Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color

Abstract

Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.

Investigating the genetic architecture of eye colour in a Canadian cohort

“…(37). However, the ILRUN locus identified in the present study was not amongst their novel signals, nor we were able to replicate it.…”

“…In our sample we have identified significant differences in self-reporting of eye colour between sexes, and although these may be a reflection of true sex differences, as has been previously reported in other studies reporting self-assessed categorical eye colour (9), we cannot discard the possibility of a self-reporting bias. This limitation is counter-balanced by the relatively large sample size, in comparison to the majority of previous studies (16,51,52), with the exception of the largest recent GWAS of eye colour (37). Furthermore, significantly associated loci from self-reported eye colour are useful in forensics, for predicting eye colour categories, which the human eye can easily distinguish.…”

“…The copyright holder for this preprint this version posted September 30, 2021. ; https://doi.org/10.1101/2021.09.29.462299 doi: bioRxiv preprint Finally, the largest eye colour GWAS to date conducted in populations of mainly European ancestry reported several novel loci, which had not been previously associated with eye colour, and a subset of them has not been previously associated with any pigmentation traits (eye, hair or skin pigmentation) (37). However, the ILRUN locus identified in the present study was not amongst their novel signals, nor we were able to replicate it.…”

“…DTL, MITF, PDCD6/AHRR, ADRB2, GCNT2 and SIK1). After considering a Bonferroni correction (0.05/112; p-value ≤ 4.46e-04), 16 SNPs remained significant, all of which overlap known pigmentation genes (IRF4, TYRP1, TYR, OCA2 and HERC2).Lastly, we checked if the independent SNPs associated with eye colour identified with GCTA-COJO by Simcoe et al(37) overlap with our eye colour SNPs highlighted by GCTA-COJO (Supplementary Table2).We identified an overlap of three SNPs: rs12203592 (IRF4), rs1126809 (TYR) and rs1129038 (HERC2). Interestingly, even though Simcoe et al identified several independent loci in the OCA2/HERC2 region, the known rs12913832 SNP is not among them, likely because another SNP in perfect LD has a lower pvalue, which is similar to what we observe in our GCTA-COJO analysis (i.e.…”

Quantitative Human Paleogenetics: What can Ancient DNA Tell us About Complex Trait Evolution?

“…Nevertheless, genomic analyses in previously understudied populations-like sub-Saharan African groups-suggest that perhaps hundreds of skin pigmentation alleles of small effect remain to be found (Martin et al, 2017b). Similarly, recent studies have shown that eye pigmentation is far more polygenic than previous thought (Simcoe et al, 2021). Recent quantitative and molecular genomic studies are painting an increasingly complex picture of the architecture of these traits, featuring more considerable roles for epistasis, pleiotropy and small-effect variants than were previously assumed (for an extensive review of skin pigmentation, see Quillen et al, 2019).…”