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 approximately 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%.
Rudan
Igor
I
Department of Community Health Sciences, University of Edinburgh Medical School, Edinburgh EH8 9AG, Scotland, United Kingdom.
Smolej-Narancic
Nina
N
Campbell
Harry
H
Carothers
Andrew
A
Wright
Alan
A
Janicijevic
Branka
B
Rudan
Pavao
P
D000328:Adult; D001794:Blood Pressure / Q000502:physiology; D003241:Consanguinity; D017523:Croatia / Q000453:epidemiology; D005260:Female; D005828:Genetics, Population; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics*; D007178:Inbreeding; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D015233:Models, Statistical; D015995:Prevalence; D040641:Quantitative Trait Loci