This has resulted in a different interpretation of GWAS findings: the basic genetic components of most common diseases are rare genetic variants rather than more common ones. Furthermore, the rare genetic variants occur in more remote functional regions of the genome that GWAS do not study. Hence, there is a gap between what researchers see in GWAS findings and what they are now discovering may be the causal variants of diseases. This gap is often called the “missing heritability.”
Missing Heritability
The term missing heritability refers to the low percentage of information about the overall genetic component and risk of common diseases gleaned from GWAS. Common variants account for only a small proportion of genetic components, and the missing heritability lies in the huge class of rare genetic variants that GWAS do not see. As Dr. Goldstein explains, “Variants that are primary drivers of disease are relatively rare in the human population.”
He offers a reason for the missing heritability while questioning the missing heritability notion: “Variants confer risk of disease, and natural selection acts against them so they don’t become too common. Therefore, there is no reason to think about the issue of so-called missing heritability. We did not interrogate the whole genome; we interrogated the common variants that pass through the filter of natural selection. So it’s clear that in many diseases, but not all, a lot of action will be rare variants not detected in GWAS.”
Autoimmune diseases may be an exception to this thinking. “Some variants that are major risk factors, for example, variants selected in response to infectious agents that have consequences for autoimmune diseases, appear more commonly in the general population,” noted Dr. Goldstein.
Sequencing
One of the approaches to overcome the shortcomings of GWAS may be sequencing, which has been found to be better than GWAS at discovering causal variants in common diseases. GWAS, however, are a good starting point: GWAS can define interesting regions that can be further explored by sequencing.
Sequencing of the whole genome of specific patient or of the coding regions of the genome (exome) is an effective and often less costly method for detecting rare variants thought to be the basic components of most common diseases. Whole genome sequencing of individuals reinforces the idea that rare variants are more likely to be functional or causal than common ones.
Next-generation DNA sequencing is another sequencing approach that can identify causal genetic variation in families. This method involves sequencing the entire genome of certain members of a family with multiple occurrences of a disease. Dr. Goldstein described a study of isolated, unexplained genetic conditions in which he studied 12 families with unknown congenital disorders where the child does not match anything known. He collected DNA from both unaffected parents and affected child. By sequencing these trios, he is looking for causal mutations for the child’s disorder.
