Study defines average human genome and normal genetic disease risk

A new study has characterized the "average" human genome, providing key information on normal human genetic variation and genetic disease risk.

Researchers at the University of Exeter concluded that everyone – regardless of their current health status – could potentially be told they are at risk for numerous conditions based on their genetics alone. 

Led by the University of Exeter, the study is published today in Genome Medicine and is also being presented at the American Society of Human Genetics annual meeting. The research was supported by the Medical Research Council, the Wellcome and the NIHR Biomedical Research Center: Exeter. The team analysed data from two major population biobanks that include whole genome sequencing, totalling nearly one million individuals.

Key findings include that every person's genome includes around five million variants, or locations in the DNA that differ between individuals. These include around 10,000 that alter gene sequences, which can have a positive or negative effect – ranging from lactose intolerance to drug response – but are often biologically neutral. Every person also has between one and three rare variants that have previously been shown to cause serious genetic diseases, and another 50 rare variants that are currently of uncertain clinical relevance.

The team also analyzed numerous polygenic risk scores, which take into account all known genetic factors to calculate risk of getting a disease in future. Looking at polygenic scores for 28 common conditions – such as diabetes, cardiovascular disease and schizophrenia – they found that most people would be categorized as at high risk of genetic risk for around three conditions. The team did not investigate the health status of any of the participants, so many of these participants might not have any diseases. The study underlines that such findings can be part of normal genetic variation, and other factors are crucial in development of disease.

Whole genome sequencing has become such an important tool in diagnosing genetic disease, and we're increasingly moving towards genetic screening for predicting disease. Yet most people are unaware of just how much genetic variation is present in every genome. Actually, variation is the norm. For the first time, our study outlines what to expect in the average human genome, which can benefit clinicians and patients across the word in understanding, interpreting and contextualizing genomics.

Importantly, we found that everyone carries a small number of genetic variants linked to disease, although many of these will not actually cause disease in that individual. It is therefore crucial to consider context when interpreting findings from genetic testing, including symptoms or family history of disease as well as other clinical and environmental risk factors. Our findings also provide important context for professionals who are interpreting genetic testing results or commissioning genetic screening programs."

Professor Caroline Wright, Senior Author, University of Exeter

Researchers analyzed data from UK Biobank, and from the All of US study, in the US. Although the studies are large, participation is skewed towards people of Western European origin, and the research team recognizes the need for data on more diverse populations to continue to evolve understanding and impact.

Among the findings, they also found that individuals in the two biobanks who were recruited alongside their parents had around 63 "new" variants in their genome, not present in either parent. Known as "de novo", these mutations occurred mostly in the fathers' sperm and some in the mothers' eggs. The number increased particularly with the age of the father (around 1.2 more mutations per year), which has important implications for reproductive decision-making.

The paper is titled 'The average individual genome: a survey of nearly 1 million whole-genome sequences', and is published in Genome Medicine.