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In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. Ocular coloboma is the most common significant developmental eye defect with an incidence of ~1 in 5,000 live births. It results from failure of optic fissure closure during embryogenesis. The position and extent of the fusion failure dictates the clinical appearance and functional effect. ~30% of coloboma cases are associated with other systemic malformations. These UK10K samples will mostly comprise isolated coloboma cases without systemic involvement (aka non-syndromal coloboma). There is strong evidence from family studies that coloboma has a major genetic component with autosomal dominance being the most common pattern of inheritance. However, many cases are isolated or show complex patterns of familial clustering. The genes responsible for isolated coloboma are largely unknown, but in a small number of families mutations in SHH, CHX10, and PAX6 have been identified indicating marked genetic heterogeneity. Thus in addition to the clinical benefits of achieving a molecular diagnosis there are also major scientific advantages to identifying coloboma genes, as these are likely to provide insights into the complex process of optic fissure closure, that is critical to normal eye development. In the longer term, understanding the molecular basis of the disease may provide clues to therapeutic strategies.For further information with regard to this cohort please contact David Fitzpatrick (

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001000179 Illumina Genome Analyzer II Illumina HiSeq 2000 75
EGAD00001000185 Illumina Genome Analyzer II Illumina HiSeq 2000 98
EGAD00001000206 Illumina Genome Analyzer II Illumina HiSeq 2000 123
EGAD00001000307 Illumina Genome Analyzer II Illumina HiSeq 2000 117
EGAD00001000415 Illumina Genome Analyzer II Illumina HiSeq 2000 123
Publications Citations
Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.
Am J Hum Genet 94: 2014 915-923
Mutations in MAB21L2 result in ocular Coloboma, microcornea and cataracts.
PLoS Genet 11: 2015 e1005002
The UK10K project identifies rare variants in health and disease.
Nature 526: 2015 82-90
A recurrent de novo mutation in ACTG1 causes isolated ocular coloboma.
Hum Mutat 38: 2017 942-946