Human Genetics

Human Genetics

Human Genetics

Our Approach

bloodcells.jpgAnnie Cavanagh, Wellcome Images
The Human Genetics Programme studies the genetic aetiology of common cardiometabolic,  immunity and inflammatory diseases, and associated biological traits.

The Human Genetics Programme seeks to bring genomics to population-scale studies (in the UK, and in diverse populations); progress beyond locus discovery and mapping, to causal variant and pathway identification; provide mechanistic insights into how individual variants impact health and disease; and gain knowledge of variable phenotypic expressivity, and assess reversibility of developmental phenotypes, which may yield important therapeutic insights.

The Human Genetics Programme will:
  • use genetic and genomic approaches to improve understanding of the aetiology of rare and complex inherited disease, to characterise healthy variation in humans of different ancestry and to advance knowledge of human population evolution, demography and history.
  • study cohorts of 10,000s - 100,000s healthy participants from the UK population for 100s to 1000s of quantitative traits, relating these to cardiometabolic and other diseases; and identify thousands of homozygously null genes compatible with human life.
  • begin studies using electronic health records for patient recruitment (e.g. in patients with drug-induced liver injury), endophenotyping (e.g. in patients with osteoarthritis) and provision of detailed medical information for apparently healthy individuals carriers of homozygous loss-of-function mutations in lipid metabolism genes.
  • leverage diverse human populations (African, isolated European and cosmopolitan European) to elucidate the genetic architecture of cardiometabolic diseases and traits; and with the study of ancient DNAs gain insights into human evolution, history and diversity.
  • use a multidimensional functional genomics approach (including rare genetic variation studies, studies of intestinal microbiota, studies of gene effects in subsets of immune cells) to understand consequences of disease-associated variants on genome regulation, focusing on disorders of inflammation and immunity; and understand the effect of genetic variation on normal immune response (e.g. variation in response to immune stimulation through studies of vaccinated individuals).
  • continue to search for mutated genes causing rare developmental and metabolic disorders, model these disease phenotypes in engineered mice, and with use of mouse models examine the possibility that some phenotypic elements of these conditions may be reversible.
  • begin to explore the cell biology underlying variability in organism-level phenotypic expression of genetic abnormalities.
Our Work

The main areas of research of the Human Genetics Programme can be summarised as:

Genomics of UK biomedical resources

We are facilitating powered population-scale genetic studies in medically relevant traits, by aligning genomic approaches to samples from individuals with existing electronic health records (eHRs) in established cohorts and registries.

Complex traits in diverse populations

We are studying diverse human populations with different LD (linkage disequilibrium) structures to elucidate the genetic architecture of cardiometabolic and infectious diseases and traits, and inform population genetic studies. By combining whole-genome sequencing and genotyping approaches in thousands of people (>100,000) we are carrying out powered association analysis to delve further into human history and evolution.

Integrated genomics of inflammation and immunity

We are employing post-GWAS (genome-wide association study) multidimensional functional genomic analyses to understand the consequences of disease-associated variant on genome regulation, focusing on disorders of inflammation and immunity.

Causes, mechanisms and reversibility of rare diseases

We seek to extensively characterise the genetic architecture of rare metabolic and developmental disorders through whole-genome sequencing approaches (in partnership with Genomics England); to integrate investigations (including functional genomics) in cells and mice to support inferences of causality; and provide insights into disease mechanism.

Parts of our research build on our ability to characterise human genetic variation globally, in isolated (Finnish, Greek and Italian isolates) and cosmopolitan populations (1000 Genomes Project, UK10K, African Genome Variation Project), to harness information pertaining to human population diversity and evolution. While other elements seek to provide new resources and foundations for worldwide research, for example we are working with our network of partners in Africa to jointly undertake GWAS on 100,000 participants from Africa, across a range of cardiometabolic and infectious traits. This will bring these studies to a scale equivalent to that obtained in European cohorts.

Our work will also continue to focus on a core set of traits and phenotypes with significant impact on morbidity and mortality: haematological, cardiometabolic, inflammation and immunity and developmental disorders. And in all of these areas we aspire to understand the impact of rare and very rare variation in these diseases and traits.



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