Abstract
AGE AT ONSET AND CAUSES OF DISEASE BARTON CHILDS* and CHARLES R. SCRIVERt We know a good deal about the origins and pathogenesis of monogenic diseases, but we still know too little of how and what the genes contribute to multifactorial diseases. We seldom know which loci are involved, or which alleles inhabit them. Nor can we say how the effects of each gene modify those of others in the deranged homeostasis that constitutes the phenotype. And we can seldom specify the elements of the environment that interact with the effects of the genes. Current Views ofMultifactorial Disease Traditional thinking about multifactorial disease is based on models of liability [1, 2]. Some combinations of risk factors, including both genes and experiences, meet requirements for onset of signs and symptoms, or for passing a threshold beyond which lies disease. Mathematical schemes have been devised to determine the relative contributions of genes and experiences to such phenotypes and for segregation analysis. These analyses, although helpful in thinking about multifactorial diseases, cannot give information about either the genes or the environmental elements involved or about how they account for phenotypes in individuals [3, 4]. Others have suggested that some of the heterogeneity of mutifactorial diseases is explained by the expression of relatively few genes of major effect [5]. For example, susceptibility to premature heart attacks [6], duodenal ulcer [7], and autoimmune diseases [8] is marked by genes at single loci. Furthermore, strains of animals have been developed with greatly heightened susceptibility to infections and hypertension, owing to alleles at comparatively few loci [9, 10]. *Department of Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland 21205. tMontreal Children's Hospital, 2300 Tupper Street, Montreal, Quebec, H3H 1P3 Canada.© 1986 by The University of Chicago. All rights reserved. 003 1-5982/86/2903-0494$0 1 .00 Perspectives in Biology and Medicine, 29, 3, Part 1 ¦ Spring 1986 | 437 5000 G Females ^ 100 10 20 304050 Age (Years) Fig. 1.—Age-specific mortality rates, Canada 1982 Genetic Disease in the Context ofAge at Onset But we still have a long way to go. We need some coherent account of the effects of the genes in all disease; we need unifying contexts in which to bring monogenic and multifactorial conditions together conceptually. One such unifying context is age. It is a part of the lore of human genetics that the younger cases of a disease with a broad span of ages at onset may be more severely affected and more likely to have similarly afflicted relatives. Accordingly, age at onset, defined as the age when symptoms become overt, is a useful criterion for establishing heterogeneity of cause. The question is, Why does a particular person contract diabetes or gout at age 8 rather than at 35 or at 80 years? The answer to the question is likely to be: different causes. How can we test the idea that age at onset reflects heterogeneity of cause? One way to begin is to examine mortality according to age, as in figure 1. This curve appears to differentiate diseases by age at onset. The causes of death composing the two arms of the curve are not the same. Those on the left are characterized by anomalous development and difficulties in adaptation to life after birth. Those on the right are 438 I Barton Childs and Charles R. Scriver ¦ Causes ofDisease mainly diseases associated with personal habits, occupations, patterns of living, specific environments, and perhaps responses to life's many stresses. And the effects of these agencies are superimposed upon those of advancing senescence. So while mortality in early life is apt to be characterized by inability to adapt to generally prevailing environments, that in later life is more likely to include defects in adjustment to more specific, often culturally imposed, conditions. In this paper, we consider what discernible effects on the characteristics of disease could be a result of a decline, with age, of the genetic contribution. The Decline with Age of Heritability of Disease The genetic variability of a population of coevals decreases throughout the life of the cohort as a result of nonrandom selection against individuals. The most disadaptive genes—those imposing the heaviest burdens in the form...