Five reasons why inbreeding may have considerable effect on post-reproductive human health

As the genetic architecture of common complex diseases of late onset is emerging through intensive research, it is intriguing to assess the predicted effect of inbreeding on those diseases. In this paper, we propose five reasons why we believe inbreeding may have a considerable effect on post-reproductive human health. (i) The joint effect of inbreeding depression on all polygenic quantitative phenotypes that confer risk for late-onset 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 capacity to compensate against environmental risks. (iv) Heterozygote advantage in loci under balancing selection could be reduced by inbreeding. (v) Published empirical evidence in animals and humans consistently report large inbreeding effects on late-onset traits. Since inbreeding is common in many populations and the effects of inbreeding depression could substantially contribute to disease burden and reduced life expectancy we believe there is now a clear need for further genetic epidemiological research in humans to investigate this issue.