Studying quantitative endophenotypes was advocated to help unravel the genetic architecture of common diseases.
1,2 Successes met by this approach include mapping of genes modulating QT elongation measured by ECG and cardiac arrhythmia risk,
3 IgE levels and asthma risk,
4 serum uric acid level and gout risk,
5 and lipid levels and coronary heart disease risk.
6 Ocular conditions, in particular the most common one, refractive error, lend themselves very well to this approach. Myopia and hypermetropia can be viewed largely as defects in the eye growth processes that normally adjust AL of the eye to the optical power of the cornea and lens. The values of the separate refractive components (axial length [AL], power of the cornea, and power of the lens), which if uncoordinated lead to refractive errors, have long been recognized as being normally distributed in general population surveys, whereas the distribution of refraction itself has a greater density around emmetropic values.
7 Researchers in several large studies of unselected individuals, predominantly twins, have investigated to what extent genetic variation contributes to ocular quantitative components, and results have generally supported a substantial polygenic contribution. These include reports on AL, anterior chamber depth (ACD), corneal curvature (CC), and spherical equivalent refraction (SER) in a Sardinian isolate (
n = 741; mean age, 41 years)
8 ; in the Australian GEM twin study (
n = 1224; mean age, 52 years)
9 ; and in a Danish twin cohort (
n = 114; age range, 20–45 years)
10 together with lens thickness (LT), and analysis of refraction alone in a UK female twin cohort (
n = 506; mean age, 62.4 years)
11 and in the Beaver Dam population study (
n = 2138; age range, 43–84 years).
12 For corneal thickness (CT) there is, to our knowledge, only one previous report of heritability, 95% in a European sample of UK and Australian twins (
n = 256; mean age, 38 years).
13 This trait is now a recognized risk factor for progression from ocular hypertension to primary open-angle glaucoma,
14 as well as a determinant of corneal refractive power.