Individual QTLs controlling quantitative variation in blood pressure inherited in a Mendelian mode

Abstract

We studied three possible genotypes at 10 well-defined blood pressure (BP) QTLs using congenic rat lines. The central question was whether the hypertensive or normotensive allele is dominant, or whether there is partial dominance. The congenic strains were employed to investigate the BP effects of alleles originating from normotensive rats in the background of hypertensive Dahl salt-sensitive (DSS) rats. The normotensive alleles at eight QTLs were fully dominant over DSS alleles, which we tentatively interpreted as indicating that DSS rats incurred a loss of function at these loci and that the QTLs produced BP-reducing agents. In contrast, the normotensive allele of only one QTL was recessive over its DSS counterpart, implying a gain of function at this QTL or a null allele involved in generating a BP-elevating agent. Only one locus, C17QTL, had alleles exhibiting partial dominance. These estimates of dominance differ considerably from those obtained by QTL analysis in a F2 cross. This disagreement demonstrates the importance of establishing a cause-effect relationship between a QTL and its phenotypic effect via congenic strains. The dominance relationships suggest pertinent strategies for gene identification and pharmaceutical intervention.

Genetics of Polygenic Hypertension from Animal Models to Humans

“…Further support for the concept of the 'monogenic' nature of individual QTLs came from the analyses of heterozygotes of 10 representative QTLs [29]. Eight out of 10 of these QTLs demonstrate full dominance of normotensive alleles, i.e.…”

“…MAPs in ( ) indicate estimates from systolic arterial pressures by indirect measurement. The mode of inheritance underlined was assessed as heterozygotes in reference [29]. Epistatic interactions between 2 QTLs were determined in 'double' congenic strains harboring them.…”

Novel genes as primary triggers for polygenic hypertension

“…Previously, we localized multiple BP QTLs on chromosome (Chr) 10 using congenic strains made from crossing hypertensive Dahl salt-sensitive (DSS) and normotensive Lewis rats [3]. These QTLs function independently of one another and behave as if each of them were a 'monogenic trait' [4], suggesting that a single gene may constitute the underlying cause for each of them. The current investigation aims to identify the responsible genes for these QTLs by positional genetics.…”

Hypertension Suppression, Not a Cumulative Thrust of Quantitative Trait Loci, Predisposes Blood Pressure Homeostasis to Normotension

“…This outcome showed complete dominance of the Lewis genome and is consistent with our previous evidence that most heterozygous congenic strains possessed the same BP effect as homozygotes. 10 Thus, the most direct and efficient strategy to identify chromosome regions harboring a HS appeared to be the following.…”