Communications of the ACM
Discovering Genes Involved in Disease and the Mystery of Missing Heritability
Credit: Charles Wiese
We live in a remarkable time for the study of human genetics. Nearly 150 years ago, Gregor Mendel published his laws of inheritance, which lay the foundation for understanding how the information that determines traits is passed from one generation to the next. Over 50 years ago, Watson and Crick discovered the structure of DNA, which is the molecule that encodes this genetic information. All humans share the same three billion-length DNA sequence at more than 99% of the positions. Almost 100 years ago, the first twin studies showed this small fraction of genetic differences in the sequence accounts for a substantial fraction of the diversity of human traits. These studies estimate the contribution of the genetic sequence to a trait by comparing the relative correlation of traits between pairs of maternal twins (which inherit identical DNA sequences from their parents) and pairs of fraternal twins (which inherit a different mix of the genetic sequence from each parent).5,29 This contribution is referred to as the "heritability" of a trait. For example, twin studies have shown that genetic variation accounts for 80% of the variability of height in the population.5,15,26 The amount of information about a trait encoded in the genetic sequence suggests it is possible to predict the trait directly from the genetic sequence and this is a central goal of human genetics.
Key Insights
Only in the past decade has technology developed to be able to cost effectively obtain DNA sequence information from individuals and a large number of the actual genetic differences have been identified and implicated in having an effect on traits. On the average, individuals who carry such a genetic difference, often referred to as a genetic variant, will have a different value for a trait compared to individuals who do not carry the variant. For example, a recently published paper reporting on a large study to identify the genetic differences that affect height reported hundreds of variants in the DNA sequence that either increase or decrease an individual's height if the individual carries the variant.2,23 Knowing these variants and their effects allows us to take the first steps in predicting traits only using genetic information. For example, if an individual carried many variants that increased height, we would predict the individual's height is higher than the population average. While predicting an easily measured trait such as height from genetic information seems like an academic exercise, the same ideas can be used to predict disease-related traits such as risk of heart attack or response to a certain drug. These predictions can help guide selecting the best treatment options. Over 1,000 genetic variants have been implicated in hundreds of traits including many human disease-related traits of great medical importance.16,31
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