A Genome-Wide Association Study Identifies Protein Quantitative Trait Loci (pQTLs)

作者：David R. Melzer, John R. B. Perry, Dena G. Hernandez, Annamaria Corsi, Kara Nicola Stevens, Ian Rafferty, Fulvio Lauretani, Anna Murray, J. Raphael Gibbs, Giuseppe Paolisso, Sajjad Rafiq, Javier Simón‐Sánchez, Hana Lango Allen, Sonja W. Scholz, Michael N. Weedon, Sampath Arepalli, Neil E. Rice, Nicole Washecka, Alison Jane Hurst, Angela F. Britton, William Henley, Joyce C. H. van de Leemput, Rongling Li, Anne B. Newman, Greg J. Tranah, Tamara Harris, Vijay Panicker, Colin Mark Dayan, Amanda J. Bennett, Mark I. McCarthy, Aimo Ruokonen, Marjo‐Riitta Järvelin, Jack M. Guralnik, Stefania Bandinelli, Timothy Mark Frayling, Andrew B. Singleton, Luigi Ferrucci · 发表于：PLoS Genetics · 年份：2008 · DOI：10.1371/journal.pgen.1000072 · 被引用次数：500 · 研究领域：Genetic Associations and Epidemiology、Hepatitis C virus research、Diabetes and associated disorders

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1)...