Inbreeding and risk of late onset complex disease.

I nbreeding has been shown in almost all species to be associated with impairment of function because of homozygosity of recessive alleles. This occurs across a wide range of traits and suggests a large number of deleterious alleles in the human genome. This has been predicted from the reduced early survival of offspring in first cousin marriages and from similar results in other organisms. As most identified genetic variants causing complex disease in humans are partially recessive we predict that inbreeding in humans might influence a wide range of complex diseases. Numerous reports on the health effects of inbreeding have focused mainly on its impact on reproduction, childhood mortality, and rare Mendelian disorders. 3 For example, a 4– 5% increase in childhood mortality has been found in the offspring of first cousin marriages, and similar results have been reported in other species. 4 5 However, the effects of inbreeding on late onset disorders are largely unknown, despite the fact that deleterious effects of inbreeding in other species are known to increase with age, as predicted by selection theory. 7 The reported finding of greater inbreeding effects for traits such as blood pressure and serum cholesterol in middle age compared with early adult life is consistent with this. In order to investigate the hypothesis that the heritable component of late onset diseases includes a major class of deleterious recessive alleles, we recently studied the effects of inbreeding on blood pressure among 2760 adult individuals from 25 villages in a Dalmatian island isolate. The study showed a large effect of inbreeding on blood pressure equivalent to a rise in systolic blood pressure of ,20 mm Hg and diastolic blood pressure of ,12 mm Hg in offspring of first cousin marriages. The effect appeared to be mediated by several hundred recessive alleles as a result of increased homozygosity. In support of this finding, several studies of small inbred communities worldwide have reported an increased prevalence of hypertension. 11–15 In the present study, we extend this observation by investigating the relation between inbreeding and the prevalence of 10 late onset complex diseases of public health importance. The study was carried out in 14 of the original 25 isolate villages on three neighbouring islands in middle Dalmatia, Croatia. These island populations present a wide range of levels of inbreeding and endogamy, reduced genetic variation at both individual and (sub)population levels, and relative uniformity of environment, 16–18 and thus provide a good setting for investigating inbreeding effects.