The search for the genetic roots of psychiatric illnesses and behavioral disorders such as schizophrenia, autism and ADHD has a long history, but until recently, it was one marked by frustration and skepticism. In the past few years, new techniques have begun to reveal strong evidence for the role of specific genes in some cases of these conditions but in a way few people expected.
To understand what makes the new discoveries so novel, it’s necessary to appreciate how our genes can go wrong. The human genetic code can be thought of as an encyclopedia in multiple volumes. Our normal genome contains 46 chromosomes, so that’s 46 volumes. Each chromosome is a long string of the chemical DNA and the information is “written” in the form of a molecular alphabet with just four letters: A, T, C and G.
There are three ways in which something can go wrong here. First, a whole chromosome can be either missing or duplicated. This drastic change is almost always fatal. (The exceptions include Downs Syndrome.)
Second, single-nucleotide polymorphisms (SNPs, or “snips” as everyone calls them) are when a single base-pair is different, corresponding to a misprinted character.
Finally, copy-number variants (CNVs) are when a stretch of DNA is either missing (deleted), or repeated (duplicated), a bit like a page that’s either fallen out or been printed twice. As you can imagine, CNVs tend to be more serious than SNPs, because they affect more of the DNA. This is only a general rule, however. There are plenty of serious SNPs, and plenty of harmless CNVs. It all depends on where they happen, and whether they interfere with important genes.
For a long time, it was widely assumed that SNPs were responsible for psychiatric disorders, in what’s called the “common-variant model” of disease. The idea was that any given risk variant might be quite common, but it would only increase your risk of suffering a disease by a small amount. Those who carried a large number of risk variants would develop the disease. Those with a moderate number might get mild symptoms, and so on.
Yet this just didn’t work out. About ten years ago, it became feasible to scan huge numbers of SNPs quickly and cheaply. These “genome-wide association studies” (GWAS) tested hundreds of thousands of variants. Moving quickly to exploit the new technology, psychiatrists conducted GWAS after GWAS comparing people with diseases to those without — but very little came out. There are a few common SNPs which seem to be associated with some disorders, like autism and schizophrenia, but only a handful, and they have very small effects.