The world's largest publicly available dataset of human genomic variation has returned its first results in the form of seven simultaneously published studies.
In a large-scale collaborative effort, researchers gathered genetic information from more than 140,000 people globally, and made it publicly available online in the Genome Aggregation Database (gnomAD). The first group of papers to make use of this database – published simultaneously in several Nature journals – provide important insights into human biology and disease, tools for better diagnosis, and new rationales for treatment.
'The gnomAD resource is proving hugely valuable to understand which genes are important in human health and disease, and to understand which specific variants in those genes cause problems' said Dr James Ware, from the MRC London Institute of Medical Sciences at Imperial College London, co-author on three of the papers.
Because of the large size of the dataset and the diverse population represented, natural patterns of genetic variation can be precisely characterised. In one of the papers, in a research effort led by a team from the Broad Institute in Massachusetts, all human genes were classified by their likelihood of tolerating disruption. In effect, loss-of-function of genes which are essential for life – or which can cause serious genetic conditions – is likely to be very rare among the general population, and vice versa for non-essential genes. This resource provides important insights into human biology and importantly will contribute to accurate diagnosis of genetic disease.
Another three papers explored sources of clinically relevant genetic variation about which little was so far known on a global scale: respectively variation in gene 'control' elements, multi-nucleotide variants, and structural variation. These studies were able to pinpoint how such sources of genetic variation may cause specific conditions.
'Currently we only know the genetic changes that lead to rare diseases in around half of cases, which leaves many patients and their families in the dark about what is causing their often distressing conditions,' said Dr Nicola Whiffin, from the National Heart and Lung Institute who co-authored three of the papers. 'The use of this new genetic library has already enabled us to tell some patients we have found the genetic causes of their condition, which could open the door for personalised treatments.'
In another avenue of research, two of the papers focused on the safety of drug treatments which target particular genes. One set out the rationale for looking at people with naturally occurring loss-of-function variants to help assess the effects of drugs that target those genes while another focused on a specific example, using this approach to suggest that a potential treatment for Parkinson's disease might be safe.
Although the gnomAD database and resulting studies will provide an invaluable resource, a Nature editorial points out that the database is skewed towards people of European ancestry (representing around half of the samples):
'Although this is an improvement on previous studies, people from regions such as Central Asia, Oceania, the Middle East and much of Africa are almost absent. This means researchers are probably missing variants that are important for understanding gene function – and disease risk – in these regions'.