Effects of inbreeding on human quantitative traits and complex common diseases of late-onset

Abstract

Studying the effects of inbreeding in human populations could provide insights into the genetic architecture of medically relevant quantitative traits and common complex diseases of late onset. In a historic example of 2,761 examinees from isolated village populations of the islands of Brae, Hvar and Korcula, Croatia, collected through field work undertaken in the 1970's and 1980's, individual inbreeding coefficients were computed based on genealogical records. Inbreeding showed a strong positive effect on blood pressure and negative on cortical index. The 14 villages were revisited in 2000 to assess the prevalence of learning disability and of common complex diseases of late onset. A cohort study and an ecological study, after appropriate standardization, both showed that inbreeding increased the prevalence of coronary heart disease, stroke, psychiatric disorders, cancer, gout, asthma, glaucoma and peptic ulcer, but not type II diabetes. A strong effect on the prevalence of learning disability was also noted in 10 villages. In a followup study on 1,001 examinees from 10 other villages sampled on neighbouring islands in 2002, positive effects of outbreeding on fitness, height, blood pressure, cholesterol and triglyceride values were detected. The possible explanations for the observed effects include: (i) The joint effect of inbreeding depression on all polygenic quantitative phenotypes that confer risk for lateonset diseases is predicted to be multiplicative rather than additive, (ii) The "genetic load" of rare "Mendelian" variants with large deleterious effects in post-reproductive adults is unknown, but could be much greater than expected as these variants were invisible to selection through human history, (iii) Deleterious effects resulting from autozygosity in hundreds of affected rare recessive variants of small effect under common disease/rare variant (CD/RV) hypothesis could result in epistatic effects that could jointly impair the capacity to compensate against environmental risks, (iv) Heterozygote advantage in loci under balancing selection could be reduced by inbreeding. Consanguinity is common in many populations and the possible effects of inbreeding depression on disease burden and reduced life expectancy should be further investigated.