Heightened Genetic Disease Risk Linked to Remote Regions in the U.K.

Individuals from isolated parts of the U.K. could have variations in their genetic code that increase their chance of developing certain diseases, according to a new study “Regionally enriched rare deleterious exonic variants in the U.K. and Ireland” in Nature Communications.

The most genetically distinct populations were found in Shetland and Orkney, where some disease-causing variants were more than 100 times more common than elsewhere in the U.K. Scientists at the University of Edinburgh and Regeneron also identified populations in north and south Wales, southeast Scotland, Ireland and parts of England who carry genetic variants that are up to 73 times more common than in the general population.

“It is unclear how patterns of regional genetic differentiation in the U.K. and Ireland might impact the protein-coding fraction of the genome. We exploit UK Biobank (UKB) and Viking Genes whole exome sequencing data to study regional genetic differentiation across the U.K. and Ireland in protein coding genes, encompassing 44,696 unrelated individuals from 20 regions of origin,” write the investigators.

“We demonstrate substantial exonic differentiation among Shetlanders, Orcadians, individuals with full or partial Ashkenazi Jewish ancestry and in several mainland regions (particularly north and south Wales, southeast Scotland and Ireland). With stringent filtering criteria, we find 67 regionally enriched (≥5-fold) variants likely to have adverse biomedical consequences in homozygous individuals.”

“Here, we show that regional genetic variation across the U.K. and Ireland should be considered in the design of genetic studies and may inform effective genetic screening and counseling.”

The findings highlight the important link between ancestry and health, particularly among remote communities, according to the researchers. Populations in isolated locations are less genetically diverse than cities, with fewer people moving into and out of the area. As a result, rare genetic variants can become common and pass down through generations.

The University of Edinburgh-led research team looked at anonymized genetic information from more than 44,000 people across 20 regions in the U.K., based on data from the UK BioBank and VIKING Genes studies. They were unable to include all regions across the U.K., due to a lack of data.

Six disease-causing variants were identified among those from Shetland, including one linked to Batten disease, a life-limiting neurodegenerative condition in children. An estimated one in 41 Shetlanders are carriers of the condition.

These so-called “genetic islands” were found not just off the U.K.’s coast. The study uncovered several on the mainland. The research team found nine disease-causing variants at much higher frequencies in Wales, including one causing an inherited form of kidney stones disorder, which is 44 times more common in south Wales than in the general population.

The ten English regions included in the study were not as genetically distinct, the study found. This could reflect the lack of geographic or cultural barriers between the regions, such as sea channels, mountains, or language differences. Despite this, a number of rare variants were found to be more prevalent in areas including Lancashire, Staffordshire, and Nottinghamshire.

People from Lancashire are 73 times more likely than the general U.K. population to carry a variant linked to Zellweger syndrome, a disease affecting the brain, liver and kidney, which is fatal in the first year of life.

The findings highlight the need for further research into rare genetic variants in regions across the U.K. Any future genetic screening programs, designed to identify those at risk of disease, should be tailored to include common variants in the region, the research team says.

“The enrichment of otherwise rare disease-causing genetic variants in regional populations in Britain, particularly in Shetland, but also Orkney and Wales, should inform genomic medicine strategies,” noted Jim Flett Wilson, DPhil, study lead from the University of Edinburgh’s Usher Institute. “Targeted screening for genetic disorders is common in Jewish populations, including in England. Our results show that genetic screening is also warranted in other U.K. communities, particularly Shetland.”

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