Fig. 1: Outline of the case–control study design.

A case–control analysis was performed to gain insights into the contribution of protein-coding and regulatory variation (at the common and rare ends of the allele-frequency spectrum) in albinism. The majority of participants in the ‘case’ cohort (1208/1313) were identified through the database of the University Hospital of Bordeaux Molecular Genetics Laboratory, France. All these probands had at least one key ocular feature of albinism, i.e. nystagmus or prominent foveal hypoplasia. The remaining 105/1313 cases were identified through the Genomics England 100,000 Genomes Project dataset and had a diagnosis of albinism or a phenotype deemed consistent with partial/ocular albinism. The ‘control’ cohort included 29,497 unrelated individuals from the Genomics England 100,000 Genomes Project dataset, none of whom had a recorded diagnosis of albinism. Genotypes that include selected TYR haplotypes in homozygous state were studied. Haplotypes of interest were defined as those formed by combinations of TYR variants that are predicted to be functionally relevant; three variants met the pre-determined criteria set for regulatory (TYR c.−301C>T) and common protein-coding (TYR c.575C>A and c.1205G>A) variants. The associated haplotypic blocks were analysed further using logistic regression (see Methods). 100K_GP Genomics England 100,000 Genomes Project, eQTLs expression quantitative trait loci, MAF minor allele frequency, CADD Combined Annotation Dependent Depletion score, HGMD Human Gene Mutation Database v2021.2. TYR variant numbering is based on the transcript with the following identifiers: NM_000372.5 and ENST00000263321.6.