Inbreeding and the Genetic Complexity of Human Hypertension

Considerable uncertainty exists regarding the genetic architecture underlying common late-onset human diseases. In particular, the contribution of deleterious recessive alleles has been predicted to be greater for late-onset than for early-onset traits. We have investigated the contribution of recessive alleles to human hypertension by examining the effects of inbreeding on blood pressure (BP) as a quantitative trait in 2760 adult individuals from 25 villages within Croatian island isolates. We found a strong linear relationship between the inbreeding coefficient (F) and both systolic and diastolic BP, indicating that recessive or partially recessive quantitative trait locus (QTL) alleles account for 10–15% of the total variation in BP in this population. An increase in F of 0.01 corresponded to an increase of ~3 mm Hg in systolic and 2 mm Hg in diastolic BP. Regression of F on BP indicated that at least several hundred (300– 600) recessive QTL contribute to BP variability. A model of the distribution of locus effects suggests that the 8–16 QTL of largest effect together account for a maximum of 25% of the dominance variation, while the remaining 75% of the variation is mediated by QTL of very small effect, unlikely to be detectable using current technologies and sample sizes. We infer that recent inbreeding accounts for 36% of all hypertension in this population. The global impact of inbreeding on hypertension may be substantial since, although inbreeding is declining in Western societies, an estimated 1 billion people globally show rates of consanguineous marriages >20%.