eye color phenotypes and disease associations

see also:

• ophthalmology
• genetics
• color blindness / color vision deficiency

• phenotypic eye iris color is a genetic trait with those with blue eyes having a northern European genetic history (probably originated around the Baltic Sea region) while those of pure Asian or African ancestry, mostly have brown eyes
• the genetics is more complicated than originally thought (“blue eyes being recessive, brown eyes being dominant”) and is actually a complex genetic trait, involving interaction of some major genes and many minor genes and thus although it is uncommon, parents with blue eyes can have children with brown eyes
• globally, 70-80% have brown eyes, 8-10% have blue eyes, 5% have hazel eyes, 5% have amber eyes, 3% have grey eyes and 2% have green eyes
  • green eyes are mainly in northern Europeans although probably originated in Bronze Age Ukraine/Siberians from the Steppe, or from the Caucasus:
    • Europe overall - 8% have green eyes
    • Iceland: 8-10% of men and 18-21% of women
    • Netherlands: 6% of men and 17% of women
    • 16% of Americans with Celtic ancestry
    • Liqian village in north-western China have high percentage of people with green eyes and blonde hair (may have descended from Roman soldiers?)
• there is also a cross over into the genetics of many other eye conditions such as colour blindness, age-related macular degeneration and glaucoma

• the main pigment in the iris is the dark brown melanin
• the scattering of light from the collagen fibres in the sclera make it appear white
• the haemoglobin in the blood vessels appears red
• blue iris is an example of a structural colour rather than a pigment colour - just as the sky is blue from the Tyndall effect
  • this is due to frequency-dependence of the scattering of light by the turbid medium in the stroma of the iris
• brown irises have the same layer with more melanin and appear brown
  • there are two groups of melanin pigments in irises, and as with in other tissues, these can co-polymerise resulting in a range of colors:
    • eumelanin
      • has two forms:
        • linked to 5,6-dihydroxyindole (DHI)
          • DHI-derived eumelanin is dark brown or black and insoluble
          • the main form in Fitzpatrick type V and VI skin (60-70% of skin melanin)
          • this form increases in skin following sun exposure while DHICA-eumelanin and pheomelanin levels DECREASE
          • a small amount of this form in hair without other pigments results in grey hair
        • linked to 5,6-dihydroxyindole-2-carboxylic acid (DHICA)
          • DHICA-derived eumelanin is lighter brown and soluble in alkali.
          • a small amount of this form in hair without other pigments results in blonde hair
    • pheomelanin
      • impart a range of yellowish to reddish colors
      • in hair with little eumelanin, pheomelanins produce red or ginger hair, and similarly in skin, impart a more pinkish complexion (eg. strawberry blondes)
      • production is highly dependent on cysteine availability, which is transported into the melanosome, reacting with dopaquinone to form cys-dopa
• in complete absence of melanin (Albinism), the iris appears red from the red of the retina
• eye colour can change with age
  • an infants born with blue eyes often darkens as it gets older (brown, hazel or green), while only 6% of infants with brown eyes become lighter

• common in some breeds of cats, dogs, cattle and horses due to inbreeding, heterochromia is uncommon in humans and unlike other animals, it is not related to lack of genetic diversity in humans and may be inherited, or caused by genetic mosaicism, chimerism, disease, or injury
• complete heterochromia:
  • one iris is a different color from the other (eg. David Bowie)
• sectoral heterochromia:
  • part of one iris is a different color from its remainder
• central heterochromia:
  • there is a ring around the pupil or possibly spikes of different colors radiating from the pupil

• over 150 genes influence eye colour and skin colour, with the enzyme tyrosinase playing a key 1st step role in melanin production
• approx. 50 gene loci explain half of eye colour variation using common SNPs
• historically it was thought that there were just two main genes for iris color:¹⁾
  • EYCL1 (also called the gey gene) - has one allele that gives rise to green eyes and one allele that gives rise to blue eyes
  • EYCL3 (also called the bey2 gene) - has one allele for brown eyes and one for blue eyes
  • the allele for brown eyes is the most dominant allele and is always dominant over the other two alleles and the allele for green eyes is always dominant over the allele for blue eyes, which is always recessive
    • if two parents with brown eyes each passed on a pair of blue alleles to their offspring, then the child would be born with blue eyes
    • if one of the parents passed on a green allele, then the child would have green eyes and if a brown allele was present, then the child would have brown eyes irrespective of what the other three alleles were
• seven OCA genes have been identified (and many more known to influence pigment)
  • OCA genes as well as the intron 86 (modulates expression of OCA2) of the nearby HERC2 gene on chromosome 15 have a key role in melanin production and also influence skin and hair colour
  • the protein produced from the OCA2 gene, known as the P protein, is involved in the maturation of melanosomes and thus plays a crucial role in the amount and quality of melanin that is present in the iris
  • OCA2 mutations are linked to lighter skin tones in East Asians and cause a form of albinism more common in Africans
  • a three-SNP haplotype in intron 1 of OCA2 explains most human eye-colour variation
• other genes in skin lightening include:
  • SLC24A5 and SLC45A2 - play significant roles in skin lightening in Europeans and some Asian populations
  • MC1R gene is associated with fair skin, red hair and increased UV sensitivity of skin
• albinism
  • ocular albinism affects not only eye pigmentation but visual acuity, as well and typically test poorly, within the 20/60 to 20/400 range
  • oculocutaneous albinism type 2 (OCA2)
    • is the most common type of albinism and is especially frequent among people of black African descent and white Europeans
  • “yellow oculocutaneous albinism”
    • more prevalent among the Amish, who are of primarily Swiss and German ancestry
• light coloured eyes (blue, green, hazel)
  • blue eyes
    • the OCA2 mutation giving rise to blue eyes in the Baltic region occurred 6000-10,000yrs ago
    • The highest association for blue/non-blue eye colour was found with three OCA2 SNPs: rs7495174 T/C, rs6497268 G/T and rs11855019 T/C in intron 1 of OCA2. These three SNPs are in one major haplotype block, with TGT representing 78.4% of alleles. The TGT/TGT diplotype found in 62.2% of samples was the major genotype seen to modify eye colour, with a frequency of 0.905 in blue or green compared with only 0.095 in brown eye colour. ²⁾
    • homozygous carriers of HERC2 haplotype H1 are more likely to have blue or gray eyes (homozygous for H2 haplotype more like results in brown eyes)
    • bronze age settlers coming from the Ukrainian steppe regions contributed 90% of the DNA to modern day Irish including the “Celtic” blue and green eyes

• fair skin and UV sensitivity with melanoma risk
• Dupuytren's contracture and related fibromatous disorders:
  • frozen shoulder
  • plantar fibrosis
  • knuckle fibromatous pads
  • Peyronie's disease of the penis
• chronic alcoholism
• idiopathic pulmonary fibrosis (IPF) ³⁾

• see also https://en.wikipedia.org/wiki/Heterochromia_iridum
• loss of pigmentation:
  • neurofibromatosis
  • Down syndrome
  • pigment dispersion
  • primary melanocytic tumours of the iris
  • iritis such as:
    • herpes simplex iritis
    • Fuchs Heterochromic Cyclitis
• increased pigmentation:
  • naevi
  • melanoma
  • Lisch nodules - hamartomas seen in neurofibromatosis
• white areas:
  • Brushfield spots in some normal people
  • Down syndrome
• NB. Fleischer ring (as in keratoconus) is due to haemosiderin deposits in the cornea
• NB. Kayser–Fleischer rings are caused by copper deposits in descemet's membrane of cornea, and are indicative of Wilson's disease