Deep genotype imputation captures virtually all heritability of autoimmune vitiligo

Abstract

Autoimmune vitiligo is a complex disease involving polygenic risk from at least 50 loci previously identified by genome-wide association studies. The objectives of this study were to estimate and compare vitiligo heritability in European-derived patients using both family-based and 'deep imputation' genotype-based approaches. We estimated family-based heritability (h2FAM) by vitiligo recurrence among a total 8034 first-degree relatives (3776 siblings, 4258 parents or offspring) of 2122 unrelated vitiligo probands. We estimated genotype-based heritability (h2SNP) by deep imputation to Haplotype Reference Consortium and the 1000 Genomes Project data in unrelated 2812 vitiligo cases and 37 079 controls genotyped genome wide, achieving high-quality imputation from markers with minor allele frequency (MAF) as low as 0.0001. Heritability estimated by both approaches was exceedingly high; h2FAM = 0.75-0.83 and h2SNP = 0.78. These estimates are statistically identical, indicating there is essentially no remaining 'missing heritability' for vitiligo. Overall, ~70% of h2SNP is represented by common variants (MAF > 0.01) and 30% by rare variants. These results demonstrate that essentially all vitiligo heritable risk is captured by array-based genotyping and deep imputation. These findings suggest that vitiligo may provide a particularly tractable model for investigation of complex disease genetic architecture and predictive aspects of personalized medicine.

Figure 1

Distribution of SNPs, h²_SNP and average h²_SNP explained for vitiligo. (A) Distribution of genotyped and imputed variants included in h²_SNP estimation. All included variants were either genotyped or had imputation INFO > 0.70 in all three GWAS cohorts. The 15 variant bins were created by stratifying first by LD-score tercile, then by MAF group. (B) h²_SNP explained by each LD/MAF variant bin. (C) Average heritability explained per variant in each LD/MAF bin. For each bin, the h²_SNP estimate was divided by the total number of variants in the MAF bin. For (A) and (C), the color key is the same as in (A).

Figure 2

Comparison of three h²_FAM estimates and h²_SNP. Each bar represents a total narrow-sense heritability estimate for sibling-based h²_FAM (green), parent–offspring-based h²_FAM (orange), all first-degree relative-based h²_FAM (blue) and GCTA-LDMS-i h²_SNP (pink). The errors represent a 95% confidence interval for each estimate.