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

Genetic diseases have been historically segregated into rare Mendelian and common complex conditions.1,2 Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits.3-8 Aiming to gain insights into the genetic architecture of rare recessive disorders, we studied a cohort of 1,313 individuals with albinism, an archetypal Mendelian condition. 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, disease-associated missense change, TYR c.1205G>A [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 increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants increases diagnostic yield and informs genetic counselling in families with albinism.