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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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PSRC1, CELSR2, and SORT1 Liver Expression Is Associated with a CAD Risk Allele and Plasma LDL Cholesterol LevelsThe CAD risk allele for SNP rs599839 was established in a previous WTCCC study [16] (lilac panel). In the HLC, this same SNP is strongly associated with PSRC1, CELSR2, and SORT1 expression, with the CAD risk allele associated with lower relative expression (pink panel). In the BXH/wt cross designed to study metabolic traits that increase cardiovascular risk (green panel), all three of these expression traits were strongly correlated with plasma LDL cholesterol levels, a major CAD risk factor (scatter plots associated with the green panel). Given the association of these genes to plasma LDL-cholesterol levels, we examined whether rs599839 was associated with LDL cholesterol in a previously published GWAS [35] and found this SNP was significantly associated with LDL cholesterol levels, where the CAD risk allele was associated with higher LDL cholesterol levels in this cohort. Lower levels of CELSR2 and SORT1 expression were associated with the risk allele in humans, and with higher LDL cholesterol levels in mouse, making them ideal candidate susceptibility genes for the CAD and LDL cholesterol associations to this locus. On the other hand, lower levels of PSRC1 expression were associated with the risk allele in humans, but with lower LDL cholesterol levels in mouse, suggesting that PSRC1 is not the gene increasing CAD risk, but instead may be acting to protect against it.
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pbio-0060107-g002: PSRC1, CELSR2, and SORT1 Liver Expression Is Associated with a CAD Risk Allele and Plasma LDL Cholesterol LevelsThe CAD risk allele for SNP rs599839 was established in a previous WTCCC study [16] (lilac panel). In the HLC, this same SNP is strongly associated with PSRC1, CELSR2, and SORT1 expression, with the CAD risk allele associated with lower relative expression (pink panel). In the BXH/wt cross designed to study metabolic traits that increase cardiovascular risk (green panel), all three of these expression traits were strongly correlated with plasma LDL cholesterol levels, a major CAD risk factor (scatter plots associated with the green panel). Given the association of these genes to plasma LDL-cholesterol levels, we examined whether rs599839 was associated with LDL cholesterol in a previously published GWAS [35] and found this SNP was significantly associated with LDL cholesterol levels, where the CAD risk allele was associated with higher LDL cholesterol levels in this cohort. Lower levels of CELSR2 and SORT1 expression were associated with the risk allele in humans, and with higher LDL cholesterol levels in mouse, making them ideal candidate susceptibility genes for the CAD and LDL cholesterol associations to this locus. On the other hand, lower levels of PSRC1 expression were associated with the risk allele in humans, but with lower LDL cholesterol levels in mouse, suggesting that PSRC1 is not the gene increasing CAD risk, but instead may be acting to protect against it.

Mentions: Another GWAS involving the WTCCC resulted in the identification of seven loci associated with coronary artery disease (CAD) [16]. The seven top-hitting SNPs associated with CAD at each of the seven loci in this study were represented on the Affymetrix 500K array. Therefore, we examined the HLC data to identify expression traits that were significantly associated with any of the seven CAD-associated SNPs. Given the roughly 40,000 expression traits examined at each of the seven SNPs (280,000 tests in all), we set a nominal p-value threshold of 0.05/280,000 = 1.79 × 10−7 for significance. Only one of the seven SNPs identified in the WTCCC CAD study, rs599839 on Chromosome 1p13.3, was significantly associated with any of the HLC expression traits (Figure 2). Four different expression traits were identified as significantly associated with rs599839 (Table 4). One of the four expression traits corresponded to a gene, PSRC1, that had been identified as a candidate susceptibility gene in the WTCCC CAD study [16].


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)

PSRC1, CELSR2, and SORT1 Liver Expression Is Associated with a CAD Risk Allele and Plasma LDL Cholesterol LevelsThe CAD risk allele for SNP rs599839 was established in a previous WTCCC study [16] (lilac panel). In the HLC, this same SNP is strongly associated with PSRC1, CELSR2, and SORT1 expression, with the CAD risk allele associated with lower relative expression (pink panel). In the BXH/wt cross designed to study metabolic traits that increase cardiovascular risk (green panel), all three of these expression traits were strongly correlated with plasma LDL cholesterol levels, a major CAD risk factor (scatter plots associated with the green panel). Given the association of these genes to plasma LDL-cholesterol levels, we examined whether rs599839 was associated with LDL cholesterol in a previously published GWAS [35] and found this SNP was significantly associated with LDL cholesterol levels, where the CAD risk allele was associated with higher LDL cholesterol levels in this cohort. Lower levels of CELSR2 and SORT1 expression were associated with the risk allele in humans, and with higher LDL cholesterol levels in mouse, making them ideal candidate susceptibility genes for the CAD and LDL cholesterol associations to this locus. On the other hand, lower levels of PSRC1 expression were associated with the risk allele in humans, but with lower LDL cholesterol levels in mouse, suggesting that PSRC1 is not the gene increasing CAD risk, but instead may be acting to protect against it.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-0060107-g002: PSRC1, CELSR2, and SORT1 Liver Expression Is Associated with a CAD Risk Allele and Plasma LDL Cholesterol LevelsThe CAD risk allele for SNP rs599839 was established in a previous WTCCC study [16] (lilac panel). In the HLC, this same SNP is strongly associated with PSRC1, CELSR2, and SORT1 expression, with the CAD risk allele associated with lower relative expression (pink panel). In the BXH/wt cross designed to study metabolic traits that increase cardiovascular risk (green panel), all three of these expression traits were strongly correlated with plasma LDL cholesterol levels, a major CAD risk factor (scatter plots associated with the green panel). Given the association of these genes to plasma LDL-cholesterol levels, we examined whether rs599839 was associated with LDL cholesterol in a previously published GWAS [35] and found this SNP was significantly associated with LDL cholesterol levels, where the CAD risk allele was associated with higher LDL cholesterol levels in this cohort. Lower levels of CELSR2 and SORT1 expression were associated with the risk allele in humans, and with higher LDL cholesterol levels in mouse, making them ideal candidate susceptibility genes for the CAD and LDL cholesterol associations to this locus. On the other hand, lower levels of PSRC1 expression were associated with the risk allele in humans, but with lower LDL cholesterol levels in mouse, suggesting that PSRC1 is not the gene increasing CAD risk, but instead may be acting to protect against it.
Mentions: Another GWAS involving the WTCCC resulted in the identification of seven loci associated with coronary artery disease (CAD) [16]. The seven top-hitting SNPs associated with CAD at each of the seven loci in this study were represented on the Affymetrix 500K array. Therefore, we examined the HLC data to identify expression traits that were significantly associated with any of the seven CAD-associated SNPs. Given the roughly 40,000 expression traits examined at each of the seven SNPs (280,000 tests in all), we set a nominal p-value threshold of 0.05/280,000 = 1.79 × 10−7 for significance. Only one of the seven SNPs identified in the WTCCC CAD study, rs599839 on Chromosome 1p13.3, was significantly associated with any of the HLC expression traits (Figure 2). Four different expression traits were identified as significantly associated with rs599839 (Table 4). One of the four expression traits corresponded to a gene, PSRC1, that had been identified as a candidate susceptibility gene in the WTCCC CAD study [16].

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