Mapping Gene Expression in the Human Liver

F. Peter (Fred) Guengerich, Ph.D.
Center for Molecular Toxicology
Vanderbilt University School of Medicine
NIEHS Grant P30ES000267

A large multi-investigator research project to map gene expression in the human liver has yielded more than 6,000 associations between single nucleotide polymorphisms and liver gene expression traits. Many of the identified genes have already been associated with human diseases. Results from this genome wide association study also identified new candidate genes for type 1 diabetes, coronary artery disease, and the so-called "bad" cholesterol, or low-density lipoprotein.

A genome-wide association study, also known as a GWAS, is a laboratory approach involving the rapid scanning of markers across complete genomes of many people to find genetic variations associated with particular diseases. Once new genetic associations are identified, researchers can use the information to develop better strategies to detect, treat and prevent the disease. Such studies are particularly useful in finding genetic variations that contribute to common, complex diseases, such as asthma, cancer, diabetes, heart disease and mental illnesses.

Four hundred individual human liver samples were used in this study. The researchers profiled more than 39,000 gene transcripts and genotyped 782,476 unique single nucleotide polymorphisms. Most of the GWAS reporting associations to disease traits lack supporting data on the roles candidate susceptibility genes play in disease development. However the NIEHS-backed study provides direct evidence of how integrating genotypic and expression data in mice and humans provides functional support for candidate susceptibility genes. The researchers highlight the gene RSP26 as a susceptibility gene for type 1 diabetes, and not ERBB3 identified in a previous GWAS. They also identified SORT1 and CELSR2 as candidate genes for susceptibility to coronary artery disease and high levels of low-density lipoprotein.

Citation: 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. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 2008 May 6;6(5):e107.