Many SNPs make up heritability

The Human Genome Project was supposed to shine a light on the phenomenon of heritability, illuminating how certain complex traits are passed down from parent to offspring.

The tool of choice was the genome-wide association (GWA) study, which compares the genomes of two individuals, one with a particular trait and one without.

The differences between these two genomes, in the form of single nucleotide polymorphisms (SNPs), were supposed to account for the genetic component of phenotypic variation.

Unfortunately, GWA studies have proven less than spectacular in picking out the SNPs that contribute to complex traits - a problem known as "missing heritability".

Now, a new study by researchers at the Queensland Institute of Medical Research (QIMR) has uncovered evidence that complex traits are linked to many SNPs, each of which has a such a small individual effect that it is undetectable in a conventional GWA study.

“We know from family studies there is high heritability of these complex traits however, we could not fully account for the variation by studying common genetic changes," said lead author, Professor Peter Visscher, from QIMR’s Queensland Statistical Genetics Laboratory.

"We were beginning to think that very rare mutations must play an important role. The question we wanted to answer was where is the missing heritability - the so-called dark matter of the genome?"

The researchers looked at the height data of 3,925 Australians and ran GWA studies to determine the genetic variations that accounted for the differences in height.

They found that 294,831 SNPs, when compared simultaneously, contributed to 45 per cent of the variability in height.

However, each individual SNP had such a small impact on height that it was not detectable with current statistical standards of significance. At least, not without suffering an unacceptably high false positive count.

“What we found was that many of the gene effects on height were so small that individually we were unable to detect them. However, when we studied the impact of all the common variants together we realised their cumulative effect was in fact very significant.”

As height is known to be roughly 80 per cent heritable, the remaining heritability was accounted for by the fact that some alleles are linked to each other, so if one is inherited, it's more likely the other will be inherited as well.

This phenomenon, called linkage disequilibrium, complicates the statistical analysis of SNPs and masks some of the alleles that are associated with complex traits in GWA studies.

The research has implications on the heritability for diseases and mental illnesses, like schizophrenia.

"If other complex traits in humans, including common diseases, have genetic architecture similar to that of height, then our results imply that larger GWASs will be needed to find individual SNPs that are significantly associated with these traits, because the variance typically explained by each SNP is so small," they write.

The research was published overnight in the journal Nature Genetics, DOI:10.1038/ng.608.