A genome-wide search for susceptibility loci to human essential hypertension.
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.
Sharma
P
P
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. psharma@hgmp.mrc.ac.uk
Fatibene
J
J
Ferraro
F
F
Jia
H
H
Monteith
S
S
Brown
C
C
Clayton
D
D
O'Shaughnessy
K
K
Brown
M J
MJ
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