Thread by @ewanbirney

Great to see this pre-print on rare-meets-common TYR/ human pigmentation genetics by Vincent Michaud (Bordeaux) and senior author Panagiotis (Panos) Sergouniotis (Manchester) - I am a co-author medrxiv.org/content/10.110…

One key thing is that it is a promoter variant which is associated with albinism and related eye phenotypes, not in fact as non-synonymous variant in LD (one needs to capture rare recombinations, and an example of needing deep phenotype positive ascertainmemt - case collections).

(The Promoter variant is the first SNP TYR c.-301C>T [rs4547091] - and it's LD NS proxy is c.575C>A (p.Ser192Tyr) [rs1042602] - by default, any program/analysis would have probably assigned function to the protein coding change)

This promoter variant significantly the other protein altering variant later on in the TYR gene: c.1205G>A (p.Arg402Gln) and it is this combination of high expression with this protein altered variant which produces a high risk of albinism - as high as "classic" rare alleles!

Pigmentation at the back of the eye (RPE layer) also changes eye development, and we can see this both in the foveal thickness for this haplotype in the UK BioBank and in visual acuity - a haplotype specific effect (local epistasis if you like).

This goes to better understanding the risk - it is also worth noting here we need to get linkage of these SNPs together (in this case, both reasonably common) to accurately determine the risk of this phenotype

(Vincent and Panos were able to do this analysis by only looking at homozygote halpotypes, which goes to how common the SNPs are; less common SNPs would need more direct phasing to get the haplotype structure).

In many ways I see this as the first of many studies bridging rare and common - in some sense common SNPs have become here rare and "highly penetrant" haplotypes; rare SNPs clearly contribute to common endophenotypes in Hetreozygous form.

(Editorial - the "rare" / "common" human genetics split is sort of arbitary. It is all "genetics" with differing allele frequencies, different effect sizes and here, GxG terms)

Anyway, lovely "1 figure" paper by Vincent and Panos - @tuuliel, @dgmacarthur, @HeidiRehm @SharonPlon @mehurles and other rare-meets-common geneticists - give it a read!