Researchers at the University of Oslo have mapped which parts of our DNA carry the inherited differences behind complex traits and disorders. The more complex the trait, the more of those differences lie in the DNA between genes rather than in the genes themselves. This suggests that much of what shapes psychiatric and cognitive conditions lies in the parts of the genome that we understand the least.

Schizophrenia, height, cholesterol. Each has its own genetic signature. That signature is made up of genetic variants: small differences in the DNA sequence that make one person's genome differ from another's. Some traits, such as the amount of cholesterol in the blood, are shaped by relatively few genetic variants. Other traits, such as schizophrenia, are shaped by many thousands of them, each contributing almost nothing on its own. Geneticists call this polygenicity.

Heritability tells us how much of the variation in a trait between people is linked to the common DNA differences we can measure. But identifying where in the genome that heritability is located has been more difficult.

Researchers at the Centre for Precision Psychiatry, University of Oslo, have now found that polygenicity is what predicts the answer. Across 34 traits and disorders, the found a consistent pattern: the more polygenic the trait, the more of its heritability lay far from genes, in the long stretches of DNA between them.

A shift from genes to intergenic DNA
The researchers divided the genome into three adjacent regions. When a cell copies a gene into RNA, some pieces are kept and the rest are cut out. The pieces kept are exons, and make up about 2.5 per cent of the genome. The pieces cut out are introns, and make up 45 per cent. The intergenic stretches between genes make up the rest.

It has long been known that more than 85 per cent of heritability lies outside exons. What nobody had done was line the traits up, from the least polygenic to the most, and check whether that balance shifts along the way. It does, and closely.

Introns were the fixed point, holding about half of heritability in nearly every trait. The movement was between exons and the intergenic regions: the more variants shaping a trait, the more of its heritability lay between the genes, and the less of it in exons.

The range is wide. For schizophrenia, exons carry 8 per cent of heritability. For height, 20 per cent. For sex hormone-binding globulin, a protein measured in routine blood tests, they carry 29 per cent. “Complex traits do not all have the same genetic architecture”, says Julian Fuhrer, first author of the study. “At one end of the spectrum, heritability is concentrated near genes. At the other, it is spread thinly across regions far away from them”.

Implications for genetic research
The result bears on how future studies are designed. Sequencing only the protein-coding part of the genome is far cheaper than sequencing all of it, and efficient when a trait's effects are concentrated in coding regions. That assumption weakens as traits become more polygenic.

“For the most polygenic traits, the answer is mostly somewhere else”, says Oleksandr Frei, senior author of the study. “Where budgets allow, sequencing the whole genome is the better choice for complex traits such as psychiatric and cognitive conditions”.

The researchers extended MiXeR, a statistical model developed in Oslo with collaborators at the University of California San Diego, to estimate heritability across 74 functional categories of the genome. They applied the method to published European-ancestry association data for 34 traits and disorders.