title: A genome-wide search for susceptibility loci to human essential hypertension.
abstract: We undertook a systematic search of the entire human genome with the affected sibling-pair model to identify major susceptibility loci to essential hypertension. Affected nuclear families (n=263) were recruited and divided according to definite or probable genetic contribution to hypertension depending on number of hypertensive siblings. The largest nuclear families were first screened with a set of microsatellite markers. Regions on the genome with P<0.05 were tested against the second set of smaller families. An exclusion map was generated to identify regions in which hypertension-causing genes are unlikely to reside. Sibling-pair linkage analysis identified a single locus on chromosome 11q (P<0.004) in the first pass. A second pass with nuclear families that had only affected sibling pairs was, as expected, insufficient to support linkage to 11q. Multipoint exclusion-linkage analysis showed that 3 genetic loci are necessary to explain familial aggregation of essential hypertension. Our preliminary findings suggest that no single region within the human genome contains genes with a major contribution to essential hypertension. We show that the disease is indeed polygenic, with each gene providing a relatively small risk. Our exclusion map will help future investigators to concentrate on areas likely to contain these genes. The region on chromosome 11 is the first to point to a new candidate gene for hypertension that has arisen out of a genome search, but replication of these results at a higher significance is necessary before positional cloning can be justified.
authors.affiliation: Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. psharma@hgmp.mrc.ac.uk
authors.forename: P
authors.initials: P
authors.lastname: Sharma
authors.forename: J
authors.initials: J
authors.lastname: Fatibene
authors.forename: F
authors.initials: F
authors.lastname: Ferraro
authors.forename: H
authors.initials: H
authors.lastname: Jia
authors.forename: S
authors.initials: S
authors.lastname: Monteith
authors.forename: C
authors.initials: C
authors.lastname: Brown
authors.forename: D
authors.initials: D
authors.lastname: Clayton
authors.forename: K
authors.initials: K
authors.lastname: O'Shaughnessy
authors.forename: M J
authors.initials: MJ
authors.lastname: Brown
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016678:Genome; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D044465:White People / Q000235:genetics