If you want to predict how tall your children might one day be, a good bet would be to look in the mirror, and at your mate. Studies going back almost a century have estimated that height is 80-90% heritable. So if 29 centimetres separate the tallest 5% of a population from the shortest, then genetics would account for as many as 27 of them (1).
This year, three groups of researchers (2-4) scoured the genomes of huge populations (the largest study (4) looked at more than 30,000 people) for genetic variants associated with the height differences. More than 40 turned up.
But there was a problem: the variants had tiny effects. Altogether, they accounted for little more than 5% of height's heritability--just 6 centimetres by the calculations above.
Even though these genome-wide association studies (GWAS) turned up dozens of variants, they did "very little of the prediction that you would do just by asking people how tall their parents are", says Joel Hirschhorn at the Broad Institute in Cambridge, Massachusetts, who led one of the studies (3).
Height isn't the only trait in which genes have gone missing, nor is it the most important. Studies looking at similarities between identical and fraternal twins estimate heritability at more than 90% for autism (5) and more than 80% for schizophrenia (6). And genetics makes a major contribution to disorders such as obesity, diabetes and heart disease. GWAS, one of the most celebrated techniques of the past five years, promised to deliver many of the genes involved (see 'Where's the reward?', page 20). And to some extent they have, identifying more than 400 genetic variants that contribute to a variety of traits and common diseases. But even when dozens of genes have been linked to a trait, both the individual and cumulative effects are disappointingly small and nowhere near enough to explain earlier estimates of heritability. "It is the big topic in the genetics of common disease right now," says Francis Collins, former head of the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland. The unexpected results left researchers at a point "where we all had to scratch our heads and say, 'Huh?'", he says.
Although flummoxed by this missing heritability, geneticists remain optimistic that they can find more of it. "These are very early days, and there are things that are doable in the next year or two that may well explain another sizeable chunk of heritability," says Hirschhorn. So where might it be hiding?
Right under everyone's noses
The inability to find some genes could be explained by the limitations of GWAS. These studies have identified numerous one-letter variations in DNA called single nucleotide polymorphisms (SNPs) that co-occur with a disease or other trait in thousands of people. But a given SNP represents a much bigger block of genetic material. So, for example, if two people share one of these variants at a key location, both may be scored as having the same version of any height-related gene in...