The human genome, encoded on the Brooklyn Bridge

What do we know now?

How is current research investigating the genetic basis of disease?

Access to data about the entire genome is increasing knowledge of many diseases, but it is also reinforcing our awareness of how complex cells, tissues and bodies are. Although the press may still report on a ‘gene for’ conditions like arthritis or depression, studies almost always show that there are multiple factors involved.

One powerful research approach is to use genome-wide association studies (GWAS). These involve going through the entire genome looking for common genetic variants – usually single ‘letter’ differences known as single nucleotide polymorphisms (SNPs) – to see whether they are associated with a disease or physical trait. 

GWAS have identified thousands of variants associated with disease or other physical traits. In some cases they have honed in on the precise genetic culprit: for example, one GWAS study found that variations in the HMGCR gene – the target of cholesterol-lowering statin drugs – are linked to changes in the level of cholesterol circulating in the blood.

However, since the SNPs identified in GWAS studies are markers for a wider region in which they sit, it’s difficult to pinpoint exactly which variants within the region are the real causative agents. Moreover, around 88 per cent of the SNPs associated with particular diseases either lie between genes on the genome (intergenic) or, if they are inside a gene, get removed by RNA splicing during transcription (intronic), so they never actually form a protein. And most effects are caused by combinations of variants, not single SNPs, which makes it difficult to untangle what mechanisms they use.

As the cost of sequencing drops – and methods become faster and more precise – whole-genome sequencing may complement or even replace GWAS studies. As the name suggests, these scans look at the entire DNA sequence in a person’s genome, rather than merely looking for markers that flag up particular regions.

In 2011, researchers sequenced the genomes of 87 Icelanders and used that data in combination with GWAS to identify a rare variant associated with a high risk of developing sick sinus syndrome, which causes abnormal heart rhythm.

In 2014, scientists at Stanford University in the USA sequenced the whole genomes of 12 people with no diagnosed genetic diseases and found each person had between two and six disease-causing mutations. However, they cautioned that the sequencing provided only a rough draft: 10 to 19 per cent of genes known to be linked to disease were inadequately sequenced. And disease-causing deletions from or additions to parts of genes could have been missed.

Although it is not yet done as a matter of routine, in the future whole-genome sequencing is likely to change the practice of population screening programmes such as newborn screening. Stanford University’s pilot programme is initially only offering whole-genome sequencing to patients who are thought to have ‘mystery diseases’, hereditary diseases and inherited risk factors, but there have been calls for genomic testing to be used more widely to predict and prevent disease.

Lead image:

The human genome, encoded on the Brooklyn Bridge

Matt Green/Flickr CC BY NC ND


About this resource

This resource was first published in ‘Genes, Genomes and Health’ in January 2010 and reviewed and updated in December 2014.

Genetics and genomics, Medicine, Health, infection and disease
Genes, Genomes and Health
Education levels:
16–19, Continuing professional development