The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 07 2022
08 07 2022
Historique:
received:
18
10
2021
accepted:
15
06
2022
entrez:
8
7
2022
pubmed:
9
7
2022
medline:
14
7
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35803923
doi: 10.1038/s41467-022-31392-3
pii: 10.1038/s41467-022-31392-3
pmc: PMC9270319
doi:
Substances chimiques
Mutant Proteins
0
Monophenol Monooxygenase
EC 1.14.18.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3939Subventions
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 224643/Z/21/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 200990/Z/16/Z
Pays : United Kingdom
Organisme : Department of Health
ID : CL-2017-06-001
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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