The concept of genetic susceptibility in the contribution to human disease is not new. What is new is the emerging ability of the field of genomics to detect, assess, and interpret genetic variation in the study of susceptibility to development of disease. Deciphering the human genome sequence and the publication of the human haplotype map are key elements of this effort. However, we are only beginning to understand the contribution of genetic predisposition to complex liver disease through its interaction with environmental risk factors. In the coming decade, we anticipate the development of human studies to better dissect the genotype/phenotype relationship of complex liver diseases. This endeavor will require large, well-phenotyped patient populations of each disease of interest and proper study designs aimed at answering important questions of hepatic disease prognosis, pathogenesis, and treatment. Teamwork between patients, physicians, and genomics scientists can ensure that this opportunity leads to important biological discoveries and improved treatment of complex disease. (HEPATOLOGY 2006;44:1380-1390.)
T he complex diseases of the liver represent the majority of cases encountered in clinical hepatology. From common ones such as nonalcoholic fatty liver disease to rare ones such as primary sclerosing cholangitis, these diseases develop as a result of interaction between the human genome and the environment. Key to understanding this concept is the realization that individual genetic variants of the human genome are neither sufficient nor necessary for complex disease development and instead act as disease risk (i.e., susceptibility) factors. This is in contrast to Mendelian disorders, for which the genetic variant is usually causative of disease. The impetus of the human genome project and subsequent endeavors has led to a greater understanding of the genome's involvement in complex disease. Despite the recent progress in human genomics, the current effort in complex liver disease genetics is lacking.
We herein provide an overview of the concepts involved with complex disease and the field of genomics, review the current state of genomics research in select complex liver diseases, and discuss the opportunities and challenges we face in applying genomics to achieve a better understanding of the pathogenesis and therapy of complex disease of the liver.
The Intricacy of Complex Disease
Complex Disease Genetics. The vast majority of human diseases are genetically complex. Complex diseases are multifactorial, the result of interplay between genes and the environment. 1,2 Thus, the strong correspondence between genotype and disease phenotype characteristics of Mendelian disorders is not present in complex disease. This lack of accord makes complex diseases widely diverse in penetrance, phenotype, progression, and response to treatment. Because of this inherent heterogeneity, it is often useful to conceptualize and study complex disorders as a series of complex disease traits (Fig. ). Defining and exploiting these traits is essential if we wish to dissect the genetic contributions to etiology and pathogenesis of complex disease.
Currently, the best means for quantifying the genetic and environmental influences on complex disease is comparison of disease concordance between monozygotic (i.e., identical) and dizygotic (i.e., fraternal) twins. Be-