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

Abstract

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 We studied a cohort of 1,313 individuals with albinism aiming to gain insights into the genetic architecture of rare, autosomal recessive disorders. We investigated the contribution of regulatory and protein-coding variants at the common and rare ends of the allele-frequency spectrum. We focused on TYR, the gene encoding tyrosinase, and found that a 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, functional variants, TYR c.[-301C;575C>A;1205G>A], confers a high risk of albinism (OR>77) and is associated with reduced vision 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.

Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database

“…prion disease 8 , metabolic conditions 9 , and maturity-onset diabetes of the young (MODY) 10 , and more broadly investigating the association of pathogenic variants to 401 phenotypes in 379,768 individuals from the UK Biobank 5 . Investigations moving beyond descriptive reports and association studies towards focusing on mechanisms underlying incomplete penetrance are few and disease-specific [11][12][13][14] , with examples of how expression levels 15 , eQTL 16 , and sQTLs 17 could modulate penetrance. A statistical approach to investigate eQTL association with incomplete penetrance in neurodevelopmental disease in 1,700 trios from the Deciphering Developmental Disorder cohort did not find altered gene expression due to known eQTLs to be an explanation for incomplete penetrance in the unaffected parents carrying the variant of the affected probands 18 .…”