The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism

Vincent Michaud, Eulalie Lasseaux, David J. Green, Dave T. Gerrard, Claudio Plaisant, Tomas Fitzgerald, Ewan Birney, Benoît Arveiler (), Graeme C. Black () and Panagiotis I. Sergouniotis ()
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Vincent Michaud: University Hospital of Bordeaux
Eulalie Lasseaux: University Hospital of Bordeaux
David J. Green: University of Manchester
Dave T. Gerrard: University of Manchester
Claudio Plaisant: University Hospital of Bordeaux
Tomas Fitzgerald: European Bioinformatics Institute (EMBL- EBI)
Ewan Birney: European Bioinformatics Institute (EMBL- EBI)
Benoît Arveiler: University Hospital of Bordeaux
Graeme C. Black: University of Manchester
Panagiotis I. Sergouniotis: University of Manchester

Nature Communications, 2022, vol. 13, issue 1, 1-8

Abstract: Abstract Genetic diseases have been historically segregated into rare Mendelian disorders and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. Here, we analysed data from the Genomics England 100,000 Genomes Project and from a cohort of 1313 individuals with albinism aiming to gain insights into the genetic architecture of this archetypal rare disorder. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.−301C>T [rs4547091], modulates the penetrance of a prevalent, albinism-associated missense change, TYR c.1205G>A (p.Arg402Gln) [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[−301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and with increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants can increase diagnostic yield and can help inform genetic counselling in families with albinism.

Date: 2022
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DOI: 10.1038/s41467-022-31392-3

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