Genetic Study Reveals Elevated Risk of Rare Inherited Diseases in Scottish Traveller Founder Population
核心洞察
A landmark genetic study of Scottish Travellers identified five rare recessive pathogenic variants with up to 2,500-fold enrichment compared to non-Finnish Europeans, including variants causing kidney disease and congenital myasthenic syndrome.
Researchers from the University of Edinburgh found that full Scottish Travellers carry an average of 84.9 Mb of runs of homozygosity, over 30 times higher than the mainland British population, consistent with a history of endogamy and recent consanguinity.
The study confirmed Scottish Travellers are genetically distinct from Irish Travellers and European Roma, with indigenous Scottish origins and two internal genetic subclusters reflecting Highland and Lowland ancestries.
The first comprehensive genetic study of the Scottish Traveller community has uncovered a markedly elevated risk of rare inherited diseases, driven by a combination of founder effects, population bottlenecks, and high levels of consanguinity. Published in Nature Communications, the Traveller Genes project—led by Professor Jim Flett Wilson at the University of Edinburgh's Usher Institute—provides the first scientific evidence that otherwise ultra-rare recessive pathogenic variants have drifted to carrier frequencies exceeding 5% in this population.
The study, initiated after a request from Scottish Traveller Samantha Whyte Donaldson, recruited 148 participants with at least two self-reported Traveller grandparents between 2021 and 2022. After quality control, 125 individuals remained for analysis, with whole-exome sequencing performed on 123 participants and genome-wide SNP array genotyping on 48.
Clinically Significant Founder Variants Identified
Analysis of exome sequences through a ClinVar-based pipeline revealed 166 pathogenic or likely pathogenic (P/LP) variants with two-star or higher evidence status. Among these, five putative founder variants demonstrated striking enrichment in the Scottish Traveller population:
- CRB2 c.3089_3104dup: A frameshift variant causing focal segmental glomerulosclerosis 9 (MIM #616220) in homozygotes, leading to proteinuria and progressive renal decline. This variant showed a 2,500-fold uplift compared to non-Finnish Europeans and was absent from gnomAD.
- CANT1 c.902_906dup: A frameshift variant causing Desbuquois dysplasia 1 (MIM #251450), a chondrodysplasia, with a 2,371-fold uplift.
- HOGA1 c.569 C>T: A variant causing primary hyperoxaluria type III (MIM #613616) when homozygous, with a 1,389-fold uplift.
- PIEZO1 c.3331 C>T: A truncating variant causing lymphatic malformation 6 (MIM #616843), a form of generalized lymphatic dysplasia, with a 2,075-fold uplift and detected only in Scottish Traveller samples.
- DOK7 c.1124_1127dup: A frameshift variant causing congenital myasthenic syndrome 10 (MIM #254300), with a 30-fold uplift.
Two additional variants showed approximately 12- to 14-fold enrichment: VWF (搜索) c.2561 G>A, associated with Von Willebrand disease (搜索), and ASL (搜索) c.35 G>A, causing argininosuccinic aciduria (搜索).
Professor Wilson emphasized the importance of this research for addressing health inequalities: "Every population I've looked at has its own set of genetic risks," he said, noting his prior work identifying elevated cancer risks in Orkney and Shetland populations.
High Burden of Homozygosity and Consanguinity
The study documented a substantial burden of runs of homozygosity (ROH) among full Scottish Travellers—those with four Traveller grandparents. The average sum of ROH segments ≥5 Mb was 84.9 Mb, compared to just 2.8 Mb in British and Irish mainland reference populations, representing a greater than 30-fold increase. The genomic inbreeding coefficient (FROH) reached 3.8%, comparable to offspring of first cousins once removed.
The burden was particularly pronounced in the Scot-TravA genetic subcluster, with an average sum of ROH ≥5 Mb of 83.3 Mb and an FIS of 0.036, similar to levels observed in the Pakistani community in Bradford, England. Scot-TravB showed lower but still elevated levels, with an average of 23.8 Mb—approximately 8-fold higher than reference populations.
Indigenous Scottish Origins Confirmed
Contrary to historical speculation linking Scottish Travellers to Romani or Pictish populations, the genetic analyses firmly established indigenous Scottish origins. Principal components analysis showed Scottish Travellers clustering with reference Scottish samples while forming their own distinct genetic cluster. No evidence of genetic relationship with European Roma was detected.
"We don't really want to be anything other than Scottish and I will stand up in any platform and say I'm a Scot," said Jess Smith, a 78-year-old elder and storyteller of Traveller history in Scotland.
Two major genetic subclusters were identified: Scot-TravA, which appears to have drifted farther from settled populations and likely captures Highland Traveller ancestry, and Scot-TravB, which shows greater similarity to settled Scots and may reflect Lowland Traveller ancestry with more historical admixture.
Mitochondrial DNA and Population Bottleneck
Analysis of complete mitochondrial genomes from 91 individuals revealed that 24% of Scottish Traveller matrilines belong to a single founder haplotype, T2f1a1, with eight lineages accounting for 64% of the maternal gene pool. All mitochondrial haplogroups identified were of Western European origin.
Demographic modeling using IBDNe estimated a recent population bottleneck, with the effective population size of Scot-TravA dropping from approximately 18,000 to just 278 individuals over eight generations—a 98% decrease. Scot-TravB experienced a similar but less severe reduction, from approximately 17,800 to 887 individuals.
Implications for Clinical Care and Screening
The findings carry significant implications for healthcare delivery. Among 82 participants with at least two Scottish Traveller grandparents, 68 (84%) carried two or more different recessive P/LP variants, and 13% carried five or more. The study authors advocate for a bespoke community-based reproductive carrier screening program, similar to the J-netics model serving Jewish populations in the UK.
Samantha Whyte Donaldson underscored the urgency: "Unfortunately Scottish Travellers do have a shorter life expectancy compared to the settled population. Prejudice and discrimination is one part of it but health disparities are another, so I'm hoping the Scottish government sees this and thinks: 'What can we do in terms of things like screening programmes'?"
The researchers stressed that while the relative risk is dramatically elevated, the absolute risk remains low—these rare diseases are still very uncommon in the community. Nevertheless, clinicians caring for Scottish Travellers should be aware of the predicted enrichment for the five most uplifted disorders and the generally higher prevalence of otherwise rare recessive Mendelian diseases.
The study received a favorable opinion from the NHS NRA London—London Bridge Research Ethics Committee (21/PR/1229), and all participants provided written informed consent. The authors note that the historic and systemic discrimination faced by the Traveller community has contributed to the worst outcomes in education, health, employment, and criminal justice in Scotland, making culturally sensitive engagement essential for any future screening initiatives.