Measuring the genetic contribution of a single locus to a multilocus disease

Abstract

An increasing number of diseases are being demonstrated to be due to determinants at > 1 genetic locus. It becomes of interest to determine the genetic contribution of a specific single locus. A method of estimating a coefficient of genetic contribution is decribed herein, based on a comparison of monozygotic twin concordance data for a specific disease, the empirical sibling recurrence risks, and the sharing of identical by descent genes at the specific locus of interest by pairs of siblings who are both affected. The value of the method is that it requires relatively few assumptions, and does not require knowledge of the mode of inheritance of disease susceptibility at the gene locus of interest. If there are major environmental determinants, this method will give a lower bound for the single locus of interest. To illustrate the method, it is applied to 2 specific diseases, insulin dependent diabetes mellitus (IDDM) and gluten-sensitive enteropathy (GSE), and a specific locus, the HLA gene complex. The best estimates would appear to be that the HLA genes provide a coefficient of 60% for IDDM susceptibility, but only 30% for GSE. A possible reason for these differences is the markedly increased disease susceptibility of the DR3/DR4 heterozygotes for IDDM.