https://www.science.org/doi/full/10.1126/science.1156409

Abstract

Genetic mapping provides a powerful approach to identify genes and biological processes underlying any trait influenced by inheritance, including human diseases. We discuss the intellectual foundations of genetic mapping of Mendelian and complex traits in humans, examine lessons emerging from linkage analysis of Mendelian diseases and genome-wide association studies of common diseases, and discuss questions and challenges that lie ahead.

By the early 1900s, geneticists understood that Mendel's laws of inheritance underlie the transmission of genes in diploid organisms. They noted that some traits are inherited according to Mendel's ratios, as a result of alterations in single genes, and they developed methods to map the genes responsible. They also recognized that most naturally occurring trait variation, while showing strong correlation among relatives, involves the action of multiple genes and nongenetic factors.

Introduction

Although it was clear that these insights applied to humans as much as to fruit flies, it took most of the century to turn these concepts into practical tools for discovering genes contributing to human diseases. Starting in the 1980s, the use of naturally occurring DNA variation as markers to trace inheritance in families led to the discovery of thousands of genes for rare Mendelian diseases. Despite great hopes, the approach proved unsuccessful for common forms of human diseases—such as diabetes, heart disease, and cancer—that show complex inheritance in the general population.

Over the past year, a new approach to genetic mapping has yielded the first general progress toward mapping loci that influence susceptibility to common human diseases. Still, most of the genes and mutations underlying these findings remain to be defined, let alone understood, and it remains unclear how much of the heritability of common disease they explain. Below, we discuss the intellectual foundations of genetic mapping, examine emerging lessons, and discuss questions and challenges that lie ahead.