Rosetrees researcher profile: Dr. Nicky Whiffin, Imperial College London

Who Rosetrees Trust is funding

Dr. Nicky Whiffin is a research fellow in the National Heart and Lung Institute, at Imperial College London. Her research focuses on exploring genetic variants that cause rare diseases. Although individually rare, these diseases collectively affect >250 million people worldwide. Genetic testing is widespread in the clinical management of rare diseases, but current strategies only find a genetic cause for ~50% of cases.

Nicky is part of the Cardiovascular Genetics and Genomics team at Imperial College, led by her fellowship sponsor Dr. James Ware. The group focuses on a specific class of rare diseases called inherited cardiomyopathies. These conditions are diseases of the heart muscle, resulting in heart failure and often sudden death.

To date, much of genetic research into rare disease has focused on regions of the DNA that code directly for proteins, which accounts for ~1.5% of the genome, and these regions have been the traditional focus in clinical diagnostic settings. This is because studies of ‘non-coding’ DNA, rich in functional elements that regulate protein production, have certain limitations including the requirement for large sample sizes, and difficulties in interpreting the effect of any individual variant. Despite these challenges, there is strong supporting evidence indicating that variants in non-coding DNA cause disease.

Nicky is using state-of-the-art techniques to narrow down the 98.5% of the genome that is non-coding to identify small regions and individual variants that cause rare diseases. The data output from this project will enable investigation of the contribution of rare non-coding variants to the pathogenesis of rare diseases, including cardiomyopathies. Nicky’s research is also highly translational, because it will inform genetic testing and impact patient care.

Nicky said: To a patient with a rare disease, knowing the precise genetic cause is invaluable. This genetic diagnosis can be used to screen other family members to identify those also at risk of disease, to suggest personalised treatment approaches and can often end a long ‘diagnostic odyssey’ for patients and their families. This research is increasing our understanding of non-coding variants that cause rare diseases and how they do so. Ultimately this will enable more patients to receive a valuable genetic diagnosis.

Dr. Nicky Whiffin

How Rosetrees Trust have supported Dr. Nicky Whiffin

Nicky is a Rosetrees/Stoneygate 2018 Imperial College Research Fellow, receiving funding for her fellowship from 2018 to 2022, under the sponsorship of Dr. James Ware. This springboard award has enabled Nicky to build her independent research program and foster a strong collaboration with Dr. Daniel MacArthur and researchers at the Broad Institute in Boston where she is a visiting scientist.

What the outcomes are of Rosetrees Trust-/Stoneygate-funded research from Dr. Nicky Whiffin

Nicky is a member of the analysis team of the Genome Aggregation Database (gnomAD), a collaboration of >100 principle investigators spearheaded by Dr. MacArthur. GnomAD is used across the globe, by both researchers and for clinical diagnostics, and is central to the analysis for this project.

Briefly, gnomAD is a population reference dataset that brings together exome and genome sequencing data from largescale sequencing projects, accessible to the wider scientific community. The resource gives us an accurate picture of which genetic variants exist naturally in the population, helping us to identify those which are unlikely to cause rare diseases. Nicky and James are members of the gnomAD consortium, contributing to the creation and analysis of the data. This database is continuously being scaled-up, growing from sequencing data of ~60,000 individuals (as the precursor ExAC database) to more than 140,000 individuals (~15,000 whole-genomes). The latest release contains whole-genome sequencing data for >70,000 individuals.

Today, the gnomAD consortium released a package of 7 publications in Nature Journals (Whiffin et al., 2020a; Whiffin et al., 2020b; Karczewski et al., 2020; Collins et al., 2020; Cummings et al., 2020; Wang et al., 2020; Minikel et al., 2020). Nicky led the analysis for two of the papers, published in Nature Communications (Whiffin et al., 2020a) and Nature Medicine (Whiffin et al., 2020b).

In the first of these, Nicky, supported by James and Dr. MacArthur, used the whole-genome sequenced subset of gnomAD to identify and characterise a new class of variants, found outside of protein coding regions, that reduce protein translation and lead to rare disease, published in Nature Communications (Whiffin et al., 2020a). Here, the team demonstrated the power of using large population datasets to identify specific non-coding bases that are under strong selection, using an approach that had previously only been applied to protein-coding variants. When this research was first published on the pre-print sever bioRxiv, Nicky was approached by others in the community who had determined new genetic diagnoses for previously unsolved patients as a direct result of this work.

The second of these papers, published in Nature Medicine (Whiffin et al., 2020b), is a large collaboration between the gnomAD consortium and the direct-to-consumer genetic testing company 23andMe, which also uses the UK Biobank resource. This work was co-led by Irina Armean from the Broad Institute and Aaron Kleinman from 23andMe. Together, they looked specifically at loss-of-function variants in the gene LRRK2. Variants that cause increased LRRK2 kinase function are a known cause of Parkinson’s disease, and drug companies are currently developing LRRK2 inhibitors as a potential treatment strategy. In early model organism studies, however, completely knocking-out LRRK2 resulted in severe side-effects in the lung/liver/kidney. Here, the team looked directly in over 4 million humans, from their three datasets. They assessed the phenotypic impact of a lifelong natural reduction in LRRK2 protein levels, caused by heterozygous loss-of-function variants. The team found no detectable increase in severe disease phenotypes in individuals with these variants, suggesting that reducing LRRK2 protein levels in humans should not cause any severe disease side-effects, at least due to on-target effects. This is promising news for patients with Parkinson’s disease.

What the future holds for Dr. Nicky Whiffin

Nicky has recently been awarded a prestigious Sir Henry Dale fellowship from the Wellcome Trust. Moving from Imperial to the Wellcome Centre for Human Genetics at the University of Oxford, Nicky will become a group leader and continue her research exploring the effect of non-coding variants in rare diseases.

Written by: Dr. Rebecca Downing and Dr. Nicky Whiffin