicted to be involved in T1D.

Mentions: What the genetic association and atlas data lack is a more refined context within which to assess the functional role a given gene plays in a system. We have previously described a method to reconstruct probabilistic, causal networks by integrating genetic and gene expression data [25,28–30]. Examining candidate susceptibility genes in the context of these networks can provide insights into the pathways in which they operate. We constructed whole-gene networks from three F2 intercross populations constructed from the B6, C3H, and CAST strains (see Methods for details). Liver and adipose expression data were generated from these populations and integrated with the genotypic data also generated in these populations to reconstruct the networks as previously described [28,30]. We then examined RPS26 and ERBB3 in the context of these networks (Figure 1).


Mapping the genetic architecture of gene expression in human liver.

Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum PY, Kasarskis A, Zhang B, Wang S, Suver C, Zhu J, Millstein J, Sieberts S, Lamb J, GuhaThakurta D, Derry J, Storey JD, Avila-Campillo I, Kruger MJ, Johnson JM, Rohl CA, van Nas A, Mehrabian M, Drake TA, Lusis AJ, Smith RC, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich R - PLoS Biol. (2008)

Local Networks for Rps26 and Erbb3 Derived from Causal, Probabilistic Whole-Gene Networks Constructed from the Liver, Adipose, Muscle, and Brain Gene Expression Data Generated from the BXH/wt and BXC Mouse Crosses(A) The Rps26 subnetwork includes a number of known T1D associated genes (green nodes), and RPS26 in this subnetwork is directly linked to H2-Eb1, a mouse ortholog of HLA-DRB1, a previously identified T1D susceptibility gene that is also strongly associated with a cis eSNP in the HLC (Table 2). The known T1D genes annotated by the Gene Ontology are significantly enriched in this subnetwork (Table 3).(B) The Erbb3 subnetwork is not associated with any pathways known or predicted to be involved in T1D.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2365981&req=5

pbio-0060107-g001: Local Networks for Rps26 and Erbb3 Derived from Causal, Probabilistic Whole-Gene Networks Constructed from the Liver, Adipose, Muscle, and Brain Gene Expression Data Generated from the BXH/wt and BXC Mouse Crosses(A) The Rps26 subnetwork includes a number of known T1D associated genes (green nodes), and RPS26 in this subnetwork is directly linked to H2-Eb1, a mouse ortholog of HLA-DRB1, a previously identified T1D susceptibility gene that is also strongly associated with a cis eSNP in the HLC (Table 2). The known T1D genes annotated by the Gene Ontology are significantly enriched in this subnetwork (Table 3).(B) The Erbb3 subnetwork is not associated with any pathways known or predicted to be involved in T1D.
Mentions: What the genetic association and atlas data lack is a more refined context within which to assess the functional role a given gene plays in a system. We have previously described a method to reconstruct probabilistic, causal networks by integrating genetic and gene expression data [25,28–30]. Examining candidate susceptibility genes in the context of these networks can provide insights into the pathways in which they operate. We constructed whole-gene networks from three F2 intercross populations constructed from the B6, C3H, and CAST strains (see Methods for details). Liver and adipose expression data were generated from these populations and integrated with the genotypic data also generated in these populations to reconstruct the networks as previously described [28,30]. We then examined RPS26 and ERBB3 in the context of these networks (Figure 1).

Bottom Line: Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits.By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study.We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.

View Article: PubMed Central - PubMed

Affiliation: Rosetta Inpharmatics, Seattle, Washington, United States of America. eric_schadt@merck.com

ABSTRACT
Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.

Show MeSH
Related in: MedlinePlus