The co-occurrence of genetic variants in the TYR and OCA2 genes confers susceptibility to albinism

Abstract

Although rare genetic conditions are mostly caused by DNA sequence alterations that functionally disrupt individual genes, large-scale studies using genome sequencing have started to unmask additional complexity. Understanding how combinations of variants in different genes shape human phenotypes is expected to provide important insights into the clinical and genetic heterogeneity of rare disorders. Here, we use albinism, an archetypal rare condition associated with hypopigmentation, as an exemplar for the study of genetic interactions. We analyse data from the Genomics England 100,000 Genomes Project alongside a cohort of 1120 individuals with albinism, and investigate the effect of dual heterozygosity for the combination of two established albinism-related variants: TYR:c.1205 G > A (p.Arg402Gln) [rs1126809] and OCA2:c.1327 G > A (p.Val443Ile) [rs74653330]. As each of these changes alone is insufficient to cause disease when present in the heterozygous state, we sought evidence of synergistic effects. We show that, when both variants are present, the probability of receiving a diagnosis of albinism is significantly increased (odds ratio 12.8; 95% confidence interval 6.0 - 24.7; p-value 2.1 ×10^-8). Further analyses in an independent cohort, the UK Biobank, support this finding and highlight that heterozygosity for the TYR:c.1205 G > A and OCA2:c.1327 G > A variant combination is associated with statistically significant alterations in visual acuity and central retinal thickness (traits that are considered albinism endophenotypes). The approach discussed in this report opens up new avenues for the investigation of oligogenic patterns in apparently Mendelian disorders.

Fig. 1. Outline of the case-control study design.

A case-control analysis was performed to gain insights into the role of genotypes involving dual heterozygosity for TYR:c.1205 G > A (p.Arg402Gln) [rs1126809] and OCA2:c.1327 G > A (p.Val443Ile) [rs74653330] in albinism. These two missense changes were selected as they are the commonest albinism-related variants in European-like populations. The majority of participants in the “case” cohort (1015/1120) 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 (see “Methods”). The remaining 105/1120 cases were identified through the Genomics England 100,000 Genomes Project dataset and had a diagnosis of albinism or partial/ocular albinism. The “control” cohort included 29,451 unrelated individuals from the Genomics England 100,000 Genomes Project dataset, none of whom had a recorded diagnosis of albinism. To reduce the likelihood of obtaining spurious signals due to population stratification effects or due to the presence of albinism-related variants other than the two studied changes, we focused only on individuals who: (i) were projected to have European-like ancestries; (ii) did not have a genotype in keeping with a molecular diagnosis of albinism; (iii) were not heterozygous for a pathogenic or a likely pathogenic variant in TYR or OCA2 (with the exception of TYR:c.1205 G > A and OCA2:c.1327 G > A). The following two covariates were used: sex and number of common albinism-associated alleles, i.e. DNA sequence alterations in the genomic locations corresponding to TYR:c.− 301 C > T [rs4547091] and TYR:c.575 C > A (p.Ser192Tyr) [rs1042602]. These two variants have been previously shown to modify the effect of TYR:c.1205 G > A, a common missense change that can act as a low penetrance variant^–. To assess the robustness of the findings we performed additional analyses in subsets of the cohort. Validation studies in an independent cohort (UK Biobank) were also conducted. 100K_GP, Genomics England 100,000 Genomes Project; het, heterozygous; UKB, UK Biobank. TYR and OCA2 variant numbering was based on the transcripts with the following identifiers: NM_000372.5/ENST00000263321.6. and NM_000275.3/ENST00000354638.8.

Fig. 2. The combination of the TYR:c.1205 G > A (p.Arg402Gln) and OCA2:c.1327 G > A (p.Val443Ile) variants in a dual heterozygous state confers susceptibility to albinism.

The probability of receiving a diagnosis of albinism (i.e. the risk of albinism) was calculated for the following genotype groups: (i) group A (reference group): homozygous for TYR:c.1205 = and OCA2:c.1327 =; (ii) group B (single TYR heterozygote group): heterozygous for TYR:c.1205 G > A and homozygous for OCA2:c.1327 =; (iii) group C (single OCA2 heterozygote group): homozygous for TYR:c.1205 G = and heterozygous for OCA2:c.1327 G > A; (iv) group D (dual heterozygote group): heterozygous for the TYR:c.1205 G > A and OCA2:c.1327 G > A variant combination. A log₁₀ scale is used. The circle in the middle of each horizontal line (95% confidence interval) represents the point estimate of each odds ratio. Group A was used as the reference group to which all other groups were compared using Firth regression analysis (i.e. the odds ratio for this group was fixed at 1). Further information, including numerical data, can be found in Supplementary Table 2.

Fig. 3. R eplication studies in the UK Biobank cohort.

The combination of the TYR:c.1205 G > A (p.Arg402Gln) and OCA2:c.1327 G > A (p.Val443Ile) variants in a dual heterozygous state is associated with (a) a higher probability of receiving an albinism diagnosis (i.e. a higher risk of albinism), (b) lower visual acuity and (c) increased central retinal thickness in UK Biobank participants. The following genotype groups were studied: (i) group A (reference group): homozygous for TYR:c.1205 = and OCA2:c.1327 =; (ii) group B (single TYR heterozygote group): heterozygous for TYR:c.1205 G > A and homozygous for OCA2:c.1327 =; (iii) group C (single OCA2 heterozygote group): homozygous for TYR:c.1205 G = and heterozygous for OCA2:c.1327 G > A; group D (dual heterozygote group): heterozygous for the TYR:c.1205 G > A and OCA2:c.1327 G > A variant combination. In (3a), a log₁₀ scale is used. The circle in the middle of each horizontal line (95% confidence interval) represents the point estimate of each odds ratio. In (3b and c), the bounds of each rectangular box correspond to the upper and lower quartile, representing the interquartile range and showing where the central 50% of the data lies. The vertical line inside each box denotes the median value. The edges of the whiskers extending from each box correspond to the most extreme data points (that are not considered outliers). It is noted that individuals with albinism tend to have reduced visual acuity (i.e. higher LogMAR value than 0.2) and increased central retinal thickness (due to underdevelopment of the fovea). More details on the utilised approach can be found in the Methods and in Supplementary Fig. 2. Further information, including numerical data, can be found in Supplementary Tables 3–6.